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Espinosa-Bustos C, Bertrand J, Villegas-Menares A, Guerrero S, Di Marcotullio L, Navacci S, Schulte G, Kozielewicz P, Bloch N, Villela V, Paulino M, Kogan MJ, Cantero J, Salas CO. New Smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer. Bioorg Chem 2024; 151:107681. [PMID: 39106711 DOI: 10.1016/j.bioorg.2024.107681] [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: 03/28/2024] [Revised: 06/27/2024] [Accepted: 07/27/2024] [Indexed: 08/09/2024]
Abstract
Aberrant activation of the Hedgehog (Hh) signalling pathway has been associated with the development and progression of pancreatic cancer. For this reason, blockade of Hh pathway by inhibitors targeting the G protein-coupled receptor Smoothened (SMO) has been considered as a therapeutic target for the treatment of this cancer. In our previous work, we obtained a new SMO ligand based on a purine scaffold (compound I), which showed interesting antitumor activity in several cancer cell lines. In this work, we report the design and synthesis of 17 new purine derivatives, some of which showed high cytotoxic effect on Mia-PaCa-2 (Hh-dependent pancreatic cancer cell lines) and low toxicity on non-neoplastic HEK-293 cells compared with gemcitabine, such as 8f, 8g and 8h (IC50 = 4.56, 4.11 and 3.08 μM, respectively). Two of these purines also showed their ability to bind to SMO through NanoBRET assays (pKi = 5.17 for 8f and 5.01 for 8h), with higher affinities to compound I (pKi = 1.51). In addition, docking studies provided insight the purine substitution pattern is related to the affinity on SMO. Finally, studies of Hh inhibition for selected purines, using a transcriptional functional assay based on luciferase activity in NIH3T3 Shh-Light II cells, demonstrated that 8g reduced GLI activity with a IC50 = 6.4 μM as well as diminished the expression of Hh target genes in two specific Hh-dependent cell models, Med1 cells and Ptch1-/- mouse embryonic fibroblasts. Therefore, our results provide a platform for the design of SMO ligands that could be potential selective cytotoxic agents for the treatment of pancreatic cancer.
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Affiliation(s)
- Christian Espinosa-Bustos
- Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Jeanluc Bertrand
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Alondra Villegas-Menares
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Simón Guerrero
- Facultad de Medicina, Universidad de Atacama, 153601 Copiapó, Chile
| | - Lucia Di Marcotullio
- Department of Molecular Medicine, Faculty Pharmacy and Medicine, Sapienza University, 00161 Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, 00161 Rome, Italy
| | - Shirin Navacci
- Department of Molecular Medicine, Faculty Pharmacy and Medicine, Sapienza University, 00161 Rome, Italy
| | - Gunnar Schulte
- Department of Physiology and Pharmacology, Karolinska Institute, 17165 Solna, Stockholm, Sweden
| | - Pawel Kozielewicz
- Department of Physiology and Pharmacology, Karolinska Institute, 17165 Solna, Stockholm, Sweden
| | - Nicolas Bloch
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Valentina Villela
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
| | - Margot Paulino
- Departamento DETEMA, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay
| | - Marcelo J Kogan
- Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, 8380492 Santiago, Chile; Advanced Center of Chronic Diseases (ACCDiS), Universidad de Chile, 8380492 Santiago, Chile
| | - Jorge Cantero
- Departamento DETEMA, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay
| | - Cristian O Salas
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile.
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Capasso G, Mouawad N, Castronuovo M, Ruggeri E, Visentin A, Trentin L, Frezzato F. Focal adhesion kinase as a new player in the biology of onco-hematological diseases: the starting evidence. Front Oncol 2024; 14:1446723. [PMID: 39281374 PMCID: PMC11392731 DOI: 10.3389/fonc.2024.1446723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 07/31/2024] [Indexed: 09/18/2024] Open
Abstract
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase mainly found in the focal adhesion regions of the plasma membrane and it has a crucial role in migration and the remodeling of cellular morphology. FAK is also linked to several aspects of cancer biology, from cytokine production to angiogenesis, drug resistance, invasion, and metastasis, as well as epithelial-to-mesenchymal transition. The gene locus of FAK is frequently amplified in several human tumors, thus causing FAK overexpression in several cancers. Furthermore, FAK can influence extracellular matrix production and exosome secretion through cancer-associated fibroblasts, thus it has an important role in tumor microenvironment regulation. Although the role of FAK in solid tumors is well known, its importance in onco-hematological diseases remains poorly explored. This review collects studies related to FAK significance in onco-hematological diseases and their microenvironments. Overall, the importance of FAK in blood tumors is increasingly evident, but further research is required to confirm it as a new therapeutic target in hematological contexts.
