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Mascaraque M, Courtois S, Royo-García A, Barneda D, Stoian AM, Villaoslada I, Espiau-Romera P, Bokil A, Cano-Galiano A, Jagust P, Heeschen C, Sancho P. Fatty acid oxidation is critical for the tumorigenic potential and chemoresistance of pancreatic cancer stem cells. J Transl Med 2024; 22:797. [PMID: 39198858 PMCID: PMC11351511 DOI: 10.1186/s12967-024-05598-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 08/11/2024] [Indexed: 09/01/2024] Open
Abstract
BACKGROUND We have previously demonstrated the significant reliance of pancreatic Cancer Stem Cells (PaCSCs) on mitochondrial oxidative phosphorylation (OXPHOS), which enables versatile substrate utilization, including fatty acids (FAs). Notably, dysregulated lipid scavenging and aberrant FA metabolism are implicated in PDAC progression. METHODS & RESULTS Our bioinformatics analyses revealed elevated expression of lipid metabolism-related genes in PDAC tissue samples compared to normal tissue samples, which correlated with a stemness signature. Additionally, PaCSCs exhibited heightened expression of diverse lipid metabolism genes and increased lipid droplet accumulation compared to differentiated progenies. Treatment with palmitic, oleic, and linolenic FAs notably augmented the self-renewal and chemotherapy resistance of CD133+ PaCSCs. Conversely, inhibitors of FA uptake, storage and metabolism reduced CSC populations both in vitro and in vivo. Mechanistically, inhibition of FA metabolism suppressed OXPHOS activity, inducing energy depletion and subsequent cell death in PaCSCs. Importantly, combining a FAO inhibitor and Gemcitabine treatment enhanced drug efficacy in vitro and in vivo, effectively diminishing the CSC content and functionality. CONCLUSION Targeting FAO inhibition represents a promising therapeutic strategy against this highly tumorigenic population.
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Affiliation(s)
- Marta Mascaraque
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
- Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain
| | - Sarah Courtois
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Alba Royo-García
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - David Barneda
- Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Andrei M Stoian
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Isabel Villaoslada
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Pilar Espiau-Romera
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Ansooya Bokil
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Andrés Cano-Galiano
- Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Petra Jagust
- Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Christopher Heeschen
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute - FPO - IRCCS, Candiolo, TO, Italy.
| | - Patricia Sancho
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain.
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2
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Moond V, Maniyar B, Harne PS, Bailey-Lundberg JM, Thosani NC. Harnessing endoscopic ultrasound-guided radiofrequency ablation to reshape the pancreatic ductal adenocarcinoma microenvironment and elicit systemic immunomodulation. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:1056-1073. [PMID: 39351436 PMCID: PMC11438557 DOI: 10.37349/etat.2024.00263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/19/2024] [Indexed: 10/04/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognostics and substantial therapeutic challenges, with dismal survival rates. Tumor resistance in PDAC is primarily attributed to its fibrotic, hypoxic, and immune-suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), an Food and Drug Administration (FDA)-approved minimally invasive technique for treating pancreatic cancer, disrupts tumors with heat and induces coagulative necrosis, releasing tumor antigens that may trigger a systemic immune response-the abscopal effect. We aim to elucidate the roles of EUS-RFA-mediated thermal and mechanical stress in enhancing anti-tumor immunity in PDAC. A comprehensive literature review focused on radiofrequency immunomodulation and immunotherapy in pancreatic tumors to understand the pathophysiological mechanisms of RFA and its effect on the TME, which could prevent recurrence and resistance. We reviewed clinical, preclinical, and in vitro studies on RFA mechanisms in pancreatic adenocarcinoma, discussing the unique immunomodulatory effects of EUS-RFA. Recent findings suggest that combining RFA with immune adjuvants enhances responses in pancreatic adenocarcinoma. EUS-RFA offers a dual benefit against PDAC by directly reducing tumor viability and indirectly enhancing anti-tumor immunity. Observations of neutrophil-mediated immunomodulation and programmed cell death ligand 1 (PD-L1) modulation support integrating EUS-RFA with targeted immunotherapies for managing pancreatic adenocarcinoma. Integrating EUS-RFA in PDAC treatment promises direct cytoreduction and synergistic effects with molecular targeted therapies. Prospective clinical trials are crucial to assess the efficacy of this combined approach in improving outcomes and survival rates in advanced PDAC cases.
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Affiliation(s)
- Vishali Moond
- Department of Internal Medicine, Saint Peter’s University Hospital/Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Bhumi Maniyar
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, University of Texas Health Science Center, Houston, TX 77030, USA
| | - Prateek Suresh Harne
- Department of Gastroenterology and Hepatology, University of Texas Health Science Center, Houston McGovern Medical School, Houston TX 77030, USA
| | - Jennifer M. Bailey-Lundberg
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, University of Texas Health Science Center, Houston, TX 77030, USA
| | - Nirav C. Thosani
- Department of Internal Medicine, Saint Peter’s University Hospital/Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
- Division of Elective Surgery and Interventional Gastroenterology, Department of Surgery, University of Texas Health Science Center, Houston TX 77030, USA
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3
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López-Gil JC, García-Silva S, Ruiz-Cañas L, Navarro D, Palencia-Campos A, Giráldez-Trujillo A, Earl J, Dorado J, Gómez-López G, Monfort-Vengut A, Alcalá S, Gaida MM, García-Mulero S, Cabezas-Sáinz P, Batres-Ramos S, Barreto E, Sánchez-Tomero P, Vallespinós M, Ambler L, Lin ML, Aicher A, García García de Paredes A, de la Pinta C, Sanjuanbenito A, Ruz-Caracuel I, Rodríguez-Garrote M, Guerra C, Carrato A, de Cárcer G, Sánchez L, Nombela-Arrieta C, Espinet E, Sanchez-Arevalo Lobo VJ, Heeschen C, Sainz B. The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells. Gut 2024; 73:1489-1508. [PMID: 38754953 PMCID: PMC11347225 DOI: 10.1136/gutjnl-2023-330995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 04/11/2024] [Indexed: 05/18/2024]
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.
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Affiliation(s)
- Juan Carlos López-Gil
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Department of Biochemistry, Autónoma University of Madrid (UAM), Madrid, Spain
| | - Susana García-Silva
- Microenvironment and Metastasis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Laura Ruiz-Cañas
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Biobanco Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Diego Navarro
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Department of Biochemistry, Autónoma University of Madrid (UAM), Madrid, Spain
| | - Adrián Palencia-Campos
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Antonio Giráldez-Trujillo
- Grupo de Oncología Cutánea, Servicio de Anatomía Patológica, Hospiral Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Julie Earl
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
| | - Jorge Dorado
- Stem Cells and Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Gonzalo Gómez-López
- Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Ana Monfort-Vengut
- Cell Cycle and Cancer Biomarkers Laboratory, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
| | - Sonia Alcalá
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Department of Biochemistry, Autónoma University of Madrid (UAM), Madrid, Spain
| | - Matthias M Gaida
- Institute of Pathology, JGU-Mainz, University Medical Center Mainz, Mainz, Germany
- TRON, JGU-Mainz, Translational Oncology at the University Medical Center, Mainz, Germany
- Research Center for Immunotherapy, JGU-Mainz, University Medical Center Mainz, Mainz, Germany
| | - Sandra García-Mulero
- Department of Pathology and Experimental Therapy, Universidad de Barcelona Facultad de Medicina y Ciencias de La Salud, Barcelona, Spain
- Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), IDIBELL, Barcelona, Spain
| | - Pablo Cabezas-Sáinz
- Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, Universidade de Santiago de Compostela, Lugo, Spain
| | - Sandra Batres-Ramos
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Emma Barreto
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Spain
| | - Patricia Sánchez-Tomero
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Mireia Vallespinós
- Stem Cells and Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Leah Ambler
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Meng-Lay Lin
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Alexandra Aicher
- Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Ana García García de Paredes
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Gastroenterology and Hepatology, Hospital Universitario Ramon y Cajal, Madrid, Spain
| | | | - Alfonso Sanjuanbenito
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- Pancreatic and Biliopancreatic Surgery Unit, Hospital Universitario Ramon y Cajal, Madrid, Spain
| | - Ignacio Ruz-Caracuel
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- Ramon y Cajal University Hospital Anatomy Pathology Service, Madrid, Spain
- Molecular Pathology of Cancer Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Mercedes Rodríguez-Garrote
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- Medical Oncology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Carmen Guerra
- Experimental Oncology Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Alfredo Carrato
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
- Medical Oncology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Guillermo de Cárcer
- Cell Cycle and Cancer Biomarkers Laboratory, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
| | - Laura Sánchez
- Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, Universidade de Santiago de Compostela, Lugo, Spain
| | - César Nombela-Arrieta
- Department of Medical Oncology and Hematology, University and University Hospital Zurich, Zürich, Switzerland
| | - Elisa Espinet
- Department of Pathology and Experimental Therapy, Universidad de Barcelona Facultad de Medicina y Ciencias de La Salud, Barcelona, Spain
- Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), IDIBELL, Barcelona, Spain
| | - Víctor Javier Sanchez-Arevalo Lobo
- Grupo de Oncología Cutánea, Servicio de Anatomía Patológica, Hospiral Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
- Grupo de Oncología Molecular, Instituto de Investigaciones Biosanitarias, Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain
| | - Christopher Heeschen
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute - FPO - IRCCS, Candiolo (TO), Italy
| | - Bruno Sainz
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Cancer Department, Instituto de Investigaciones Biomédicas (IIBM) Sols-Morreale CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer Group (BIOPAC), Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Área Cáncer, Centro de Investigación Biomédica en Red (CIBERONC), ISCIII, Madrid, Spain
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4
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Liu Y, Okesola BO, Osuna de la Peña D, Li W, Lin M, Trabulo S, Tatari M, Lawlor RT, Scarpa A, Wang W, Knight M, Loessner D, Heeschen C, Mata A, Pearce OMT. A Self-Assembled 3D Model Demonstrates How Stiffness Educates Tumor Cell Phenotypes and Therapy Resistance in Pancreatic Cancer. Adv Healthc Mater 2024; 13:e2301941. [PMID: 38471128 PMCID: PMC11468796 DOI: 10.1002/adhm.202301941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 01/16/2024] [Indexed: 03/14/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense and stiff extracellular matrix (ECM) associated with tumor progression and therapy resistance. To further the understanding of how stiffening of the tumor microenvironment (TME) contributes to aggressiveness, a three-dimensional (3D) self-assembling hydrogel disease model is developed based on peptide amphiphiles (PAs, PA-E3Y) designed to tailor stiffness. The model displays nanofibrous architectures reminiscent of native TME and enables the study of the invasive behavior of PDAC cells. Enhanced tuneability of stiffness is demonstrated by interacting thermally annealed aqueous solutions of PA-E3Y (PA-E3Yh) with divalent cations to create hydrogels with mechanical properties and ultrastructure similar to native tumor ECM. It is shown that stiffening of PA-E3Yh hydrogels to levels found in PDAC induces ECM deposition, promotes epithelial-to-mesenchymal transition (EMT), enriches CD133+/CXCR4+ cancer stem cells (CSCs), and subsequently enhances drug resistance. The findings reveal how a stiff 3D environment renders PDAC cells more aggressive and therefore more faithfully recapitulates in vivo tumors.
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Affiliation(s)
- Ying Liu
- Barts Cancer InstituteQueen Mary University of LondonLondonEC1M 6BQUK
- School of Engineering and Materials ScienceQueen Mary University of LondonLondonE1 4NSUK
| | - Babatunde O. Okesola
- School of Life SciencesFaculty of Medicine and Health SciencesUniversity of NottinghamNottinghamNG7 2RDUK
| | - David Osuna de la Peña
- Barts Cancer InstituteQueen Mary University of LondonLondonEC1M 6BQUK
- School of Engineering and Materials ScienceQueen Mary University of LondonLondonE1 4NSUK
| | - Weiqi Li
- School of Engineering and Materials ScienceQueen Mary University of LondonLondonE1 4NSUK
| | - Meng‐Lay Lin
- Barts Cancer InstituteQueen Mary University of LondonLondonEC1M 6BQUK
| | - Sara Trabulo
- Barts Cancer InstituteQueen Mary University of LondonLondonEC1M 6BQUK
| | - Marianthi Tatari
- Barts Cancer InstituteQueen Mary University of LondonLondonEC1M 6BQUK
| | - Rita T. Lawlor
- Department of Diagnostics and Public HealthSection of PathologyUniversity of VeronaVerona37134Italy
- ARC‐NetApplied Research on Cancer CentreUniversity of VeronaVerona37134Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public HealthSection of PathologyUniversity of VeronaVerona37134Italy
- ARC‐NetApplied Research on Cancer CentreUniversity of VeronaVerona37134Italy
| | - Wen Wang
- School of Engineering and Materials ScienceQueen Mary University of LondonLondonE1 4NSUK
| | - Martin Knight
- Centre for BioengineeringSchool of Engineering and Materials ScienceQueen Mary University of LondonLondonE1 4NSUK
- Centre for Predictive in vitro ModelsQueen Mary University of LondonLondonE1 4NSUK
| | - Daniela Loessner
- Barts Cancer InstituteQueen Mary University of LondonLondonEC1M 6BQUK
- Department of Chemical and Biological EngineeringFaculty of EngineeringMonash UniversityMelbourneVIC3800Australia
- Department of Materials Science and EngineeringFaculty of EngineeringMonash UniversityMelbourneVIC3800Australia
- Department of Anatomy and Developmental BiologyFaculty of MedicineNursing and Health SciencesMonash UniversityMelbourneVIC3800Australia
| | - Christopher Heeschen
- Pancreatic Cancer HeterogeneityCandiolo Cancer Institute – FPO – IRCCSCandiolo (TO)10060Italy
| | - Alvaro Mata
- School of PharmacyUniversity of NottinghamUniversity ParkNottinghamNG7 2RDUK
- Biodiscovery InstituteUniversity of NottinghamUniversity ParkNottinghamNG7 2RDUK
- Department of Chemical and Environmental EngineeringUniversity of NottinghamUniversity ParkNottinghamNG7 2RDUK
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5
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Liu J, Huang J, Lu J, Ouyang R, Xu W, Zhang J, Chen-Xiao K, Wu C, Shang D, Go VLWB, Guo J, Xiao GG. Obg-like ATPase 1 exacerbated gemcitabine drug resistance of pancreatic cancer. iScience 2024; 27:110027. [PMID: 38883822 PMCID: PMC11177196 DOI: 10.1016/j.isci.2024.110027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 04/01/2024] [Accepted: 05/16/2024] [Indexed: 06/18/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a poor prognosis due to inefficient diagnosis and tenacious drug resistance. Obg-like ATPase 1 (OLA1) is overexpressed in many malignant tumors. The molecular mechanism of OLA1 underlying gemcitabine (GEM)-induced drug resistance was investigated in this study. An enhanced expression of OLA1 was observed in a GEM acquired resistant pancreatic cancer cell lines and in patients with pancreatic cancer. Overexpressed OLA1 showed poor overall survival rates in patients with pancreatic cancer. Dysregulation of the OLA1 reduced expression of CD44+/CD133+, and improved the sensitivity of pancreatic cancer cells to GEM. OLA1 highly expression facilitated the formation of the OLA1/Sonic Hedgehog (SHH)/Hedgehog-interacting protein (HHIP) complex in nuclei, resulting in the inhibition of negative feedback of Hedgehog signaling induced by HHIP. This study suggests that OLA1 may be developed as an innovative drug target for an effective therapy of pancreatic cancer.