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Affiliation(s)
- Guido Capasso
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Nayla Mouawad
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Maria Castronuovo
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Edoardo Ruggeri
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Andrea Visentin
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Livio Trentin
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Federica Frezzato
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
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Guo S, Zheng S, Liu M, Wang G. Novel Anti-Cancer Stem Cell Compounds: A Comprehensive Review. Pharmaceutics 2024; 16:1024. [PMID: 39204369 PMCID: PMC11360402 DOI: 10.3390/pharmaceutics16081024] [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: 05/30/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024] Open
Abstract
Cancer stem cells (CSCs) possess a significant ability to renew themselves, which gives them a strong capacity to form tumors and expand to encompass additional body areas. In addition, they possess inherent resistance to chemotherapy and radiation therapies used to treat many forms of cancer. Scientists have focused on investigating the signaling pathways that are highly linked to the ability of CSCs to renew themselves and maintain their stem cell properties. The pathways encompassed are Notch, Wnt/β-catenin, hedgehog, STAT3, NF-κB, PI-3K/Akt/mTOR, sirtuin, ALDH, MDM2, and ROS. Recent studies indicate that directing efforts towards CSC cells is essential in eradicating the overall cancer cell population and reducing the likelihood of tumor metastasis. As our comprehension of the mechanisms that stimulate CSC activity, growth, and resistance to chemotherapy advances, the discovery of therapeutic drugs specifically targeting CSCs, such as small-molecule compounds, holds the potential to revolutionize cancer therapy. This review article examines and analyzes the novel anti-CSC compounds that have demonstrated effective and selective targeting of pathways associated with the renewal and stemness of CSCs. We also discussed their special drug metabolism and absorption mechanisms. CSCs have been the subject of much study in cancer biology. As a possible treatment for malignancies, small-molecule drugs that target CSCs are gaining more and more attention. This article provides a comprehensive review of the current state of key small-molecule compounds, summarizes their recent developments, and anticipates the future discovery of even more potent and targeted compounds, opening up new avenues for cancer treatment.
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Affiliation(s)
- Shanchun Guo
- RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA;
| | - Shilong Zheng
- RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA;
| | - Mingli Liu
- Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA;
| | - Guangdi Wang
- RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA;
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Berrino C, Omar A. Unravelling the Mysteries of the Sonic Hedgehog Pathway in Cancer Stem Cells: Activity, Crosstalk and Regulation. Curr Issues Mol Biol 2024; 46:5397-5419. [PMID: 38920995 PMCID: PMC11202538 DOI: 10.3390/cimb46060323] [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: 05/02/2024] [Revised: 05/24/2024] [Accepted: 05/25/2024] [Indexed: 06/27/2024] Open
Abstract
The Sonic Hedgehog (Shh) signalling pathway plays a critical role in normal development and tissue homeostasis, guiding cell differentiation, proliferation, and survival. Aberrant activation of this pathway, however, has been implicated in the pathogenesis of various cancers, largely due to its role in regulating cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells with the ability to self-renew, differentiate, and initiate tumour growth, contributing significantly to tumorigenesis, recurrence, and resistance to therapy. This review focuses on the intricate activity of the Shh pathway within the context of CSCs, detailing the molecular mechanisms through which Shh signalling influences CSC properties, including self-renewal, differentiation, and survival. It further explores the regulatory crosstalk between the Shh pathway and other signalling pathways in CSCs, highlighting the complexity of this regulatory network. Here, we delve into the upstream regulators and downstream effectors that modulate Shh pathway activity in CSCs. This review aims to cast a specific focus on the role of the Shh pathway in CSCs, provide a detailed exploration of molecular mechanisms and regulatory crosstalk, and discuss current and developing inhibitors. By summarising key findings and insights gained, we wish to emphasise the importance of further elucidating the interplay between the Shh pathway and CSCs to develop more effective cancer therapies.
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MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P. Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways. Int J Mol Sci 2024; 25:4102. [PMID: 38612911 PMCID: PMC11012648 DOI: 10.3390/ijms25074102] [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: 02/28/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.
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Affiliation(s)
- Maya R. MacLean
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Olivia L. Walker
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Raj Pranap Arun
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Wasundara Fernando
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Biology, Acadia University, Wolfville, NS B4P 2R6, Canada
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Nova Scotia Health Authority, Halifax, NS B3H 4R2, Canada
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Prateeksha P, Sharma VK, Singh SM, Sharma M, Diwan D, Hesham AEL, Guleria S, Nguyen QD, Gupta VK, Singh BN. Tetrahydrocannabinols: potential cannabimimetic agents for cancer therapy. Cancer Metastasis Rev 2023; 42:823-845. [PMID: 36696005 DOI: 10.1007/s10555-023-10078-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 12/31/2022] [Indexed: 01/26/2023]
Abstract
Tetrahydrocannabinols (THCs) antagonize the CB1 and CB2 cannabinoid receptors, whose signaling to the endocannabinoid system is essential for controlling cell survival and proliferation as well as psychoactive effects. Most tumor cells express a much higher level of CB1 and CB2; THCs have been investigated as potential cancer therapeutic due to their cannabimimetic properties. To date, THCs have been prescribed as palliative medicine to cancer patients but not as an anticancer modality. Growing evidence of preclinical research demonstrates that THCs reduce tumor progression by stimulating apoptosis and autophagy and inhibiting two significant hallmarks of cancer pathogenesis: metastasis and angiogenesis. However, the degree of their anticancer effects depends on the origin of the tumor site, the expression of cannabinoid receptors on tumor cells, and the dosages and types of THC. This review summarizes the current state of knowledge on the molecular processes that THCs target for their anticancer effects. It also emphasizes the substantial knowledge gaps that should be of concern in future studies. We also discuss the therapeutic effects of THCs and the problems that will need to be addressed in the future. Clarifying unanswered queries is a prerequisite to translating the THCs into an effective anticancer regime.
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Affiliation(s)
- Prateeksha Prateeksha
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, 79410, USA
| | - Vivek K Sharma
- Herbal Nanobiotechnology Lab, Pharmacology Division, CSIR-National Botanical Research Institute, Lucknow, 226001, India
| | - Shiv M Singh
- Department of Botany, Faculty of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Minaxi Sharma
- Haute Ecole Provinciale de Hainaut-Condorcet, Rue de la Sucrerie, 7800, Mons, ATH, Belgium
| | - Deepti Diwan
- Washington University, School of Medicine, Saint Louis, MO 63108, USA
| | - Abd El-Latif Hesham
- Genetics Department, Faculty of Agriculture, Beni-Suef University, Beni-Suef, 62521, Egypt
| | - Sanjay Guleria
- Natural Product-cum-Nano Lab, Division of Biochemistry, Faculty of Basic Sciences, Sher-e-Kashmir University of Agricultural Sciences and Technology of Jammu, Main Campus Chatha, Jammu and Kashmir, 180009, India
| | - Quang D Nguyen
- Department of Bioengineering and Alcoholic Drink Technology, Institute of Food Science and Technology, Hungarian University of Agriculture and Life Sciences, Ménesi út 45, Budapest, H-1118, Hungary
| | - Vijai K Gupta
- Biorefining and Advanced Materials Research Center, SRUC, Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK
- Center for Safe and Improved Food, SRUC, Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK
| | - Brahma N Singh
- Herbal Nanobiotechnology Lab, Pharmacology Division, CSIR-National Botanical Research Institute, Lucknow, 226001, India.
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Bubin R, Uljanovs R, Strumfa I. Cancer Stem Cells in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2023; 24:ijms24087030. [PMID: 37108193 PMCID: PMC10138709 DOI: 10.3390/ijms24087030] [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: 03/10/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
The first discovery of cancer stem cells (CSCs) in leukaemia triggered active research on stemness in neoplastic tissues. CSCs represent a subpopulation of malignant cells, defined by unique properties: a dedifferentiated state, self-renewal, pluripotency, an inherent resistance to chemo- and radiotherapy, the presence of certain epigenetic alterations, as well as a higher tumorigenicity in comparison with the general population of cancer cells. A combination of these features highlights CSCs as a high-priority target during cancer treatment. The presence of CSCs has been confirmed in multiple malignancies, including pancreatic ductal adenocarcinoma, an entity that is well known for its dismal prognosis. As the aggressive course of pancreatic carcinoma is partly attributable to treatment resistance, CSCs could contribute to adverse outcomes. The aim of this review is to summarize the current information regarding the markers and molecular features of CSCs in pancreatic ductal adenocarcinoma and the therapeutic options to remove them.