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Affiliation(s)
- Jianzhou Liu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
- Institute of clinical medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jing Huang
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Jun Lu
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Runze Ouyang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Wenchao Xu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jianlu Zhang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Kevin Chen-Xiao
- Department of Nutritional Sciences and Toxicology, University of California Berkeley, San Francisco, CA, USA
| | - Chengjun Wu
- School of Biomedical Engineering, Dalian University of Technology, Dalian, China
| | - Dong Shang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China
| | - Vay Liang W Bill Go
- The UCLA Agi Hirshberg Center for Pancreatic Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Junchao Guo
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Gary Guishan Xiao
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
- The UCLA Agi Hirshberg Center for Pancreatic Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Functional Genomics and Proteomics Laboratory, Osteoporosis Research Center, Creighton University Medical Center, Omaha, NE, USA
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6
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Khan AQ, Hasan A, Mir SS, Rashid K, Uddin S, Steinhoff M. Exploiting transcription factors to target EMT and cancer stem cells for tumor modulation and therapy. Semin Cancer Biol 2024; 100:1-16. [PMID: 38503384 DOI: 10.1016/j.semcancer.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 03/21/2024]
Abstract
Transcription factors (TFs) are essential in controlling gene regulatory networks that determine cellular fate during embryogenesis and tumor development. TFs are the major players in promoting cancer stemness by regulating the function of cancer stem cells (CSCs). Understanding how TFs interact with their downstream targets for determining cell fate during embryogenesis and tumor development is a critical area of research. CSCs are increasingly recognized for their significance in tumorigenesis and patient prognosis, as they play a significant role in cancer initiation, progression, metastasis, and treatment resistance. However, traditional therapies have limited effectiveness in eliminating this subset of cells, allowing CSCs to persist and potentially form secondary tumors. Recent studies have revealed that cancer cells and tumors with CSC-like features also exhibit genes related to the epithelial-to-mesenchymal transition (EMT). EMT-associated transcription factors (EMT-TFs) like TWIST and Snail/Slug can upregulate EMT-related genes and reprogram cancer cells into a stem-like phenotype. Importantly, the regulation of EMT-TFs, particularly through post-translational modifications (PTMs), plays a significant role in cancer metastasis and the acquisition of stem cell-like features. PTMs, including phosphorylation, ubiquitination, and SUMOylation, can alter the stability, localization, and activity of EMT-TFs, thereby modulating their ability to drive EMT and stemness properties in cancer cells. Although targeting EMT-TFs holds potential in tackling CSCs, current pharmacological approaches to do so directly are unavailable. Therefore, this review aims to explore the role of EMT- and CSC-TFs, their connection and impact in cellular development and cancer, emphasizing the potential of TF networks as targets for therapeutic intervention.
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Affiliation(s)
- Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
| | - Adria Hasan
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow 226026, India; Department of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow 226026, India
| | - Snober S Mir
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow 226026, India; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India
| | - Khalid Rashid
- Department of Urology,Feinberg School of Medicine, Northwestern University, 303 E Superior Street, Chicago, IL 60611, USA
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India; Laboratory Animal Research Center, Qatar University, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar
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7
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Chang CH, Liu F, Militi S, Hester S, Nibhani R, Deng S, Dunford J, Rendek A, Soonawalla Z, Fischer R, Oppermann U, Pauklin S. The pRb/RBL2-E2F1/4-GCN5 axis regulates cancer stem cell formation and G0 phase entry/exit by paracrine mechanisms. Nat Commun 2024; 15:3580. [PMID: 38678032 PMCID: PMC11055877 DOI: 10.1038/s41467-024-47680-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/09/2024] [Indexed: 04/29/2024] Open
Abstract
The lethality, chemoresistance and metastatic characteristics of cancers are associated with phenotypically plastic cancer stem cells (CSCs). How the non-cell autonomous signalling pathways and cell-autonomous transcriptional machinery orchestrate the stem cell-like characteristics of CSCs is still poorly understood. Here we use a quantitative proteomic approach for identifying secreted proteins of CSCs in pancreatic cancer. We uncover that the cell-autonomous E2F1/4-pRb/RBL2 axis balances non-cell-autonomous signalling in healthy ductal cells but becomes deregulated upon KRAS mutation. E2F1 and E2F4 induce whereas pRb/RBL2 reduce WNT ligand expression (e.g. WNT7A, WNT7B, WNT10A, WNT4) thereby regulating self-renewal, chemoresistance and invasiveness of CSCs in both PDAC and breast cancer, and fibroblast proliferation. Screening for epigenetic enzymes identifies GCN5 as a regulator of CSCs that deposits H3K9ac onto WNT promoters and enhancers. Collectively, paracrine signalling pathways are controlled by the E2F-GCN5-RB axis in diverse cancers and this could be a therapeutic target for eliminating CSCs.
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Affiliation(s)
- Chao-Hui Chang
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - Feng Liu
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - Stefania Militi
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - Svenja Hester
- Target Discovery Institute, Nuffield Department of Medicine, Old Road, University of Oxford, Oxford, OX3 7FZ, UK
| | - Reshma Nibhani
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - Siwei Deng
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - James Dunford
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - Aniko Rendek
- Department of Histopathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Zahir Soonawalla
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS, Oxford, UK
| | - Roman Fischer
- Target Discovery Institute, Nuffield Department of Medicine, Old Road, University of Oxford, Oxford, OX3 7FZ, UK
| | - Udo Oppermann
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK
| | - Siim Pauklin
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK.
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8
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Feng Y, Cai L, Pook M, Liu F, Chang CH, Mouti MA, Nibhani R, Militi S, Dunford J, Philpott M, Fan Y, Fan GC, Liu Q, Qi J, Wang C, Hong W, Morgan H, Wang M, Sadayappan S, Jegga AG, Oppermann U, Wang Y, Huang W, Jiang L, Pauklin S. BRD9-SMAD2/3 Orchestrates Stemness and Tumorigenesis in Pancreatic Ductal Adenocarcinoma. Gastroenterology 2024; 166:139-154. [PMID: 37739089 PMCID: PMC11304550 DOI: 10.1053/j.gastro.2023.09.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 09/06/2023] [Accepted: 09/11/2023] [Indexed: 09/24/2023]
Abstract
BACKGROUND & AIMS The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs. METHODS By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signaling pathway. RESULTS Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. CONCLUSIONS Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.
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Affiliation(s)
- Yuliang Feng
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Liuyang Cai
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Guangdong, China
| | - Martin Pook
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Feng Liu
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Chao-Hui Chang
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Mai Abdel Mouti
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Reshma Nibhani
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Stefania Militi
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - James Dunford
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Martin Philpott
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Yanbo Fan
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Guo-Chang Fan
- Departments of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Qi Liu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jun Qi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Cheng Wang
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
| | - Wanzi Hong
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, China
| | - Hannah Morgan
- Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, Ohio
| | - Mingyang Wang
- College of Engineering and Applied Science, University of Cincinnati, Cincinnati, Ohio
| | - Sakthivel Sadayappan
- Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, Ohio
| | - Anil G Jegga
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Computer Science, University of Cincinnati College of Engineering, Cincinnati, Ohio
| | - Udo Oppermann
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; Oxford Translational Myeloma Centre, Botnar Research Centre, Oxford, United Kingdom
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
| | - Wei Huang
- Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, Ohio.
| | - Lei Jiang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, China.
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
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9
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Sharma R, Malviya R. Cancer Stem Cells in Carcinogenesis and Potential Role in Pancreatic Cancer. Curr Stem Cell Res Ther 2024; 19:1185-1194. [PMID: 37711007 DOI: 10.2174/1574888x19666230914103420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/14/2023] [Accepted: 08/11/2023] [Indexed: 09/16/2023]
Abstract
A poor prognosis is associated with pancreatic cancer because of resistance during treatment and early distant metastases. The discovery of cancer stem cells has opened up novel avenues for research into the biology and treatment of cancer. Many investigations have pointed out the role of these types of stem cells in the oncogenesis and progression of hematologic and solid malignancies, specifically. Due to the existence of cancer stem cells in the proliferation and preservation of pancreatic tumors, such malignancies could be difficult to eradicate using conventional treatment techniques like chemotherapy and radiotherapy. It is hypothesized that pancreatic malignancies originate from a limited population of aberrant cancer stem cells to promote carcinogenesis, tumour metastasis, and therapeutic resistance. This review examines the role of pancreatic cancer stem cells in this disease and their significance in carcinogenesis, as well as the signals which modulate them, and also examines the ongoing clinical studies that are now being conducted with pancreatic stem cells.
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Affiliation(s)
- Rishav Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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10
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Tewari AB, Saini A, Sharma D. Extirpating the cancer stem cell hydra: Differentiation therapy and Hyperthermia therapy for targeting the cancer stem cell hierarchy. Clin Exp Med 2023; 23:3125-3145. [PMID: 37093450 DOI: 10.1007/s10238-023-01066-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 04/02/2023] [Indexed: 04/25/2023]
Abstract
Ever since the discovery of cancer stem cells (CSCs), they have progressively attracted more attention as a therapeutic target. Like the mythical hydra, this subpopulation of cells seems to contribute to cancer immortality, spawning more cells each time that some components of the cancer cell hierarchy are destroyed. Traditional modalities focusing on cancer treatment have emphasized apoptosis as a route to eliminate the tumor burden. A major problem is that cancer cells are often in varying degrees of dedifferentiation contributing to what is known as the CSCs hierarchy and cells which are known to be resistant to conventional therapy. Differentiation therapy is an experimental therapeutic modality aimed at the conversion of malignant phenotype to a more benign one. Hyperthermia therapy (HT) is a modality exploiting the changes induced in cells by the application of heat produced to aid in cancer therapy. While differentiation therapy has been successfully employed in the treatment of acute myeloid leukemia, it has not been hugely successful for other cancer types. Mounting evidence suggests that hyperthermia therapy may greatly augment the effects of differentiation therapy while simultaneously overcoming many of the hard-to-treat facets of recurrent tumors. This review summarizes the progress made so far in integrating hyperthermia therapy with existing modules of differentiation therapy. The focus is on studies related to the successful application of both hyperthermia and differentiation therapy when used alone or in conjunction for hard-to-treat cancer cell niche with emphasis on combined approaches to target the CSCs hierarchy.
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Affiliation(s)
- Amit B Tewari
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India
| | - Anamika Saini
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India
| | - Deepika Sharma
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India.
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11
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Izdebska WM, Daniluk J, Niklinski J. Microbiome and MicroRNA or Long Non-Coding RNA-Two Modern Approaches to Understanding Pancreatic Ductal Adenocarcinoma. J Clin Med 2023; 12:5643. [PMID: 37685710 PMCID: PMC10488817 DOI: 10.3390/jcm12175643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/18/2023] [Accepted: 08/19/2023] [Indexed: 09/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of humans' most common and fatal neoplasms. Nowadays, a number of PDAC studies are being conducted in two different fields: non-coding RNA (especially microRNA and long non-coding RNA) and microbiota. It has been recently discovered that not only does miRNA affect particular bacteria in the gut microbiome that can promote carcinogenesis in the pancreas, but the microbiome also has a visible impact on the miRNA. This suggests that it is possible to use the combined impact of the microbiome and noncoding RNA to suppress the development of PDAC. Nevertheless, insufficient research has focused on bounding both approaches to the diagnosis, treatment, and prevention of pancreatic ductal adenocarcinoma. In this article, we summarize the recent literature on the molecular basis of carcinogenesis in the pancreas, the two-sided impact of particular types of non-coding RNA and the pancreatic cancer microbiome, and possible medical implications of the discovered phenomenon.