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Affiliation(s)
- Roman Bubin
- Faculty of Medicine, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
| | - Romans Uljanovs
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
| | - Ilze Strumfa
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
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Shetu SA, James N, Rivera G, Bandyopadhyay D. Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond. Curr Issues Mol Biol 2023; 45:1914-1949. [PMID: 36975494 PMCID: PMC10047141 DOI: 10.3390/cimb45030124] [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: 01/01/2023] [Revised: 02/06/2023] [Accepted: 02/21/2023] [Indexed: 03/04/2023] Open
Abstract
Pancreatic enzymes assist metabolic digestion, and hormones like insulin and glucagon play a critical role in maintaining our blood sugar levels. A malignant pancreas is incapable of doing its regular functions, which results in a health catastrophe. To date, there is no effective biomarker to detect early-stage pancreatic cancer, which makes pancreatic cancer the cancer with the highest mortality rate of all cancer types. Primarily, mutations of the KRAS, CDKN2A, TP53, and SMAD4 genes are responsible for pancreatic cancer, of which mutations of the KRAS gene are present in more than 80% of pancreatic cancer cases. Accordingly, there is a desperate need to develop effective inhibitors of the proteins that are responsible for the proliferation, propagation, regulation, invasion, angiogenesis, and metastasis of pancreatic cancer. This article discusses the effectiveness and mode of action at the molecular level of a wide range of small molecule inhibitors that include pharmaceutically privileged molecules, compounds under clinical trials, and commercial drugs. Both natural and synthetic small molecule inhibitors have been counted. Anti-pancreatic cancer activity and related benefits of using single and combined therapy have been discussed separately. This article sheds light on the scenario, constraints, and future aspects of various small molecule inhibitors for treating pancreatic cancer-the most dreadful cancer so far.
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Affiliation(s)
- Shaila A. Shetu
- Department of Chemistry, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
| | - Nneoma James
- Department of Chemistry, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
| | - Gildardo Rivera
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Mexico
| | - Debasish Bandyopadhyay
- Department of Chemistry, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
- School of Earth Environment & Marine Sciences (SEEMS), The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
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Novel Approach to the Hedgehog Signaling Pathway: Combined Treatment of SMO and PTCH Inhibitors. JOURNAL OF BASIC AND CLINICAL HEALTH SCIENCES 2022. [DOI: 10.30621/jbachs.1193720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Purpose: Abnormal Sonic Hedgehog signaling Pathway (Shh) activation is crucial for development of cancer stem cells, neoplastic growth and epithelial-mesenchymal transition processes in adulthood. Activation of Hedgehog signaling pathway may induces the changes in cilia found in the cell membrane, iniciates the Gli1 transcription factor that is translocated to the cell nucleus and finally, the target genes are transcribed. In this study, invastigation of the antiproliferative, anti-invasive and antimigrative effect of the combined use of robotnikinin (Ptch1 antagonist) and vismodegib (Smo inhibitor) on the hedgehog signaling pathway was aimed.
Material and Methods: After demonstarting the presence of the hedgehog signaling pathway in the glioblastoma cell line U87-MG, the effect of the combined use of the robotnikinin and the vismodegib on the hedgehog signaling pathway was investigated. In-vitro cell proliferation, migration, and invasion analysis of the combination of antagonist and inhibitor and in silico drug-likeness analysis were performed.
Results: Two different combinations of robotnikinin and vismodegib were tested. In vitro studies show that the combined use of agents in combined treatments of Smo and Ptch1is more effective than their individual usage.
Conclusion: Inhibition of the hedgehog signaling pathway with specific inhibitors and antagonists is considered an innovative strategy for cancer therapy.
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Quatannens D, Verhoeven Y, Van Dam P, Lardon F, Prenen H, Roeyen G, Peeters M, Smits ELJ, Van Audenaerde J. Targeting hedgehog signaling in pancreatic ductal adenocarcinoma. Pharmacol Ther 2022; 236:108107. [PMID: 34999181 DOI: 10.1016/j.pharmthera.2022.108107] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer related death. The urgent need for effective therapies is highlighted by the lack of adequate targeting. In PDAC, hedgehog (Hh) signaling is known to be aberrantly activated, which prompted the pathway as a possible target for effective treatment for PDAC patients. Unfortunately, specific targeting of upstream molecules within the Hh signaling pathway failed to bring clinical benefit. This led to the ongoing debate on Hh targeting as a therapeutic treatment for PDAC patients. Additionally, concurrent non-canonical activation routes also result in translocation of Gli transcription factors into the nucleus. Therefore, different downstream targets of the Hh signaling pathway were identified and evaluated in preclinical and clinical research. In this review we summarize the variety of Hh signaling antagonists in different preclinical models of PDAC. Furthermore, we discuss published and ongoing clinical trials that evaluated Hh antagonists and point out the current hurdles and future perspectives in the light of redesigning Hh-targeting therapies for the treatment of PDAC patients.