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Affiliation(s)
- Wiktoria Maria Izdebska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jaroslaw Daniluk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jacek Niklinski
- Department of Clinical Molecular Biology, Medical University of Bialystok, 15-089 Bialystok, Poland
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12
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Peng M, Ying Y, Zhang Z, Liu L, Wang W. Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy. Cancers (Basel) 2023; 15:2448. [PMID: 37173915 PMCID: PMC10177210 DOI: 10.3390/cancers15092448] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/09/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
The dynamic tumor microenvironment, especially the immune microenvironment, during the natural progression and/or chemotherapy treatment is a critical frontier in understanding the effects of chemotherapy on pancreatic cancer. Non-stratified pancreatic cancer patients always receive chemotherapeutic strategies, including neoadjuvant chemotherapy and adjuvant chemotherapy, predominantly according to their physical conditions and different disease stages. An increasing number of studies demonstrate that the pancreatic cancer tumor microenvironment could be reshaped by chemotherapy, an outcome caused by immunogenic cell death, selection and/or education of preponderant tumor clones, adaptive gene mutations, and induction of cytokines/chemokines. These outcomes could in turn impact the efficacy of chemotherapy, making it range from synergetic to resistant and even tumor-promoting. Under chemotherapeutic impact, the metastatic micro-structures in the primary tumor may be built to leak tumor cells into the lymph or blood vasculature, and micro-metastatic/recurrent niches rich in immunosuppressive cells may be recruited by cytokines and chemokines, which provide housing conditions for these circling tumor cells. An in-depth understanding of how chemotherapy reshapes the tumor microenvironment may lead to new therapeutic strategies to block its adverse tumor-promoting effects and prolong survival. In this review, reshaped pancreatic cancer tumor microenvironments due to chemotherapy were reflected mainly in immune cells, pancreatic cancer cells, and cancer-associated fibroblast cells, quantitatively, functionally, and spatially. Additionally, small molecule kinases and immune checkpoints participating in this remodeling process caused by chemotherapy are suggested to be blocked reasonably to synergize with chemotherapy.
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Affiliation(s)
- Maozhen Peng
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ying Ying
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zheng Zhang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wenquan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; (M.P.); (Y.Y.); (Z.Z.)
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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13
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Feng Y, Cai L, Pook M, Liu F, Chang CH, Mouti MA, Nibhani R, Wu S, Deng S, Militi S, Dunford J, Philpott M, Fan Y, Fan GC, Liu Q, Qi J, Sadayappan S, Jegga AG, Oppermann U, Wang Y, Huang W, Jiang L, Pauklin S. BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.02.530770. [PMID: 36909530 PMCID: PMC10002796 DOI: 10.1101/2023.03.02.530770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signalling pathway. Inhibition and genetic ablation of BDR9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumours from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.
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14
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Histone Modifications Represent a Key Epigenetic Feature of Epithelial-to-Mesenchyme Transition in Pancreatic Cancer. Int J Mol Sci 2023; 24:ijms24054820. [PMID: 36902253 PMCID: PMC10003015 DOI: 10.3390/ijms24054820] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/25/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Pancreatic cancer is one of the most lethal malignant diseases due to its high invasiveness, early metastatic properties, rapid disease progression, and typically late diagnosis. Notably, the capacity for pancreatic cancer cells to undergo epithelial-mesenchymal transition (EMT) is key to their tumorigenic and metastatic potential, and is a feature that can explain the therapeutic resistance of such cancers to treatment. Epigenetic modifications are a central molecular feature of EMT, for which histone modifications are most prevalent. The modification of histones is a dynamic process typically carried out by pairs of reverse catalytic enzymes, and the functions of these enzymes are increasingly relevant to our improved understanding of cancer. In this review, we discuss the mechanisms through which histone-modifying enzymes regulate EMT in pancreatic cancer.
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15
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Liu S, Zhang T, Li S, Wu Q, Wang K, Xu X, Lu M, Shao R, Zhao W, Liu H. Biomimetic Nanobomb for Synergistic Therapy with Inhibition of Cancer Stem Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2206503. [PMID: 36587973 DOI: 10.1002/smll.202206503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/28/2022] [Indexed: 06/17/2023]
Abstract
Cancer stem cells (CSCs), a type of cell with self-renewal, unlimited proliferation, and insensitivity to common physical and chemical factors, are the key to cancer metastasis, recurrence, and chemo-resistance. Available CSCs inhibition strategies are mainly based on small molecule drugs, yet are limited by their off-target toxicity. The link between CSCs and non-CSCs interconversion is difficult to sever. In this work, a nanotherapeutic strategy based on MnOx -loaded polydopamine (MnOx /PDA) nanobombs with chemodynamic, photodynamic, photothermal and biodegradation properties to inhibit CSCs and non-CSCs concurrently is reported. The MnOx /PDA nanobombs can directly disrupt the microenvironment and tumorigenic capacity of CSCs by generating hyperthermia, oxidative stress and alleviating hypoxia. The markers of CSCs are subsequently downregulated, leading to the clearance of CSCs. Meanwhile, the synergistic therapy mediated by MnOx /PDA nanobombs can directly ablate the bulk tumor cells, thus cutting off the supply of CSCs transformation. For tumor targeting, MnOx /PDA is coated with macrophage membrane. The final tumor inhibition rate of the synergistic therapy is 70.8% in colorectal cancer (CRC) model. Taken together, the present work may open up the exploration of nanomaterial-based synergistic therapy for the simultaneous elimination of therapeutically resistant CSCs and non-CSCs.
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Affiliation(s)
- Shuang Liu
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composites, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Tianshu Zhang
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Shanshan Li
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composites, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Qingyuan Wu
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composites, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Kexin Wang
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Xican Xu
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composites, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China
| | - MingZhu Lu
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composites, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Rongguang Shao
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Wuli Zhao
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Huiyu Liu
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composites, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China
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16
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Alonso-Nocelo M, Ruiz-Cañas L, Sancho P, Görgülü K, Alcalá S, Pedrero C, Vallespinos M, López-Gil JC, Ochando M, García-García E, David Trabulo SM, Martinelli P, Sánchez-Tomero P, Sánchez-Palomo C, Gonzalez-Santamaría P, Yuste L, Wörmann SM, Kabacaoğlu D, Earl J, Martin A, Salvador F, Valle S, Martin-Hijano L, Carrato A, Erkan M, García-Bermejo L, Hermann PC, Algül H, Moreno-Bueno G, Heeschen C, Portillo F, Cano A, Sainz B. Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma. Gut 2023; 72:345-359. [PMID: 35428659 PMCID: PMC9872246 DOI: 10.1136/gutjnl-2021-325564] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 03/21/2022] [Indexed: 01/27/2023]
Abstract
OBJECTIVE The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models. DESIGN Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2KO or KCL2KO and KPCL2KI or KCL2KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation. RESULTS Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment. CONCLUSION Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.
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Affiliation(s)
- Marta Alonso-Nocelo
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Laura Ruiz-Cañas
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Patricia Sancho
- Translational Research Unit, Hospital Miguel Servet, Instituto de Investigacion Sanitaria Aragon, Zaragoza, Spain
| | - Kıvanç Görgülü
- Comprehensive Cancer Center München, Klinikum rechts der Isar der Technischen Universität München, München, Germany
| | - Sonia Alcalá
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Coral Pedrero
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Mireia Vallespinos
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Juan Carlos López-Gil
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Marina Ochando
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Elena García-García
- Departamento de Anatomía Patológica, Hospital Universitario Fundación Alcorcón, Alcorcón, Spain
| | - Sara Maria David Trabulo
- Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Paola Martinelli
- Institute for Cancer Research, Comprehensive Cancer Center, Medizinische Universitat Wien, Wien, Austria
| | - Patricia Sánchez-Tomero
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Carmen Sánchez-Palomo
- Departamento de Anatomía, Histologia y Neurociencia, Universidad Autónoma de Madrid, Madrid, Spain
| | - Patricia Gonzalez-Santamaría
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer and Human Molecular Genetics, Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain
| | - Lourdes Yuste
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Cancer and Human Molecular Genetics, Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain
| | - Sonja Maria Wörmann
- Ahmed Cancer Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Derya Kabacaoğlu
- Comprehensive Cancer Center München, Klinikum rechts der Isar der Technischen Universität München, München, Germany
| | - Julie Earl
- Molecular Epidemiology and Predictive Tumor Markers Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain, Madrid, Spain
- Gastrointestinal Tumours Research Programme, Biomedical Research Network in Cancer (CIBERONC), Madrid, Spain
| | - Alberto Martin
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
| | - Fernando Salvador
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
| | - Sandra Valle
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Laura Martin-Hijano
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Alfredo Carrato
- Molecular Epidemiology and Predictive Tumor Markers Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain, Madrid, Spain
- Gastrointestinal Tumours Research Programme, Biomedical Research Network in Cancer (CIBERONC), Madrid, Spain
- Alcala University, Madrid, Spain
| | - Mert Erkan
- University Research Center for Translational Medicine - KUTTAM, Istanbul, Turkey
| | - Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group, Area 4, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | | | - Hana Algül
- Comprehensive Cancer Center München, Klinikum rechts der Isar der Technischen Universität München, München, Germany
| | - Gema Moreno-Bueno
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer and Human Molecular Genetics, Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain
- Breast Cancer Research Programme, Biomedical Research Network in Cancer (CIBERONC), Madrid, Spain
- Fundación MD Anderson Internacional, Madrid, Spain
| | - Christopher Heeschen
- Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Center for Single-Cell Omics and Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Francisco Portillo
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Breast Cancer Research Programme, Biomedical Research Network in Cancer (CIBERONC), Madrid, Spain
| | - Amparo Cano
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer and Human Molecular Genetics, Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain
- Breast Cancer Research Programme, Biomedical Research Network in Cancer (CIBERONC), Madrid, Spain
| | - Bruno Sainz
- Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Departament of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Gastrointestinal Tumours Research Programme, Biomedical Research Network in Cancer (CIBERONC), Madrid, Spain
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Parejo-Alonso B, Royo-García A, Espiau-Romera P, Courtois S, Curiel-García Á, Zagorac S, Villaoslada I, Olive KP, Heeschen C, Sancho P. Pharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma. Biomed Pharmacother 2023; 158:114162. [PMID: 36571997 DOI: 10.1016/j.biopha.2022.114162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/14/2022] [Accepted: 12/21/2022] [Indexed: 12/25/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease characterized by its metastatic potential and chemoresistance. These traits are partially attributable to the highly tumorigenic pancreatic cancer stem cells (PaCSCs). Interestingly, these cells show unique features in order to sustain their identity and functionality, some of them amenable for therapeutic intervention. Screening of phospho-receptor tyrosine kinases revealed that PaCSCs harbored increased activation of anaplastic lymphoma kinase (ALK). We subsequently demonstrated that oncogenic ALK signaling contributes to tumorigenicity in PDAC patient-derived xenografts (PDXs) by promoting stemness through ligand-dependent activation. Indeed, the ALK ligands midkine (MDK) or pleiotrophin (PTN) increased self-renewal, clonogenicity and CSC frequency in several in vitro local and metastatic PDX models. Conversely, treatment with the clinically-approved ALK inhibitors Crizotinib and Ensartinib decreased PaCSC content and functionality in vitro and in vivo, by inducing cell death. Strikingly, ALK inhibitors sensitized chemoresistant PaCSCs to Gemcitabine, as the most used chemotherapeutic agent for PDAC treatment. Consequently, ALK inhibition delayed tumor relapse after chemotherapy in vivo by effectively decreasing the content of PaCSCs. In summary, our results demonstrate that targeting the MDK/PTN-ALK axis with clinically-approved inhibitors impairs in vivo tumorigenicity and chemoresistance in PDAC suggesting a new treatment approach to improve the long-term survival of PDAC patients.
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Affiliation(s)
- Beatriz Parejo-Alonso
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Alba Royo-García
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Pilar Espiau-Romera
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Sarah Courtois
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Álvaro Curiel-García
- Department of Medicine, Division of Digestive Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Sladjana Zagorac
- Center for Stem Cells in Cancer & Ageing (Barts Cancer Institute), London, UK
| | - Isabel Villaoslada
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain; Aragon Institute of Engineering Research, Department of Mechanical Engineering, University of Zaragoza, Zaragoza, Spain
| | - Kenneth P Olive
- Department of Medicine, Division of Digestive Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Christopher Heeschen
- Center for Single-Cell Omics and Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, China; Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute - FPO - IRCCS, Candiolo (Torino), Italy
| | - Patricia Sancho
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain.
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18
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Re-Sensitizing Cancer Stem Cells to Conventional Chemotherapy Agents. Int J Mol Sci 2023; 24:ijms24032122. [PMID: 36768445 PMCID: PMC9917165 DOI: 10.3390/ijms24032122] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/26/2022] [Accepted: 01/04/2023] [Indexed: 01/25/2023] Open
Abstract
Cancer stem cells are found in many cancer types. They comprise a distinct subpopulation of cells within the tumor that exhibit properties of stem cells. They express a number of cell surface markers, such as CD133, CD44, ALDH, and EpCAM, as well as embryonic transcription factors Oct4, Nanog, and SOX2. CSCs are more resistant to conventional chemotherapy and can potentially drive tumor relapse. Therefore, it is essential to understand the molecular mechanisms that drive chemoresistance and to target them with specific therapy effectively. Highly conserved developmental signaling pathways such as Wnt, Hedgehog, and Notch are commonly reported to play a role in CSCs chemoresistance development. Studies show that particular pathway inhibitors combined with conventional therapy may re-establish sensitivity to the conventional therapy. Another significant contributor of chemoresistance is a specific tumor microenvironment. Surrounding stroma in the form of cancer-associated fibroblasts, macrophages, endothelial cells, and extracellular matrix components produce cytokines and other factors, thus creating a favorable environment and decreasing the cytotoxic effects of chemotherapy. Anti-stromal agents may potentially help to overcome these effects. Epigenetic changes and autophagy were also among the commonly reported mechanisms of chemoresistance. This review provides an overview of signaling pathway components involved in the development of chemoresistance of CSCs and gathers evidence from experimental studies in which CSCs can be re-sensitized to conventional chemotherapy agents across different cancer types.
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19
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Liao W, Zhang L, Chen X, Xiang J, Zheng Q, Chen N, Zhao M, Zhang G, Xiao X, Zhou G, Zeng J, Tang J. Targeting cancer stem cells and signalling pathways through phytochemicals: A promising approach against colorectal cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 108:154524. [PMID: 36375238 DOI: 10.1016/j.phymed.2022.154524] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 10/10/2022] [Accepted: 10/24/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Cancer stem cells (CSCs) are strongly associated with high tumourigenicity, chemotherapy or radiotherapy resistance, and metastasis and recurrence, particularly in colorectal cancer (CRC). Therefore, targeting CSCs may be a promising approach. Recently, discovery and research on phytochemicals that effectively target colorectal CSCs have been gaining popularity because of their broad safety profile and multi-target and multi-pathway modes of action. PURPOSE This review aimed to elucidate and summarise the effects and mechanisms of phytochemicals with potential anti-CSC agents that could contribute to the better management of CRC. METHODS We reviewed PubMed, EMBASE, Web of Science, Ovid, ScienceDirect and China National Knowledge Infrastructure databases from the original publication date to March 2022 to review the mechanisms by which phytochemicals inhibit CRC progression by targeting CSCs and their key signalling pathways. Phytochemicals were classified and summarised based on the mechanisms of action. RESULTS We observed that phytochemicals could affect the biological properties of colorectal CSCs. Phytochemicals significantly inhibit self-renewal, migration, invasion, colony formation, and chemoresistance and induce apoptosis and differentiation of CSCs by regulating the Wnt/β-catenin pathway (e.g., diallyl trisulfide and genistein), the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway (e.g., caffeic acid and piperlongumine), the neurogenic locus notch homolog protein pathway (e.g., honokiol, quercetin, and α-mangostin), the Janus kinase-signal transducer and activator of transcription pathway (e.g., curcumin, morin, and ursolic acid), and other key signalling pathways. It is worth noting that several phytochemicals, such as resveratrol, silibinin, evodiamine, and thymoquinone, highlight multi-target and multi-pathway effects in restraining the malignant biological behaviour of CSCs. CONCLUSIONS This review demonstrates the potential of targeted therapies for colorectal CSCs using phytochemicals. Phytochemicals could serve as novel therapeutic agents for CRC and aid in drug development.
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Affiliation(s)
- Wenhao Liao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Lanlan Zhang
- State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xian Chen
- Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Juyi Xiang
- Center for drug evaluation, National Medical Products Administration, Beijing 100022, China
| | - Qiao Zheng
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Nianzhi Chen
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Maoyuan Zhao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Gang Zhang
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Xiaolin Xiao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Gang Zhou
- Center for drug evaluation, National Medical Products Administration, Beijing 100022, China.
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
| | - Jianyuan Tang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
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20
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Zhang H, Chen P, Yan H, Fu G, Luo F, Zhang J, Zhao S, Zhai B, Yu J, Chen L, Cui H, Chen J, Huang S, Zeng J, Xu W, Wang H, Liu J. Targeting mTORC2/HDAC3 Inhibits Stemness of Liver Cancer Cells Against Glutamine Starvation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103887. [PMID: 35187863 PMCID: PMC9284171 DOI: 10.1002/advs.202103887] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 01/27/2022] [Indexed: 06/12/2023]
Abstract
Cancer cells are addicted to glutamine. However, cancer cells often suffer from glutamine starvation, which largely results from the fast growth of cancer cells and the insufficient vascularization in the interior of cancer tissues. Herein, based on clinical samples, patient-derived cells (PDCs), and cell lines, it is found that liver cancer cells display stem-like characteristics upon glutamine shortage due to maintaining the stemness of tumor initiating cells (TICs) and even promoting transformation of non-TICs into stem-like cells by glutamine starvation. Increased expression of glutamine synthetase (GS) is essential for maintaining and promoting stem-like characteristics of liver cancer cells during glutamine starvation. Mechanistically, glutamine starvation activates Rictor/mTORC2 to induce HDAC3-mediated deacetylation and stabilization of GS. Rictor is significantly correlated with the expression of GS and stem marker OCT4 at tumor site, and closely correlates with poor prognosis of hepatocellular carcinomas. Inhibiting components of mTORC2-HDAC3-GS axis decrease TICs and promote xenografts regression upon glutamine-starvation therapy. Collectively, the data provides novel insights into the role of Rictor/mTORC2-HDAC3 in reprogramming glutamine metabolism to sustain stemness of cancer cells. Targeting Rictor/HDAC3 may enhance the efficacy of glutamine-starvation therapy and limit the rapid growth and malignant progression of tumors.
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Affiliation(s)
- Hui‐Lu Zhang
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - Ping Chen
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - He‐Xin Yan
- Renji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200120China
| | - Gong‐Bo Fu
- Department of Medical OncologyAffiliated Jinling HospitalMedical School of Nanjing UniversityNanjing210093China
| | - Fei‐Fei Luo
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - Jun Zhang
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - Shi‐Min Zhao
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - Bo Zhai
- Renji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200120China
| | - Jiang‐Hong Yu
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - Lin Chen
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - Hao‐Shu Cui
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - Jian Chen
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - Shuai Huang
- Renji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai200120China
| | - Jun Zeng
- Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
| | - Wei Xu
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
| | - Hong‐Yang Wang
- Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai200433China
- National Center for Liver CancerShanghai200433China
| | - Jie Liu
- Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical SciencesFudan UniversityShanghai200040China
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21
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Miao Z, Cao Q, Liao R, Chen X, Li X, Bai L, Ma C, Deng X, Dai Z, Li J, Dong C. Elevated transcription and glycosylation of B3GNT5 promotes breast cancer aggressiveness. J Exp Clin Cancer Res 2022; 41:169. [PMID: 35526049 PMCID: PMC9077843 DOI: 10.1186/s13046-022-02375-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/27/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer because of its aggressive biological characteristics and no effective targeted agents. However, the mechanism underlying its aggressive behavior remain poorly understood. β1,3-N-acetylglucosaminyltransferase V (B3GNT5) overexpression occurs specifically in BLBC. Here, we studied the possible molecular mechanisms of B3GBT5 promoting the aggressiveness of BLBC. METHODS The potential effects of B3GNT5 on breast cancer cells were tested by colony formation, mammosphere formation, cell proliferation assay, flow cytometry and Western blotting. The glycosylation patterns of B3GNT5 and associated functions were determined by Western blotting, quantitative real-time PCR and flow cytometry. The effect of B3GNT5 expression on BLBC was assessed by in vitro and in vivo tumorigenesis model. RESULTS In this study, we showed that B3GNT5 copy number amplification and hypomethylation of B3GNT5 promoter contributed to the overexpression of B3GNT5 in BLBC. Knockout of B3GNT5 strongly reduced surface expression of SSEA-1 and impeded cancer stem cell (CSC)-like properties of BLBC cells. Our results also showed that B3GNT5 protein was heavily N-glycosylated, which is critical for its protein stabilization. Clinically, elevated expression of B3GNT5 was correlated with high grade, large tumor size and poor survival, indicating poor prognosis of breast cancer patients. CONCLUSIONS Our work uncovers the critical association of B3GNT5 overexpression and glycosylation with enhanced CSCs properties in BLBC. These findings suggest that B3GNT5 has the potential to become a prognostic marker and therapeutic target for BLBC.
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Affiliation(s)
- Zhaorui Miao
- Department of Pathology and Pathophysiology, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Ministry of Education, Zhejiang University School of Medicine, 310058, Hangzhou, China
- Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, 310058, Hangzhou, China
| | - Qianhua Cao
- Department of Pathology and Pathophysiology, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Ministry of Education, Zhejiang University School of Medicine, 310058, Hangzhou, China
- Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, 310058, Hangzhou, China
| | - Ruocen Liao
- Department of Pathology and Pathophysiology, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Ministry of Education, Zhejiang University School of Medicine, 310058, Hangzhou, China
- Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, 310058, Hangzhou, China
| | - Xingyu Chen
- Department of Pathology and Pathophysiology, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Ministry of Education, Zhejiang University School of Medicine, 310058, Hangzhou, China
- Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, 310058, Hangzhou, China
| | - Xiaoli Li
- Abcam Plc, 1418-32 Moganshan Road, 311500, Hangzhou, China
| | - Longchang Bai
- Department of Pathology and Pathophysiology, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Ministry of Education, Zhejiang University School of Medicine, 310058, Hangzhou, China
- Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, 310058, Hangzhou, China
| | - Chenglong Ma
- Department of Pathology and Pathophysiology, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Ministry of Education, Zhejiang University School of Medicine, 310058, Hangzhou, China
- Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, 310058, Hangzhou, China
| | - Xinyue Deng
- Department of Breast Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China
| | - Zhijun Dai
- Department of Breast Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
| | - Jun Li
- Department of Pathology and Pathophysiology, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Ministry of Education, Zhejiang University School of Medicine, 310058, Hangzhou, China.
| | - Chenfang Dong
- Department of Pathology and Pathophysiology, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Ministry of Education, Zhejiang University School of Medicine, 310058, Hangzhou, China.
- Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, 310058, Hangzhou, China.
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22
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Gp130-Mediated STAT3 Activation Contributes to the Aggressiveness of Pancreatic Cancer through H19 Long Non-Coding RNA Expression. Cancers (Basel) 2022; 14:cancers14092055. [PMID: 35565185 PMCID: PMC9100112 DOI: 10.3390/cancers14092055] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The signal transducer and activator of transcription 3 (STAT3) activation correlate with the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). We demonstrated that the autocrine/paracrine interleukin-6 (IL-6) or leukemia inhibitory factor (LIF)/glycoprotein 130 (gp130)/STAT3 pathway contributes to the maintenance of stemness features and membrane-type 1 matrix metalloproteinase (MT1-MMP) expression, and modulates transforming growth factor (TGF)-β1/Smad signaling-mediated epithelial-mesenchymal transition (EMT) and invasion through regulation of TGFβ-RII expression in PDAC cancer stem cell (CSC)-like cells. Furthermore, we demonstrated that p-STAT3 acts through the IL-6 or LIF/gp130/STAT3 pathway to access the active promoter region of metastasis-related long non-coding RNA H19 and contribute to its transcription in CSC-like cells. Therefore, the autocrine/paracrine IL-6 or LIF/gp130/STAT3 pathway in PDAC CSC-like cells exhibiting H19 expression is considered to be involved in the aggressiveness of PDAC, and inhibition of the gp130/STAT3 pathway is a promising strategy to target CSCs for the elimination of PDAC (146/150). Abstract Signaling pathways involving signal transducer and activator of transcription 3 (STAT3) play key roles in the aggressiveness of pancreatic ductal adenocarcinoma (PDAC), including their tumorigenesis, invasion, and metastasis. Cancer stem cells (CSCs) have been correlated with PDAC aggressiveness, and activation of STAT3 is involved in the regulation of CSC properties. Here, we investigated the involvement of interleukin-6 (IL-6) or the leukemia inhibitory factor (LIF)/glycoprotein 130 (gp130)/STAT3 pathway and their role in pancreatic CSCs. In PDAC CSC-like cells formed by culturing on a low attachment plate, autocrine/paracrine IL-6 or LIF contributes to gp130/STAT3 pathway activation. Using a gp130 inhibitor, we determined that the gp130/STAT3 pathway contributes to the maintenance of stemness features, the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), and the invasion of PDAC CSC-like cells. The gp130/STAT3 pathway also modulates the transforming growth factor (TGF)-β1/Smad pathway required for epithelial-mesenchymal transition induction through regulation of TGFβ-RII expression in PDAC CSC-like cells. Furthermore, chromatin immunoprecipitation assays revealed that p-STAT3 can access the active promoter region of H19 to influence this metastasis-related long non-coding RNA and contribute to its transcription in PDAC CSC-like cells. Therefore, the autocrine/paracrine IL-6 or LIF/gp130/STAT3 pathway in PDAC CSC-like cells may eventually facilitate invasion and metastasis, two hallmarks of malignancy. We propose that inhibition of the gp130/STAT3 pathway provides a promising strategy for targeting CSCs for the treatment of PDAC.
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23
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Sumbly V, Landry I. Understanding pancreatic cancer stem cells and their role in carcinogenesis: a narrative review. Stem Cell Investig 2022; 9:1. [PMID: 35242873 PMCID: PMC8832159 DOI: 10.21037/sci-2021-067] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/14/2022] [Indexed: 08/13/2023]
Abstract
OBJECTIVE The purpose of this review article is to describe the pathogenesis of pancreatic cancer and to better understand the role of abnormal stem cells in the development of pancreatic cancer. BACKGROUND Pancreatic cancer is a highly fatal disease that is caused by the uncontrolled proliferation of pancreatic exocrine or neuroendocrine glands. It is believed that pancreatic cancers arise from a small population of abnormal cancer stem cells (CSCs) that promote tumorigenesis, tumor metastasis and therapeutic resistance. The molecular markers CD133, CXCR4, DCLK1, c-MET, ABCG2 and Lgr5 are routinely used to detected and observe the behaviours of pancreatic cancer stem cells (PCSCs). METHODS A comprehensive search was performed on PubMed, Google Scholar, Scopus, Clinicaltrials.gov and Web of Science using related keywords. Articles focusing on PCSCs and pancreatic cancer pathogenesis, biochemistry and clinical trials were selected. CONCLUSIONS Although very little is known about the exact cause of pancreatic cancer, PCSCs seem to play an important role in carcinogenesis. Mutated biochemical cascades include Sonic Hedgehog, K-RAS-JNK, DLL4/Notch and Nodal/Activin. Several clinical trials are trying to determine if the transplantation of hematopoietic stem cell or peripheral stem cells could be useful for the treatment of such an aggressive tumor.