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Affiliation(s)
- Delphine Quatannens
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Yannick Verhoeven
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Peter Van Dam
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Unit of Gynecologic Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Filip Lardon
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Hans Prenen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Geert Roeyen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Hepatobiliary Transplantation and Endocrine Surgery, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Marc Peeters
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Evelien L J Smits
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Jonas Van Audenaerde
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
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Inhibition of epithelial SHH signaling exerts a dual protective effect against inflammation and epithelial–mesenchymal transition in inflammatory bowel disease. Toxicol In Vitro 2022; 82:105382. [DOI: 10.1016/j.tiv.2022.105382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/29/2022] [Accepted: 05/09/2022] [Indexed: 11/19/2022]
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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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13
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Babagana M, Oh KS, Chakraborty S, Pacholewska A, Aqdas M, Sung MH. Hedgehog dysregulation contributes to tissue-specific inflammaging of resident macrophages. Aging (Albany NY) 2021; 13:19207-19229. [PMID: 34390567 PMCID: PMC8386529 DOI: 10.18632/aging.203422] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/03/2021] [Indexed: 12/31/2022]
Abstract
Age-associated low-grade sterile inflammation, commonly referred to as inflammaging, is a recognized hallmark of aging, which contributes to many age-related diseases. While tissue-resident macrophages are innate immune cells that secrete many types of inflammatory cytokines in response to various stimuli, it is not clear whether they have a role in driving inflammaging. Here we characterized the transcriptional changes associated with physiological aging in mouse resident macrophage populations across different tissues and sexes. Although the age-related transcriptomic signatures of resident macrophages were strikingly tissue-specific, the differentially expressed genes were collectively enriched for those with important innate immune functions such as antigen presentation, cytokine production, and cell adhesion. The brain-resident microglia had the most wide-ranging age-related alterations, with compromised expression of tissue-specific genes and relatively exaggerated responses to endotoxin stimulation. Despite the tissue-specific patterns of aging transcriptomes, components of the hedgehog (Hh) signaling pathway were decreased in aged macrophages across multiple tissues. In vivo suppression of Hh signaling in young animals increased the expression of pro-inflammatory cytokines, while in vitro activation of Hh signaling in old macrophages, in turn, suppressed the expression of these inflammatory cytokines. This suggests that hedgehog signaling could be a potential intervention axis for mitigating age-associated inflammation and related diseases. Overall, our data represent a resourceful catalog of tissue-specific and sex-specific transcriptomic changes in resident macrophages of peritoneum, liver, and brain, during physiological aging.
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Affiliation(s)
- Mahamat Babagana
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Kyu-Seon Oh
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Sayantan Chakraborty
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Alicja Pacholewska
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.,Present Address: Institute for Translational Epigenetics, University Hospital Cologne, Cologne, Germany
| | - Mohammad Aqdas
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Myong-Hee Sung
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
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14
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Zárate AM, Espinosa-Bustos C, Guerrero S, Fierro A, Oyarzún-Ampuero F, Quest AFG, Di Marcotullio L, Loricchio E, Caimano M, Calcaterra A, González-Quiroz M, Aguirre A, Meléndez J, Salas CO. A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo. Int J Mol Sci 2021; 22:8372. [PMID: 34445078 PMCID: PMC8395040 DOI: 10.3390/ijms22168372] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 12/14/2022] Open
Abstract
The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.
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Affiliation(s)
- Ana María Zárate
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile; (A.M.Z.); (A.F.)
| | - Christian Espinosa-Bustos
- Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile;
| | - Simón Guerrero
- Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Sergio Livingstone 1007, Independencia, Santiago 8380492, Chile; (S.G.); (F.O.-A.); (A.F.G.Q.)
- Instituto de Investigación Interdisciplinar en Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad SEK (I3CBSEK), Fernando Manterola 0789, Providencia, Santiago 7520317, Chile
| | - Angélica Fierro
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile; (A.M.Z.); (A.F.)
| | - Felipe Oyarzún-Ampuero
- Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Sergio Livingstone 1007, Independencia, Santiago 8380492, Chile; (S.G.); (F.O.-A.); (A.F.G.Q.)
- Departamento de Ciencias y Tecnología Farmacéuticas, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago 8380494, Chile
| | - Andrew F. G. Quest
- Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Sergio Livingstone 1007, Independencia, Santiago 8380492, Chile; (S.G.); (F.O.-A.); (A.F.G.Q.)
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Program of Cellular and Molecular Biology, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago 8380453, Chile
| | - Lucia Di Marcotullio
- Laboratory Affiliated to Insituto Pasteur Italia, Fondazione Cenci Bognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy;
| | - Elena Loricchio
- Center For Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy;
| | - Miriam Caimano
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy;
| | - Andrea Calcaterra
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy;
| | - Matías González-Quiroz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Universidad de Chile, Independencia 1027, Santiago 8380453, Chile;
| | - Adam Aguirre
- Laboratorio de Medicina Traslacional, Fundación Arturo López Pérez, Rancagua 878, Lower Fifth Floor, Providencia, Santiago 8320000, Chile;
| | - Jaime Meléndez
- Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile;
| | - Cristian O. Salas
- Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago 702843, Chile; (A.M.Z.); (A.F.)