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Affiliation(s)
- Vikram Sumbly
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/NYC Health & Hospitals|Queens, Jamaica, NY, USA
| | - Ian Landry
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/NYC Health & Hospitals|Queens, Jamaica, NY, USA
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24
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Deng J, Zhang J, Ye Y, Liu K, Zeng L, Huang J, Pan L, Li M, Bai R, Zhuang L, Huang X, Wu G, Wei L, Zheng Y, Su J, Zhang S, Chen R, Lin D, Zheng J. N6 -methyladenosine-Mediated Upregulation of WTAPP1 Promotes WTAP Translation and Wnt Signaling to Facilitate Pancreatic Cancer Progression. Cancer Res 2021; 81:5268-5283. [PMID: 34362795 PMCID: PMC9662857 DOI: 10.1158/0008-5472.can-21-0494] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 06/26/2021] [Accepted: 08/03/2021] [Indexed: 01/07/2023]
Abstract
Pseudogenes may play important roles in cancer. Here, we explore the mechanism and function of a pseudogene WTAPP1 in the progress of pancreatic ductal adenocarcinoma (PDAC). WTAPP1 RNA was significantly elevated in PDAC and was associated with poor prognosis in patients. Overexpression of WTAPP1 RNA promoted PDAC proliferation and invasiveness in vitro and in vivo. Mechanistically, N 6-methyladenosine (m6A) modification stabilized WTAPP1 RNA via CCHC-type zinc finger nucleic-acid binding protein (CNBP), resulting in increased levels of WTAPP1 RNA in PDAC cells. Excessive WTAPP1 RNA bound its protein-coding counterpart WT1-associated protein (WTAP) mRNA and recruited more EIF3 translation initiation complex to promote WTAP translation. Increased WTAP protein enhanced the activation of Wnt signaling and provoked the malignant phenotypes of PDAC. Decreasing WTAPP1 RNA significantly suppressed the in vivo growth and metastasis of PDAC cell lines and patient-derived xenografts. These results indicate that m6A-mediated increases in WTAPP1 expression promote PDAC progression and thus may serve as a therapeutic target. SIGNIFICANCE: This study reveals how aberrant m6A modification of the WTAPP1 pseudogene results in increased translation of its protein-coding counterpart to promote Wnt signaling, which contributes to pancreatic cancer progression.
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Affiliation(s)
- Junge Deng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jialiang Zhang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying Ye
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Kaijing Liu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lingxing Zeng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jingyi Huang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ling Pan
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Mei Li
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ruihong Bai
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lisha Zhuang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xudong Huang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guandi Wu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lusheng Wei
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanfen Zheng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiachun Su
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shaoping Zhang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Rufu Chen
- Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Dongxin Lin
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Corresponding Authors: Jian Zheng, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, 510060 Guangzhou, China. E-mail: ; and Dongxin Lin, E-mail:
| | - Jian Zheng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, Guangzhou, China.,Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Corresponding Authors: Jian Zheng, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, 510060 Guangzhou, China. E-mail: ; and Dongxin Lin, E-mail:
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25
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Truong LH, Pauklin S. Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches. Cancers (Basel) 2021; 13:5028. [PMID: 34638513 PMCID: PMC8507722 DOI: 10.3390/cancers13195028] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/01/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.
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Affiliation(s)
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK;
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26
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Pook H, Pauklin S. Mechanisms of Cancer Cell Death: Therapeutic Implications for Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2021; 13:4834. [PMID: 34638318 PMCID: PMC8508208 DOI: 10.3390/cancers13194834] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/24/2021] [Accepted: 09/24/2021] [Indexed: 12/20/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer that is strongly associated with poor prognosis and short median survival times. In stark contrast to the progress seen in other cancer types in recent decades, discoveries of new treatments in PDAC have been few and far between and there has been little improvement in overall survival (OS). The difficulty in treating this disease is multifactorial, contributed to by late presentation, difficult access to primary tumour sites, an 'immunologically cold' phenotype, and a strong tendency of recurrence likely driven by cancer stem cell (CSC) populations. Furthermore, apparently contrasting roles of tumour components (such as fibrotic stroma) and intracellular pathways (such as autophagy and TGFβ) have made it difficult to distinguish beneficial from detrimental drug targets. Despite this, progress has been made in the field, including the determination of mFOLFIRINOX as the standard-of-care adjuvant therapy and the discovery of KRASG12C mutant inhibitors. Moreover, new research, as outlined in this review, has highlighted promising new approaches including the targeting of the tumour microenvironment, enhancement of immunotherapies, epigenetic modulation, and destruction of CSCs.
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Affiliation(s)
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK;
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27
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KalantarMotamedi Y, Choi RJ, Koh SB, Bramhall JL, Fan TP, Bender A. Prediction and identification of synergistic compound combinations against pancreatic cancer cells. iScience 2021; 24:103080. [PMID: 34585118 PMCID: PMC8456050 DOI: 10.1016/j.isci.2021.103080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/28/2021] [Accepted: 08/31/2021] [Indexed: 11/30/2022] Open
Abstract
Resistance to current therapies is common for pancreatic cancer and hence novel treatment options are urgently needed. In this work, we developed and validated a computational method to select synergistic compound combinations based on transcriptomic profiles from both the disease and compound side, combined with a pathway scoring system, which was then validated prospectively by testing 30 compounds (and their combinations) on PANC-1 cells. Some compounds selected as single agents showed lower GI50 values than the standard of care, gemcitabine. Compounds suggested as combination agents with standard therapy gemcitabine based on the best performing scoring system showed on average 2.82-5.18 times higher synergies compared to compounds that were predicted to be active as single agents. Examples of highly synergistic in vitro validated compound pairs include gemcitabine combined with Entinostat, thioridazine, loperamide, scriptaid and Saracatinib. Hence, the computational approach presented here was able to identify synergistic compound combinations against pancreatic cancer cells.
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Affiliation(s)
- Yasaman KalantarMotamedi
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Ran Joo Choi
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Siang-Boon Koh
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
| | - Jo L. Bramhall
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
| | - Tai-Ping Fan
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK
| | - Andreas Bender
- Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
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28
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Liang Y, Yang L, Xie J. The Role of the Hedgehog Pathway in Chemoresistance of Gastrointestinal Cancers. Cells 2021; 10:cells10082030. [PMID: 34440799 PMCID: PMC8391142 DOI: 10.3390/cells10082030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/24/2021] [Accepted: 08/06/2021] [Indexed: 12/13/2022] Open
Abstract
The hedgehog pathway, which plays a significant role in embryonic development and stem cell regulation, is activated in gastrointestinal cancers. Chemotherapy is widely used in cancer treatment. However, chemoresistance becomes a substantial obstacle in cancer therapy. This review focuses on the recent advances in the hedgehog pathway's roles in drug resistance of gastrointestinal cancers and the novel drugs and strategies targeting hedgehog signaling.
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Affiliation(s)
- Yabing Liang
- Inner Mongolia Key Laboratory of Medical Cell Biology, Clinical Medical Research Center of the Affiliated Hospital, Inner Mongolia Medical University, Hohhot 010050, China;
| | - Ling Yang
- Inner Mongolia Key Laboratory of Medical Cell Biology, Clinical Medical Research Center of the Affiliated Hospital, Inner Mongolia Medical University, Hohhot 010050, China;
- Correspondence: (L.Y.); (J.X.)
| | - Jingwu Xie
- Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Correspondence: (L.Y.); (J.X.)
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29
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Walter K, Rodriguez-Aznar E, Ferreira MSV, Frappart PO, Dittrich T, Tiwary K, Meessen S, Lerma L, Daiss N, Schulte LA, Najafova Z, Arnold F, Usachov V, Azoitei N, Erkan M, Lechel A, Brümmendorf TH, Seufferlein T, Kleger A, Tabarés E, Günes C, Johnsen SA, Beier F, Sainz B, Hermann PC. Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells. Cancers (Basel) 2021; 13:cancers13133145. [PMID: 34201898 PMCID: PMC8268125 DOI: 10.3390/cancers13133145] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/14/2021] [Accepted: 06/18/2021] [Indexed: 12/12/2022] Open
Abstract
To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the "stemness" maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.
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Affiliation(s)
- Karolin Walter
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Eva Rodriguez-Aznar
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Monica S. Ventura Ferreira
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 52062 Aachen, Germany; (M.S.V.F.); (T.H.B.); (F.B.)
| | - Pierre-Olivier Frappart
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
- Institute of Toxicology, University Medical Centre of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Tabea Dittrich
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Kanishka Tiwary
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Sabine Meessen
- Department of Urology, Ulm University, 89081 Ulm, Germany; (S.M.); (C.G.)
| | - Laura Lerma
- Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain; (L.L.); (E.T.)
| | - Nora Daiss
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Lucas-Alexander Schulte
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Zeynab Najafova
- Department of Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany;
| | - Frank Arnold
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Valentyn Usachov
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Ninel Azoitei
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Mert Erkan
- Department of Surgery, Koç University School of Medicine, Istanbul 34450, Turkey;
- Research Center for Translational Medicine, Koç University, Istanbul 34450, Turkey
| | - Andre Lechel
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Tim H. Brümmendorf
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 52062 Aachen, Germany; (M.S.V.F.); (T.H.B.); (F.B.)
| | - Thomas Seufferlein
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Alexander Kleger
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
| | - Enrique Tabarés
- Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain; (L.L.); (E.T.)
| | - Cagatay Günes
- Department of Urology, Ulm University, 89081 Ulm, Germany; (S.M.); (C.G.)
| | - Steven A. Johnsen
- Gene Regulatory Mechanisms and Molecular Epigenetics Lab, Gastroenterology Research, Mayo Clinic, Rochester, MN 55905, USA;
| | - Fabian Beier
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital of the RWTH Aachen, 52062 Aachen, Germany; (M.S.V.F.); (T.H.B.); (F.B.)
| | - Bruno Sainz
- Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain;
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, 28049 Madrid, Spain
- Chronic Diseases and Cancer, Area 3—Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28049 Madrid, Spain
| | - Patrick C. Hermann
- Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany; (K.W.); (E.R.-A.); (P.-O.F.); (T.D.); (K.T.); (N.D.); (L.-A.S.); (F.A.); (V.U.); (N.A.); (A.L.); (T.S.); (A.K.)
- Correspondence: ; Tel.: +49-731-500-44736
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Zhang H, Steed A, Co M, Chen X. Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:684-709. [PMID: 34322664 PMCID: PMC8315560 DOI: 10.20517/cdr.2021.32] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The cancer stem cell (CSC) state and epithelial-mesenchymal transition (EMT) activation are tightly interconnected. Cancer cells that acquire the EMT/CSC phenotype are equipped with adaptive metabolic changes to maintain low reactive oxygen species levels and stemness, enhanced drug transporters, anti-apoptotic machinery and DNA repair system. Factors present in the tumor microenvironment such as hypoxia and the communication with non-cancer stromal cells also promote cancer cells to enter the EMT/CSC state and display related resistance. ATP, particularly the high levels of intratumoral extracellular ATP functioning through both signaling pathways and ATP internalization, induces and regulates EMT and CSC. The three of them work together to enhance drug resistance. New findings in each of these factors will help us explore deeper into mechanisms of drug resistance and suggest new resistance-associated markers and therapeutic targets.
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Affiliation(s)
- Haiyun Zhang
- Department of Biological Science, Ohio University, Athens, OH 45701, USA.,Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.,Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA
| | - Alexander Steed
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Milo Co
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Xiaozhuo Chen
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.,Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA.,Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.,Department of Biomedical Sciences, Ohio University, Athens, OH 45701, USA
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Zhang Z, Xu Y, Zhao C. Fzd7/Wnt7b signaling contributes to stemness and chemoresistance in pancreatic cancer. Cancer Med 2021; 10:3332-3345. [PMID: 33934523 PMCID: PMC8124113 DOI: 10.1002/cam4.3819] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/27/2021] [Accepted: 02/15/2021] [Indexed: 02/06/2023] Open
Abstract
Mining databases and data obtained from assays on human specimens had shown that Fzd7 is closely associated with Wnt7b, that Fzd7/Wnt7b expression is upregulated in pancreatic cancer tissues compared with normal tissues, and its expression is negatively correlated with survival. Fzd7/Wnt7b knockdown in Capan‐2 and Panc‐1 cells reduced the proliferative capacity of pancreatic cancer stem cells (PCSCs), reduced drug resistance, decreased the percentage of CD24+CD44+ subset of cells and the levels of ABCG2, inhibited cell‐sphere formation, and reduced gemcitabine (GEM) resistance. In contrast, Fzd7/Wnt7b overexpression increased the percentage of the CD24+CD44+ subset of cells, and increased the levels of ABCG2 detected in cell spheroids. The gem‐resistant cells exhibited higher levels of Fzd7/Wnt7b expression, an increased percentage of CD24+CD44+ cells, and higher levels of ABCG2 compared with the parental cells. Taken together, Fzd7/Wnt7b knockdown can reduce PDAC cell stemness and chemoresistance by reducing the percentage of CSCs. Mechanistically, Fzd7 binds with Wnt7b and modulates the levels of β‐catenin, and they may exert their role via modulation of the canonical Wnt pathway.
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Affiliation(s)
- Zhongbo Zhang
- Department of Pancreatic and Biliary Surgery, The First Hospital of China Medical University, Shenyang, P.R. China
| | - Yuanhong Xu
- Department of Pancreatic and Biliary Surgery, The First Hospital of China Medical University, Shenyang, P.R. China
| | - Chenghai Zhao
- Department of Pathophysiology, Basic Medical College, China Medical University, Shenyang, P.R. China
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Barman S, Fatima I, Singh AB, Dhawan P. Pancreatic Cancer and Therapy: Role and Regulation of Cancer Stem Cells. Int J Mol Sci 2021; 22:ijms22094765. [PMID: 33946266 PMCID: PMC8124621 DOI: 10.3390/ijms22094765] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 12/21/2022] Open
Abstract
Despite significant improvements in clinical management, pancreatic cancer (PC) remains one of the deadliest cancer types, as it is prone to late detection with extreme metastatic properties. The recent findings that pancreatic cancer stem cells (PaCSCs) contribute to the tumorigenesis, progression, and chemoresistance have offered significant insight into the cancer malignancy and development of precise therapies. However, the heterogeneity of cancer and signaling pathways that regulate PC have posed limitations in the effective targeting of the PaCSCs. In this regard, the role for K-RAS, TP53, Transforming Growth Factor-β, hedgehog, Wnt and Notch and other signaling pathways in PC progression is well documented. In this review, we discuss the role of PaCSCs, the underlying molecular and signaling pathways that help promote pancreatic cancer development and metastasis with a specific focus on the regulation of PaCSCs. We also discuss the therapeutic approaches that target different PaCSCs, intricate mechanisms, and therapeutic opportunities to eliminate heterogeneous PaCSCs populations in pancreatic cancer.
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Affiliation(s)
- Susmita Barman
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
| | - Iram Fatima
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
- Correspondence:
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Matsuzawa F, Kamachi H, Mizukami T, Einama T, Kawamata F, Fujii Y, Fukai M, Kobayashi N, Hatanaka Y, Taketomi A. Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells. BMC Cancer 2021; 21:200. [PMID: 33637083 PMCID: PMC7912898 DOI: 10.1186/s12885-020-07722-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. METHODS We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. RESULTS Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. CONCLUSIONS Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.
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Affiliation(s)
- Fumihiko Matsuzawa
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Hirofumi Kamachi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
| | - Tatsuzo Mizukami
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan
| | - Futoshi Kawamata
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yuki Fujii
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Nozomi Kobayashi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yutaka Hatanaka
- Research Division of Companion Diagnostics, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
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Healy FM, Prior IA, MacEwan DJ. The importance of Ras in drug resistance in cancer. Br J Pharmacol 2021; 179:2844-2867. [PMID: 33634485 DOI: 10.1111/bph.15420] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/10/2021] [Accepted: 02/21/2021] [Indexed: 12/19/2022] Open
Abstract
In this review, we analyse the impact of oncogenic Ras mutations in mediating cancer drug resistance and the progress made in the abrogation of this resistance, through pharmacological targeting. At a physiological level, Ras is implicated in many cellular proliferation and survival pathways. However, mutations within this small GTPase can be responsible for the initiation of cancer, therapeutic resistance and failure, and ultimately disease relapse. Often termed "undruggable," Ras is notoriously difficult to target directly, due to its structure and intrinsic activity. Thus, Ras-mediated drug resistance remains a considerable pharmacological problem. However, with advances in both analytical techniques and novel drug classes, the therapeutic landscape against Ras is changing. Allele-specific, direct Ras-targeting agents have reached clinical trials for the first time, indicating there may, at last, be hope of targeting such an elusive but significant protein for better more effective cancer therapy.
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Affiliation(s)
- Fiona M Healy
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK
| | - Ian A Prior
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK
| | - David J MacEwan
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK
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Courtois S, de Luxán-Delgado B, Penin-Peyta L, Royo-García A, Parejo-Alonso B, Jagust P, Alcalá S, Rubiolo JA, Sánchez L, Sainz B, Heeschen C, Sancho P. Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential. Cancers (Basel) 2021; 13:698. [PMID: 33572276 PMCID: PMC7914708 DOI: 10.3390/cancers13040698] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 01/31/2021] [Accepted: 02/05/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis depends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aim to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene DNM1L (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observe that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating the activation of the mitochondrial fission. Interestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133+ CSCs, due to the accumulation of dysfunctional mitochondria and the subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity, and invasiveness and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potential.
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Affiliation(s)
- Sarah Courtois
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragon, 50009 Zaragoza, Spain; (S.C.); (A.R.-G.); (B.P.-A.)
| | - Beatriz de Luxán-Delgado
- Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; (B.d.L.-D.); (L.P.-P.); (P.J.)
| | - Laure Penin-Peyta
- Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; (B.d.L.-D.); (L.P.-P.); (P.J.)
| | - Alba Royo-García
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragon, 50009 Zaragoza, Spain; (S.C.); (A.R.-G.); (B.P.-A.)
| | - Beatriz Parejo-Alonso
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragon, 50009 Zaragoza, Spain; (S.C.); (A.R.-G.); (B.P.-A.)
| | - Petra Jagust
- Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; (B.d.L.-D.); (L.P.-P.); (P.J.)
| | - Sonia Alcalá
- Department of Biochemistry, School of Medicine, Instituto de Investigaciones Biomédicas (IIBm) “Alberto Sols” CSIC-UAM, Autónoma University of Madrid (UAM), 28029 Madrid, Spain; (S.A.); (B.S.J.)
- Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain
| | - Juan A. Rubiolo
- Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, Universidad de Santiago de Compostela, 27002 Lugo, Spain; (J.A.R.); (L.S.)
| | - Laura Sánchez
- Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, Universidad de Santiago de Compostela, 27002 Lugo, Spain; (J.A.R.); (L.S.)
| | - Bruno Sainz
- Department of Biochemistry, School of Medicine, Instituto de Investigaciones Biomédicas (IIBm) “Alberto Sols” CSIC-UAM, Autónoma University of Madrid (UAM), 28029 Madrid, Spain; (S.A.); (B.S.J.)
- Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain
| | - Christopher Heeschen
- Center for Single-Cell Omics, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Patricia Sancho
- Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragon, 50009 Zaragoza, Spain; (S.C.); (A.R.-G.); (B.P.-A.)
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Cioffi M, Heeschen C. Immuno-targeting of pancreatic cancer stem cells: A new therapeutic strategy against a devastating disease? Oncoimmunology 2021; 1:560-562. [PMID: 22754787 PMCID: PMC3382890 DOI: 10.4161/onci.19368] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer is a highly aggressive and deadly disease harboring a distinct population of cancer stem cells (CSC) that is not affected by conventional therapies. A new therapeutic approach using the EpCAM/CD3-bispecific antibody MT110 is capable of activating and redirecting cytotoxic T cells to eliminate primary human pancreatic cancer stem cells, which resulted in long-term survival of preclinical xenografts models.
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Affiliation(s)
- Michele Cioffi
- Stem Cells & Cancer Group; Clinical Research Programme; Spanish National Cancer Research Centre (CNIO); Madrid, Spain
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Zhang C, Zhao Y, Yang Y, Zhong C, Ji T, Duan J, Wang Y. RNAi mediated silencing of Nanog expression suppresses the growth of human colorectal cancer stem cells. Biochem Biophys Res Commun 2021; 534:254-260. [PMID: 33288197 DOI: 10.1016/j.bbrc.2020.11.101] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 11/25/2020] [Indexed: 01/02/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world known for its poor recurrence-free prognosis. Previous studies have shown that it is closely linked with cancer stem cells (CSCs), which have self-renewal potential and the capacity to differentiate into diverse populations. Nanog is an important transcription factor that functions to maintain the self-renewal and proliferation of embryonic stem cells; however, many recent studies have shown that Nanog is also highly expressed in many cancer stem cells. To investigate whether Nanog plays a crucial role in maintaining the stemness of colorectal CSCs, RNA interference was used to downregulate Nanog expression in the CRC stem cell line, EpCAM+CD44+HCT-116 cells (CCSCs). We examined the anti-tumor function of Nanog in vitro and in vivo, using small interfering RNA. Our results revealed that the Nanog mRNA expression level in CCSCs was higher than that in HCT-116 cells. We found that the depletion of Nanog inhibited proliferation and promoted apoptosis in CCSCs. In addition, the invasive ability of CCSCs was markedly restricted when Nanog was silenced by small interfering RNA. Furthermore, we found that the silencing of Nanog decreased tumor size and weight and improved the survival rate of tumor-bearing mice. In conclusion, these findings collectively demonstrate that Nanog, which is highly expressed in CRC stem cells, is a key factor in the development of tumor growth, and it may serve as a potential marker of prognosis and a novel and effective therapeutic target for the treatment of CRC.
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Affiliation(s)
- Chen Zhang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China; Institute of Oceanography, Minjiang University, Fuzhou, Fujian, 350108, China
| | - Yuanyuan Zhao
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Yongjing Yang
- Department of Radiation Oncology, Cancer Hospital of Jilin Province, Changchun, 130012, China
| | - Chunlian Zhong
- Institute of Oceanography, Minjiang University, Fuzhou, Fujian, 350108, China
| | - Tianju Ji
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Jinyue Duan
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China.
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Li K, Zhang Z, Mei Y, Yang Q, Qiao S, Ni C, Yao Y, Li X, Li M, Wei D, Fu W, Guo X, Huang X, Yang H. Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-κB inhibition. Theranostics 2021; 11:3196-3212. [PMID: 33537082 PMCID: PMC7847690 DOI: 10.7150/thno.51976] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
Resistance to chemotherapy is a long-standing problem in the management of cancer, and cancer stem cells are regarded as the main source of this resistance. This study aimed to investigate metallothionein (MT)-1G involvement in the regulation of cancer stemness and provide a strategy to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). Methods: MT1G was identified as a critical factor related with gemcitabine resistance in PDAC cells by mRNA microarray. Its effects on PDAC stemness were evaluated through sphere formation and tumorigenicity. LC-MS/MS analysis of conditional medium revealed that activin A, a NF-κB target, was a major protein secreted from gemcitabine resistant PDAC cells. Both loss-of-function and gain-of-function approaches were used to validate that MT1G inhibited NF-κB-activin A pathway. Orthotopic pancreatic tumor model was employed to explore the effects on gemcitabine resistance with recombinant follistatin to block activin A. Results: Downregulation of MT1G due to hypermethylation of its promoter is related with pancreatic cancer stemness. Secretome analysis revealed that activin A, a NF-κB target, was highly secreted by drug resistant cells. It promotes pancreatic cancer stemness in Smad4-dependent or independent manners. Mechanistically, MT1G negatively regulates NF-κB signaling and promotes the degradation of NF-κB p65 subunit by enhancing the expression of E3 ligase TRAF7. Blockade of activin A signaling with follistatin could overcome gemcitabine resistance. Conclusions: MT1G suppresses PDAC stemness by limiting activin A secretion via NF-κB inhibition. The blockade of the activin A signaling with follistatin may provide a promising therapeutic strategy for overcoming gemcitabine resistance in PDAC.
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Affiliation(s)
- Kai Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Zhicheng Zhang
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yu Mei
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Qingzhu Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Shupei Qiao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Cheng Ni
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Yao Yao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Xinyuan Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Mengmeng Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Dongdong Wei
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Wangjun Fu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Xuefei Guo
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Xuemei Huang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
| | - Huanjie Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China
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Forciniti S, Dalla Pozza E, Greco MR, Amaral Carvalho TM, Rolando B, Ambrosini G, Carmona-Carmona CA, Pacchiana R, Di Molfetta D, Donadelli M, Arpicco S, Palmieri M, Reshkin SJ, Dando I, Cardone RA. Extracellular Matrix Composition Modulates the Responsiveness of Differentiated and Stem Pancreatic Cancer Cells to Lipophilic Derivate of Gemcitabine. Int J Mol Sci 2020; 22:ijms22010029. [PMID: 33375106 PMCID: PMC7792955 DOI: 10.3390/ijms22010029] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/15/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Gemcitabine (GEM) is used as the gold standard drug in PDAC treatment. However, due to its poor efficacy, it remains urgent to identify novel strategies to overcome resistance issues. In this context, an intense stroma reaction and the presence of cancer stem cells (CSCs) have been shown to influence PDAC aggressiveness, metastatic potential, and chemoresistance. METHODS We used three-dimensional (3D) organotypic cultures grown on an extracellular matrix composed of Matrigel or collagen I to test the effect of the new potential therapeutic prodrug 4-(N)-stearoyl-GEM, called C18GEM. We analyzed C18GEM cytotoxic activity, intracellular uptake, apoptosis, necrosis, and autophagy induction in both Panc1 cell line (P) and their derived CSCs. RESULTS PDAC CSCs show higher sensitivity to C18GEM treatment when cultured in both two-dimensional (2D) and 3D conditions, especially on collagen I, in comparison to GEM. The intracellular uptake mechanisms of C18GEM are mainly due to membrane nucleoside transporters' expression and fatty acid translocase CD36 in Panc1 P cells and to clathrin-mediated endocytosis and CD36 in Panc1 CSCs. Furthermore, C18GEM induces an increase in cell death compared to GEM in both cell lines grown on 2D and 3D cultures. Finally, C18GEM stimulated protective autophagy in Panc1 P and CSCs cultured on 3D conditions. CONCLUSION We propose C18GEM together with autophagy inhibitors as a valid alternative therapeutic approach in PDAC treatment.