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15
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Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease. Cancers (Basel) 2021; 13:cancers13143410. [PMID: 34298625 PMCID: PMC8304605 DOI: 10.3390/cancers13143410] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The Hedgehog/GLI (Hh/GLI) pathway plays a major role during development and it is commonly dysregulated in many diseases, including cancer. This highly concerted series of ligands, receptors, cytoplasmic signaling molecules, transcription factors, and co-regulators is involved in regulating the biological functions controlled by this pathway. Activation of Hh/GLI in cancer is most often through a non-canonical method of activation, independent of ligand binding. This review is intended to summarize our current understanding of the Hh/GLI signaling, non-canonical mechanisms of pathway activation, its implication in disease, and the current therapeutic strategies targeting this cascade. Abstract The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3β, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3β) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer.
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16
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Mohan A, Raj Rajan R, Mohan G, Kollenchery Puthenveettil P, Maliekal TT. Markers and Reporters to Reveal the Hierarchy in Heterogeneous Cancer Stem Cells. Front Cell Dev Biol 2021; 9:668851. [PMID: 34150761 PMCID: PMC8209516 DOI: 10.3389/fcell.2021.668851] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/30/2021] [Indexed: 12/12/2022] Open
Abstract
A subpopulation within cancer, known as cancer stem cells (CSCs), regulates tumor initiation, chemoresistance, and metastasis. At a closer look, CSCs show functional heterogeneity and hierarchical organization. The present review is an attempt to assign marker profiles to define the functional heterogeneity and hierarchical organization of CSCs, based on a series of single-cell analyses. The evidences show that analogous to stem cell hierarchy, self-renewing Quiescent CSCs give rise to the Progenitor CSCs with limited proliferative capacity, and later to a Progenitor-like CSCs, which differentiates to Proliferating non-CSCs. Functionally, the CSCs can be tumor-initiating cells (TICs), drug-resistant CSCs, or metastasis initiating cells (MICs). Although there are certain marker profiles used to identify CSCs of different cancers, molecules like CD44, CD133, ALDH1A1, ABCG2, and pluripotency markers [Octamer binding transcriptional factor 4 (OCT4), SOX2, and NANOG] are used to mark CSCs of a wide range of cancers, ranging from hematological malignancies to solid tumors. Our analysis of the recent reports showed that a combination of these markers can demarcate the heterogeneous CSCs in solid tumors. Reporter constructs are widely used for easy identification and quantification of marker molecules. In this review, we discuss the suitability of reporters for the widely used CSC markers that can define the heterogeneous CSCs. Since the CSC-specific functions of CD44 and CD133 are regulated at the post-translational level, we do not recommend the reporters for these molecules for the detection of CSCs. A promoter-based reporter for ABCG2 may also be not relevant in CSCs, as the expression of the molecule in cancer is mainly regulated by promoter demethylation. In this context, a dual reporter consisting of one of the pluripotency markers and ALDH1A1 will be useful in marking the heterogeneous CSCs. This system can be easily adapted to high-throughput platforms to screen drugs for eliminating CSCs.
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Affiliation(s)
- Amrutha Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.,Manipal Academy of Higher Education, Manipal, India
| | - Reshma Raj Rajan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Gayathri Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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17
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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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18
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Paget C, Duret H, Ngiow SF, Kansara M, Thomas DM, Smyth MJ. Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma. Oncoimmunology 2021; 1:1313-1322. [PMID: 23243595 PMCID: PMC3518504 DOI: 10.4161/onci.21680] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Recent evidence demonstrates that the efficacy of conventional anticancer therapies including chemotherapy requires a functional immune system. Here, we addressed the possibility that the antitumor effect of a selective Smoothened antagonist and Hedgehog (Hh) pathway inhibitor (LDE225), a promising anticancer drug, might at least partially depend on the immune system. To this aim, we used tumor cell lines derived from a murine model of radiation-induced osteosarcoma. In vitro treatment of osteosarcoma cells with LDE225 resulted in a decreased ability of tumor cells to proliferate, but had no effect on their viability. Flow cytometry analysis demonstrated that LDE225-treatment did not detectably modulate the immunogenicity of tumor cells. Moreover, LDE225 did not display any pro-apoptotic properties on osteosarcoma cells, highlighting that its antitumor profile mainly derives from a cytostatic effect. Furthermore, calreticulin exposure, a key feature of immunogenic cell death, was not provoked by LDE225, neither alone nor combined with recognized immunogenic drugs. Finally, the oral administration of LDE225 to osteosarcoma-bearing mice did significantly delay the tumor growth even in an immunocompromised setting. These data suggest that inhibiting Hh signaling can control osteosarcoma cell proliferation but does not modulate the immunogenic profile of these cells.