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Affiliation(s)
- Stefania Forciniti
- Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy; (S.F.); (E.D.P.); (G.A.); (C.A.C.-C.); (R.P.); (M.D.); (M.P.)
- Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology-Laboratory of Molecular Gastroenterology, 20089 Rozzano, Milan, Italy
| | - Elisa Dalla Pozza
- Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy; (S.F.); (E.D.P.); (G.A.); (C.A.C.-C.); (R.P.); (M.D.); (M.P.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (M.R.G.); (T.M.A.C.); (D.D.M.); (S.J.R.); (R.A.C.)
- Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Tiago Miguel Amaral Carvalho
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (M.R.G.); (T.M.A.C.); (D.D.M.); (S.J.R.); (R.A.C.)
| | - Barbara Rolando
- Department of Drug Science and Technology, University of Torino, 10124 Torino, Italy; (B.R.); (S.A.)
| | - Giulia Ambrosini
- Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy; (S.F.); (E.D.P.); (G.A.); (C.A.C.-C.); (R.P.); (M.D.); (M.P.)
| | - Cristian Andres Carmona-Carmona
- Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy; (S.F.); (E.D.P.); (G.A.); (C.A.C.-C.); (R.P.); (M.D.); (M.P.)
| | - Raffaella Pacchiana
- Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy; (S.F.); (E.D.P.); (G.A.); (C.A.C.-C.); (R.P.); (M.D.); (M.P.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (M.R.G.); (T.M.A.C.); (D.D.M.); (S.J.R.); (R.A.C.)
| | - Massimo Donadelli
- Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy; (S.F.); (E.D.P.); (G.A.); (C.A.C.-C.); (R.P.); (M.D.); (M.P.)
| | - Silvia Arpicco
- Department of Drug Science and Technology, University of Torino, 10124 Torino, Italy; (B.R.); (S.A.)
| | - Marta Palmieri
- Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy; (S.F.); (E.D.P.); (G.A.); (C.A.C.-C.); (R.P.); (M.D.); (M.P.)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (M.R.G.); (T.M.A.C.); (D.D.M.); (S.J.R.); (R.A.C.)
| | - Ilaria Dando
- Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy; (S.F.); (E.D.P.); (G.A.); (C.A.C.-C.); (R.P.); (M.D.); (M.P.)
- Correspondence:
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (M.R.G.); (T.M.A.C.); (D.D.M.); (S.J.R.); (R.A.C.)
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Stoica AF, Chang CH, Pauklin S. Molecular Therapeutics of Pancreatic Ductal Adenocarcinoma: Targeted Pathways and the Role of Cancer Stem Cells. Trends Pharmacol Sci 2020; 41:977-993. [PMID: 33092892 DOI: 10.1016/j.tips.2020.09.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/01/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late detection and highly metastatic characteristics. PDAC cells vary in their tumorigenic capabilities with the presence of a subset of PDAC cells known as pancreatic cancer stem cells (CSCs), which are more resistant to currently used therapeutics. Here, we describe the role of CSCs and tumour stroma in developing therapeutic strategies for PDAC and suggest that developmental plasticity could be considered a hallmark of cancers. We provide an overview of the molecular targets in PDAC treatments, including targeted therapies of cellular processes such as proliferation, evasion of growth suppressors, activating metastasis, and metabolic effects. Since PDAC is an inflammation-driven cancer, we also revisit therapeutic strategies targeting inflammation and immunotherapy. Lastly, we suggest that targeting epigenetic mechanisms opens therapeutic routes for heterogeneous cancer cell populations, including CSCs.
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Affiliation(s)
- Andrei-Florian Stoica
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK
| | - Chao-Hui Chang
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK.
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41
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Jagust P, Alcalá S, Jr BS, Heeschen C, Sancho P. Glutathione metabolism is essential for self-renewal and chemoresistance of pancreatic cancer stem cells. World J Stem Cells 2020; 12:1410-1428. [PMID: 33312407 PMCID: PMC7705467 DOI: 10.4252/wjsc.v12.i11.1410] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/19/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cellular metabolism regulates stemness in health and disease. A reduced redox state is essential for self-renewal of normal and cancer stem cells (CSCs). However, while stem cells rely on glycolysis, different CSCs, including pancreatic CSCs, favor mitochondrial metabolism as their dominant energy-producing pathway. This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species (ROS) and maintain stemness in oxidative CSCs. Since glutathione metabolism is critical for normal stem cell function and CSCs from breast, liver and gastric cancer show increased glutathione content, we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.
AIM To investigate the role of glutathione metabolism in pancreatic CSCs.
METHODS Primary pancreatic cancer cells of patient-derived xenografts (PDXs) were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness. Real-time polymerase chain reaction (PCR) was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres, as well as the expression of pluripotency-related genes following treatment. Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2. The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry. Pharmacological inhibitors of glutathione synthesis and recycling [buthionine-sulfoximine (BSO) and 6-Aminonicotinamide (6-AN), respectively] were used to investigate the impact of glutathione depletion on CSC-enriched cultures. Staining with propidium iodide (cell cycle), Annexin-V (apoptosis) and CD133 (CSC content) were determined by flow cytometry. Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.
RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed up-regulation of genes involved in the KEGG (Kyoto Encyclopedia of Genes and Genomes) Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts. Consistently, in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG, KLF4, SOX2 and OCT4 expression (P < 10-5). Moreover, 3 of the upregulated genes (MGST1, GPX8, GCCT) were associated with reduced disease-free survival in patients [Hazard ratio (HR) 2.2-2.5; P = 0.03-0.0054], suggesting a critical role for this pathway in pancreatic cancer progression. CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes, as well as enhanced glutathione content in its reduced form (GSH). Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres, and diminished the expression of stemness genes. Moreover, treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133. GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r = 0.96, P = 5.8 × 1011). Additionally, CD133+ cells accumulated GSH in response to gemcitabine, which was abrogated by BSO treatment (P < 0.05). Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+ cells to levels comparable to CD133- cells and significantly diminished self-renewal (P < 0.05), suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.
CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism. Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.
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Affiliation(s)
- Petra Jagust
- Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
| | - Sonia Alcalá
- Department of Biochemistry, Autónoma University of Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid 28029, Spain
| | - Bruno Sainz Jr
- Department of Biochemistry, Autónoma University of Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid 28029, Spain
| | - Christopher Heeschen
- Center for Single-Cell Omics & Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Patricia Sancho
- Hospital Universitario Miguel Servet, IIS Aragon, Zaragoza 50009, Spain
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Chen S, Huang L, Li G, Qiu F, Wang Y, Yang C, Pan J, Wu Z, Chen J, Tian Y. LncRNA STXBP5-AS1 suppresses stem cell-like properties of pancreatic cancer by epigenetically inhibiting neighboring androglobin gene expression. Clin Epigenetics 2020; 12:168. [PMID: 33160411 PMCID: PMC7648265 DOI: 10.1186/s13148-020-00961-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023] Open
Abstract
Previous studies suggest the tumor suppressor role of long non-coding RNA (lncRNA) STXBP5-AS1 in cervical and gastric cancer, but its expression pattern and functional mechanism are still elusive in pancreatic cancer (PC). Relative expression of STXBP5-AS1 in PC both in vivo and in vitro was analyzed by real-time PCR. IC50 of Gemcitabine was determined by the MTT assay. Cell proliferation in response to drug treatment was investigated by colony formation assay. Cell apoptosis was measured by both caspase-3 activity and Annexin V/PI staining. Cell invasion capacity was scored by the transwell assay in vitro, and lung metastasis was examined with the tail vein injection assay. Cell stemness was determined in vitro by sphere formation and marker profiling, respectively, and in vivo by limited dilution of xenograft tumor incidence. Subcellular localization of STXBP5-AS1 was analyzed with fractionation PCR. Association between STXBP5-AS1 and EZH2 was investigated by RNA-immunoprecipitation. The binding of EZH2 on ADGB promoter was analyzed by chromatin immunoprecipitation. The methylation was quantified by bisulfite sequencing. We showed downregulation of STXBP5-AS1 in PC associated with poor prognosis. Ectopic STXBP5-AS1 inhibited chemoresistance and metastasis of PC cells. In addition, STXBP5-AS1 compromised stemness of PC cells. Mechanistically, STXBP5-AS1 potently recruited EZH2 and epigenetically regulated neighboring ADGB transcription, which predominantly mediated the inhibitory effects of STXBP5-AS1 on stem cell-like properties of PC cells. Our study highlights the importance of the STXBP5-EZH2-ADGB axis in chemoresistance and stem cell-like properties of PC.
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Affiliation(s)
- Shi Chen
- Department of Hepato-Biliary-Pancreatic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, No. 134 East Street, Fuzhou, 350001, Fujian, China.
| | - Long Huang
- Department of Hepato-Biliary-Pancreatic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, No. 134 East Street, Fuzhou, 350001, Fujian, China
| | - Ge Li
- Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, 350001, Fujian, China
| | - Funan Qiu
- Department of Hepato-Biliary-Pancreatic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, No. 134 East Street, Fuzhou, 350001, Fujian, China
| | - Yaodong Wang
- Department of Hepato-Biliary-Pancreatic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, No. 134 East Street, Fuzhou, 350001, Fujian, China
| | - Can Yang
- Department of Hepato-Biliary-Pancreatic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, No. 134 East Street, Fuzhou, 350001, Fujian, China
| | - Jingjing Pan
- Department of Hepato-Biliary-Pancreatic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, No. 134 East Street, Fuzhou, 350001, Fujian, China
| | - Zhangwei Wu
- Department of Hepato-Biliary-Pancreatic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, No. 134 East Street, Fuzhou, 350001, Fujian, China
| | - Jiangzhi Chen
- Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, 350001, Fujian, China.
| | - Yifeng Tian
- Department of Hepato-Biliary-Pancreatic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, No. 134 East Street, Fuzhou, 350001, Fujian, China.
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Long-Term Helicobacter pylori Infection Switches Gastric Epithelium Reprogramming Towards Cancer Stem Cell-Related Differentiation Program in Hp-Activated Gastric Fibroblast-TGFβ Dependent Manner. Microorganisms 2020; 8:microorganisms8101519. [PMID: 33023180 PMCID: PMC7599721 DOI: 10.3390/microorganisms8101519] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori (Hp)-induced inflammatory reaction leads to a persistent disturbance of gastric mucosa and chronic gastritis evidenced by deregulation of tissue self-renewal and local fibrosis with the crucial role of epithelial–mesenchymal transition (EMT) in this process. As we reported before, Hp activated gastric fibroblasts into cells possessing cancer-associated fibroblast properties (CAFs), which secreted factors responsible for EMT process initiation in normal gastric epithelial RGM1 cells. Here, we showed that the long-term incubation of RGM1 cells in the presence of Hp-activated gastric fibroblast (Hp-AGF) secretome induced their shift towards plastic LGR5+/Oct4high/Sox-2high/c-Mychigh/Klf4low phenotype (l.t.EMT+RGM1 cells), while Hp-non-infected gastric fibroblast (GF) secretome prompted a permanent epithelial–myofibroblast transition (EMyoT) of RGM1 cells favoring LGR−/Oct4high/Sox2low/c-Myclow/Klf4high phenotype (l.t.EMT−RGM1 cells). TGFβ1 rich secretome from Hp-reprogrammed fibroblasts prompted phenotypic plasticity and EMT of gastric epithelium, inducing pro-neoplastic expansion of post-EMT cells in the presence of low TGFβR1 and TGFβR2 activity. In turn, TGFβR1 activity along with GF-induced TGFβR2 activation in l.t.EMT−RGM1 cells prompted their stromal phenotype. Collectively, our data show that infected and non-infected gastric fibroblast secretome induces alternative differentiation programs in gastric epithelium at least partially dependent on TGFβ signaling. Hp infection-activated fibroblasts can switch gastric epithelium microevolution towards cancer stem cell-related differentiation program that can potentially initiate gastric neoplasm.
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Márquez-González RM, Saucedo-Sariñana AM, Barros-Núñez P, Gallegos-Arreola MP, Pineda-Razo TD, Marin-Contreras ME, Flores-Martínez SE, Sánchez-Corona J, Rosales-Reynoso MA. CD44 Genotypes Are Associated with Susceptibility and Tumor Characteristics in Colorectal Cancer Patients. TOHOKU J EXP MED 2020; 250:109-119. [PMID: 32115493 DOI: 10.1620/tjem.250.109] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Colorectal cancer is the third cause of cancer and the second leading cause of death worldwide. The CD44 gene plays a key role in malignant processes, including growth, survival, epithelial to mesenchymal transition and metastasis. It is also known that some variants as rs187116 (c.67+4883G>A) and rs7116432 (c.2024+779A>G) can modulate the function of the CD44 gene and malignant transformation in several neoplasms. This study aims to explore, for the first time, the association of the CD44 rs187116 and rs7116432 variants in patients with colorectal cancer. Genomic DNA from 250 patients and 250 healthy blood donors were analyzed. The identification of variants was made by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) test and multivariate analysis. Individuals carrying the G/A and A/A genotypes for the rs187116 polymorphism showed an increased risk for colorectal cancer (OR = 3.11, 95% CI: 1.87-5.16, P = 0.001 and OR = 3.59, 95% CI: 2.06-6.25, P = 0.001, respectively). After adjusting for age and gender, these same genotypes and the G/G genotype of the rs7116432 polymorphism were associated with TNM stage and tumor location in the colon. Moreover, the A-G (rs187116 and rs7116432) haplotype was associated with increased risk; while, the haplotype G-A (rs187116 and rs7116432) was related with decreased risk. In conclusion, our results suggest that the here analyzed CD44 variants are involved with risk, TNM stage and tumor location in colorectal cancer.