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Affiliation(s)
- Christophe Paget
- Cancer Immunology Program; Peter MacCallum Cancer Centre; East Melbourne, Australia
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19
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Freitas RD, Dias RB, Vidal MTA, Valverde LDF, Gomes Alves Costa R, Damasceno AKA, Sales CBS, Siquara da Rocha LDO, Dos Reis MG, Soares MBP, Coletta RD, Pereira TA, Bezerra DP, Gurgel Rocha CA. Inhibition of CAL27 Oral Squamous Carcinoma Cell by Targeting Hedgehog Pathway With Vismodegib or Itraconazole. Front Oncol 2020; 10:563838. [PMID: 33312948 PMCID: PMC7703359 DOI: 10.3389/fonc.2020.563838] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/15/2020] [Indexed: 12/18/2022] Open
Abstract
Oral Squamous Cell Carcinoma (OSCC) presents an important challenge for the health systems worldwide. Thus, unraveling the biological mechanisms involved in OSCC pathogenesis is essential to the discovery of new drugs with anticancer potential. The Hedgehog (HH) pathway has shown promising results as a therapeutic target both in vitro and in vivo. This study aimed to investigate the effects of vismodegib and itraconazole on the expression of Hedgehog (HH) genes (PTCH1, SMO, and GLI1), cell cycle and cell death in OSCC cells. Alamar Blue assay was used to assess the cytotoxicity of vismodegib and itraconazole in a panel of oral cancer cell lines, including CAL27. The expression of HH signaling components after treatment with vismodegib and itraconazole, at concentrations of 25 or 50 μg/ml was evaluated by qPCR. Cell cycle and apoptosis were evaluated by flow cytometry after 72 h treatment with 50 μg/ml of vismodegib or itraconazole. HH signaling was activated in OSCC cell lines CAL27, SCC4, SCC9, and HSC3. Vismodegib and itraconazole significantly reduced CAL27 cell viability after 48 h of treatment. Gene expression of PTCH1, SMO, and GLI1 decreased in response to 24 h of treatment with vismodegib or itraconazole. Furthermore, CAL27 cells exhibited alterations in morphology, cell size, and cellular granularity. An increase in the DNA fragmentation was observed after treatment and both inhibitors induced apoptosis after 72 h. In conclusion, SMO inhibitors vismodegib and itraconazole demonstrably reduced the expression of HH genes in CAL27 OSCC cell line. In addition, treatment with vismodegib and itraconazole reduced cellular viability and altered the morphology of CAL27 cells, and also induced apoptosis.
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Affiliation(s)
- Raíza Dias Freitas
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil.,Department of Pathology and Forensic Medicine, School of Medicine of the Federal University of Bahia, Salvador, Brazil
| | - Rosane Borges Dias
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil.,Department of Propaedeutics, School of Dentistry of the Federal University of Bahia, Bahia, Brazil
| | - Manuela Torres Andion Vidal
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil.,Department of Pathology and Forensic Medicine, School of Medicine of the Federal University of Bahia, Salvador, Brazil
| | - Ludmila de Faro Valverde
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil.,Department of Pathology and Forensic Medicine, School of Medicine of the Federal University of Bahia, Salvador, Brazil
| | | | | | | | | | - Mitermayer Galvão Dos Reis
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil.,Department of Pathology and Forensic Medicine, School of Medicine of the Federal University of Bahia, Salvador, Brazil
| | | | - Ricardo Della Coletta
- Department of Oral Diagnostics, School of Dentistry, University of Campinas, Piracicaba, Brazil
| | - Thiago Almeida Pereira
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, United States
| | | | - Clarissa Araújo Gurgel Rocha
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil.,Department of Pathology and Forensic Medicine, School of Medicine of the Federal University of Bahia, Salvador, Brazil.,Department of Propaedeutics, School of Dentistry of the Federal University of Bahia, Bahia, Brazil
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20
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Doheny D, Manore SG, Wong GL, Lo HW. Hedgehog Signaling and Truncated GLI1 in Cancer. Cells 2020; 9:cells9092114. [PMID: 32957513 PMCID: PMC7565963 DOI: 10.3390/cells9092114] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 12/18/2022] Open
Abstract
The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.