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Affiliation(s)
- Rosa María Márquez-González
- Molecular Medicine Division, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)
| | | | - Patricio Barros-Núñez
- Research Unit of Metabolic Diseases, Pediatric UMAE, Instituto Mexicano del Seguro Social (IMSS)
| | | | | | | | | | - José Sánchez-Corona
- Molecular Medicine Division, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)
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Carr RM, Duma N, McCleary-Wheeler AL, Almada LL, Marks DL, Graham RP, Smyrk TC, Lowe V, Borad MJ, Kim G, Johnson GB, Allred JB, Yin J, Lim VS, Bekaii-Saab T, Ma WW, Erlichman C, Adjei AA, Fernandez-Zapico ME. Targeting of the Hedgehog/GLI and mTOR pathways in advanced pancreatic cancer, a phase 1 trial of Vismodegib and Sirolimus combination. Pancreatology 2020; 20:1115-1122. [PMID: 32778368 DOI: 10.1016/j.pan.2020.06.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/19/2020] [Accepted: 06/20/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND/OBJECTIVES Preclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy. METHODS Cohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle. RESULTS Nine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3-4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected. CONCLUSIONS The combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations.
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Affiliation(s)
- Ryan M Carr
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA; Department of Medical Oncology, Department of Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55902, USA
| | - Narjust Duma
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Angela L McCleary-Wheeler
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Luciana L Almada
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - David L Marks
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Rondell P Graham
- Department of Laboratory Medicine Pathology, Mayo Clinic, Rochester, MN, USA
| | - Thomas C Smyrk
- Department of Laboratory Medicine Pathology, Mayo Clinic, Rochester, MN, USA
| | - Val Lowe
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Mitesh J Borad
- Division of Hematology-Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - George Kim
- Division of Hematology-Oncology, The George Washington University, Washington, DC, USA
| | | | - Jacob B Allred
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Jun Yin
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Vun-Sin Lim
- Department of Medical Oncology, Department of Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55902, USA
| | - Tanios Bekaii-Saab
- Division of Hematology-Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Wen We Ma
- Department of Medical Oncology, Department of Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55902, USA
| | - Charles Erlichman
- Department of Medical Oncology, Department of Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55902, USA
| | - Alex A Adjei
- Department of Medical Oncology, Department of Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55902, USA.
| | - Martin E Fernandez-Zapico
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA; Department of Medical Oncology, Department of Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55902, USA.
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Zhang X, Wang F, Zeng Y, Zhu X, Peng L, Zhang L, Gu J, Han H, Yi X, Shi J. Salicylate sensitizes oral squamous cell carcinoma to chemotherapy through targeting mTOR pathway. Oral Dis 2020; 26:1131-1140. [PMID: 32267053 DOI: 10.1111/odi.13345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/28/2020] [Accepted: 03/03/2020] [Indexed: 11/30/2022]
Abstract
Oral squamous cell carcinoma (OSCC) is an extremely aggressive neoplasm, which is usually diagnosed in the advanced stage of the disease. Extensive studies have shown a link between chronic inflammation and various types of cancer, including OSCC. Salicylate is a biotransformation product of aspirin, with similar anti-inflammatory ability to aspirin but lacks aspirin's inhibitory effect on the isolated cyclooxygenase activity. Our study indicates that salicylate sensitizes OSCC to anti-cancer drugs, but the mechanisms of its action are unclear. Here, OSCC cells were used to evaluate the cytotoxicity of salicylate alone or in combination with cisplatin (CDDP). RPPA proteomic array and Western blotting were employed to determine the signaling pathways affected by salicylate. Salicylate decreased cell survival rate and induced cell apoptosis in OSCC cells but not human normal oral mucosal epithelial cells (hTERT-OME). The use of sodium salicylate (SS) dramatically sensitized OSCC cells to CDDP. RPPA array showed that SS reduced many oncogenes such as PI3K/mTOR signaling and cancer stem cell (CSC)-related genes versus control. Western and transcriptional analyses substantiated that salicylate down-regulated these CSC-associated genes and the mTOR pathway dose dependently. Salicylate preferentially repressed the ability of sorted ALDH1+ cells to form tumor spheres. Finally, salicylate suppressed tumor growth in vivo, and the combination of salicylate and CDDP further synergistically reduced the growth of tumors. Salicylate hinders OSCC cell growth and sensitizes OSCC cells to CDDP through targeting CSCs and the mTOR signaling pathway. We propose that salicylate is beneficial for OSCC patients, and salicylate may be combined with chemotherapies to effectively treat OSCC patients.
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Affiliation(s)
- Xu Zhang
- Department of Stomatology, Wuchang Hospital, Wuhan City, China
| | - Fei Wang
- Department of Neurosurgery, Tongji Hospital, Tongji University, Shanghai, China
| | - Yu Zeng
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Xuyou Zhu
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Lin Peng
- Department of Dermatology, Tongji Hospital, Tongji University, Shanghai, China
| | - Long Zhang
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Jun Gu
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Hongxiu Han
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Xianghua Yi
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
| | - Juanhong Shi
- Department of Pathology, Tongji Hospital, Tongji University, Shanghai, China
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Cancer Stem Cells: Acquisition, Characteristics, Therapeutic Implications, Targeting Strategies and Future Prospects. Stem Cell Rev Rep 2020; 15:331-355. [PMID: 30993589 DOI: 10.1007/s12015-019-09887-2] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Since last two decades, the major cancer research has focused on understanding the characteristic properties and mechanism of formation of Cancer stem cells (CSCs), due to their ability to initiate tumor growth, self-renewal property and multi-drug resistance. The discovery of the mechanism of acquisition of stem-like properties by carcinoma cells via epithelial-mesenchymal transition (EMT) has paved a way towards a deeper understanding of CSCs and presented a possible avenue for the development of therapeutic strategies. In spite of years of research, various challenges, such as identification of CSC subpopulation, lack of appropriate experimental models, targeting cancer cells and CSCs specifically without harming normal cells, are being faced while dealing with CSCs. Here, we discuss the biology and characteristics of CSCs, mode of acquisition of stemness (via EMT) and development of multi-drug resistance, the role of tumor niche, the process of dissemination and metastasis, therapeutic implications of CSCs and necessity of targeting them. We emphasise various strategies being developed to specifically target CSCs, including those targeting biomarkers, key pathways and microenvironment. Finally, we focus on the challenges that need to be subdued and propose the aspects that need to be addressed in future studies in order to broaden the understanding of CSCs and develop novel strategies to eradicate them in clinical applications. Graphical Abstract Cancer Stem Cells(CSCs) have gained much attention in the last few decades due to their ability to initiate tumor growth and, self-renewal property and multi-drug resistance. Here, we represent the CSC model of cancer, Characteristics of CSCs, acquisition of stemness and metastatic dissemination of cancer, Therapeutic implications of CSCs and Various strategies being employed to target and eradicate CSCs.
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Mcgrath NA, Fu J, Gu SZ, Xie C. Targeting cancer stem cells in cholangiocarcinoma (Review). Int J Oncol 2020; 57:397-408. [PMID: 32468022 PMCID: PMC7307587 DOI: 10.3892/ijo.2020.5074] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023] Open
Abstract
The incidence of cholangiocarcinoma has been increasing steadily over the past 50 years, but the survival rates remained low due to the disease being highly resistant to non-surgical treatment interventions. Cancer stem cell markers are expressed in cholangiocarcinoma, suggesting that they serve a significant role in the physiology of the disease. Cancer stem cells are frequently implicated in tumor relapse and acquired resistance to a number of therapeutic strategies, including chemotherapy, radiation and immune checkpoint inhibitors. Novel targeted therapies to eradicate cancer stem cells may assist in overcoming treatment resistance in cholangiocarcinoma and reduce the rates of relapse and recurrence. Several signaling pathways have been previously documented to regulate the development and survival of cancer stem cells, including Notch, janus kinase/STAT, Hippo/yes-associated protein 1 (YAP1), Wnt and Hedgehog signaling. Although pharmacological agents have been developed to target these pathways, only modest effects were reported in clinical trials. The Hippo/YAP1 signaling pathway has come to the forefront in the field of cancer stem cell research due to its reported involvement in epithelium-mesenchymal transition, cell adhesion, organogenesis and tumorigenesis. In the present article, recent findings in terms of cancer stem cell research in cholangiocarcinoma were reviewed, where the potential therapeutic targeting of cancer stem cells in this disease was discussed.
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Affiliation(s)
- Nicole A Mcgrath
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA
| | - Jianyang Fu
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA
| | - Sophie Z Gu
- Johns Hopkins University School of Medicine, Baltimore, MD 20215, USA
| | - Changqing Xie
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA
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Wang W, Zheng S, He H, Ge H, Saeed BR. N,N-diethylaminobenzaldehyde targets aldehyde dehydrogenase to eradicate human pancreatic cancer cells. Exp Ther Med 2020; 20:662-670. [PMID: 32550888 DOI: 10.3892/etm.2020.8691] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 03/10/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is a common cause of worldwide cancer-related mortality with a poor 5-year survival rate. Aldehyde dehydrogenase (ALDH) activity is a possible marker for malignant stem cells in solid organ systems, including the pancreas, and N,N-diethylaminobenzaldehyde (DEAB) is able to inhibit ALDH activity. In the present study, the role of DEAB in the treatment of pancreatic cancer cells and the potential underlying mechanisms were investigated. The ALDH activities of pancreatic cancer cell lines treated with or without DEAB were analyzed by an ALDEFLUOR™ assay. The Cell Counting Kit-8 and colony formation assays, and cell cycle analysis were used to evaluate the viability, colony-forming ability and cell quiescence of cell lines under DEAB treatment, respectively. DEAB and/or gemcitabine-induced cell apoptosis was assessed by flow cytometry. DEAB reduced ALDH activity and inhibited the proliferation, colony-forming ability and cell quiescence of pancreatic cancer cell lines. Compared with respective controls, DEAB alone and the combination of gemcitabine and DEAB significantly decreased cell viability and increased cell apoptosis. Moreover, reverse transcription-PCR and western blotting were used to measure the expressions of B cell lymphoma 2 (Bcl2) associated X protein (Bax) and Bcl2 mRNA and protein. The anti-cancer effect of DEAB was associated with upregulation of Bax expression. Therefore, targeting ALDH with DEAB may be a potential therapeutic choice for pancreatic cancer, demonstrating a synergic effect with gemcitabine.
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Affiliation(s)
- Wenwen Wang
- Department of Oncology, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214000, P.R. China
| | - Shiya Zheng
- Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Haiju He
- Department of Medicine V, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Hao Ge
- Department of Oncology, Liyang People's Hospital, Liyang, Jiangsu 213300, P.R. China
| | - Borhan R Saeed
- Department of Medicine V, University of Heidelberg, D-69120 Heidelberg, Germany
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Moore KM, Desai A, Delgado BDL, Trabulo SMD, Reader C, Brown NF, Murray ER, Brentnall A, Howard P, Masterson L, Zammarchi F, Hartley JA, van Berkel PH, Marshall JF. Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus. Theranostics 2020; 10:2930-2942. [PMID: 32194845 PMCID: PMC7053198 DOI: 10.7150/thno.38702] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022] Open
Abstract
Goals of investigation: The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% for decades because no effective therapies have been identified. Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target. Thus, we attempted to develop an αvβ6-specific peptide-drug conjugate (PDC) for therapy of PDAC. Methodology: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an αvβ6-specific 20mer peptide from the VP1 coat protein of foot-and-mouth-disease virus (FMDV) (forming conjugate SG3299) or to a non-targeting peptide (forming conjugate SG3511). PDCs were tested for specificity and toxicity on αvβ6-negative versus-positive PDAC cells, patient-derived cell lines from tumor xenografts, and on two different in vivo models of PDAC. Immunohistochemical analyses were performed to establish therapeutic mechanism. Results: The αvβ6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for αvβ6-expressing versus αvβ6-negative PDAC cell lines in vitro, and achieved significantly higher toxicity at equal dose than the non-targeted PDC SG3511 (up to 15-fold better). Moreover, SG3299 eliminated established (100mm3) Capan-1 PDAC human xenografts, extending the lifespan of mice significantly (P=0.005). Immunohistochemistry revealed SG3299 induced DNA damage and apoptosis (increased γH2AX and cleaved caspase 3, respectively) associated with significant reductions in proliferation (Ki67), β6 expression and PDAC tumour growth. Conclusions: The FMDV-peptide drug conjugate SG3299 showed αvβ6-selectivity in vitro and in vivo and can specifically eliminate αvβ6-positive cancers, providing a promising new molecular- specific therapy for pancreatic cancer.
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Affiliation(s)
- Kate M. Moore
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Ami Desai
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Bea de Luxán Delgado
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Sara Maria David Trabulo
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Claire Reader
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Nicholas F. Brown
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Elizabeth R. Murray
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Adam Brentnall
- Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventative Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Philip Howard
- Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK
| | - Luke Masterson
- Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, UK
| | - Francesca Zammarchi
- ADC Therapeutics (UK) Ltd, QMB Innovation Centre, 42 New Road, London E1 2AX, UK
| | - John A. Hartley
- Cancer Research UK Drug-DNA Interactions Research Group, University College London Cancer Institute, 72 Huntley Street, London WC1E 6BT, U.K
| | | | - John F. Marshall
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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