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Affiliation(s)
- Daniel Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
| | - Sara G. Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
| | - Grace L. Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Correspondence: ; Tel.: +1-336-716-0695
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21
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Chandra Boinpelly V, Verma RK, Srivastav S, Srivastava RK, Shankar S. α-Mangostin-encapsulated PLGA nanoparticles inhibit colorectal cancer growth by inhibiting Notch pathway. J Cell Mol Med 2020; 24:11343-11354. [PMID: 32830433 PMCID: PMC7576287 DOI: 10.1111/jcmm.15731] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/15/2020] [Accepted: 07/17/2020] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is the fourth leading cause of cancer‐related mortality. Recent studies have stated that Notch signalling is highly activated in cancer stem cells (CSCs) and plays an important role in the development and progression of CRC. Like normal colorectal epithelium, CRCs are organized hierarchically and include populations of CSCs. In order to enhance the biological activity of α‐mangostin, we formulated α‐mangostin‐encapsulated PLGA nanoparticles (Mang‐NPs) and examined the molecular mechanisms by which Mang‐NPs inhibit CRC cell viability, colony formation, epithelial‐mesenchymal transition (EMT) and induce apoptosis. Mang‐NPs inhibited cell viability, colony formation and induced apoptosis. Mang‐NPs also inhibited EMT by up‐regulating E‐cadherin and inhibiting N‐cadherin and transcription factors Snail, Slug and Zeb1. As dysregulated signalling through the Notch receptors promotes oncogenesis, we measured the effects of Mang‐NPs on Notch pathway. Mang‐NPs inhibited Notch signalling by suppressing the expression of Notch receptors (Notch1 and Notch2), their ligands (Jagged 1 and DLL4), γ‐secretase complex protein (Nicastrin) and downstream target (Hes‐1). Notch receptor signalling regulates cell fate determination in stem cell population. Finally, Mang‐NPs inhibited the self‐renewal capacity of CSCs, stem cell markers (CD133, CD44, Musashi and LGR5) and pluripotency maintaining factors (Oct4, Sox‐2, KLF‐4, c‐Myc and Nanog). Overall, our data suggest that Mang‐NPs can inhibit CRC growth, EMT and CSCs’ population by suppressing Notch pathway and its target. Therefore, Mang‐NPs can be used for the treatment and prevention of CRC.
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Affiliation(s)
| | | | - Sudesh Srivastav
- Department of Biostatistics and Data ScienceSchool of Public Health and Tropical MedicineTulane University School of MedicineNew OrleansLAUSA
| | - Rakesh K. Srivastava
- Kansas City VA Medical CenterKansas CityMOUSA
- Stanley S. Scott Cancer CenterLouisiana State University Health Sciences CenterNew OrleansLAUSA
- Department of GeneticsLouisiana State University Health Sciences CenterNew OrleansLAUSA
| | - Sharmila Shankar
- Kansas City VA Medical CenterKansas CityMOUSA
- Stanley S. Scott Cancer CenterLouisiana State University Health Sciences CenterNew OrleansLAUSA
- Department of GeneticsLouisiana State University Health Sciences CenterNew OrleansLAUSA
- John W. Deming Department of MedicineTulane University School of MedicineNew OrleansLAUSA
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22
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Yang Y, Li X, Wang T, Guo Q, Xi T, Zheng L. Emerging agents that target signaling pathways in cancer stem cells. J Hematol Oncol 2020; 13:60. [PMID: 32456660 PMCID: PMC7249421 DOI: 10.1186/s13045-020-00901-6] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 05/18/2020] [Indexed: 12/16/2022] Open
Abstract
Cancer stem cells (CSCs) contribute to the initiation, recurrence, and metastasis of cancer; however, there are still no drugs targeting CSCs in clinical application. There are several signaling pathways playing critical roles in CSC progression, such as the Wnt, Hedgehog, Notch, Hippo, and autophagy signaling pathways. Additionally, targeting the ferroptosis signaling pathway was recently shown to specifically kill CSCs. Therefore, targeting these pathways may suppress CSC progression. The structure of small-molecule drugs shows a good spatial dispersion, and its chemical properties determine its good druggability and pharmacokinetic properties. These characteristics make small-molecule drugs show a great advantage in drug development, which is increasingly popular in the market. Thus, in this review, we will summarize the current researches on the small-molecule compounds suppressing CSC progression, including inhibitors of Wnt, Notch, Hedgehog, and autophagy pathways, and activators of Hippo and ferroptosis pathways. These small-molecule compounds emphasize CSC importance in tumor progression and propose a new strategy to treat cancer in clinic via targeting CSCs.
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Affiliation(s)
- Yue Yang
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Ting Wang
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450003, People's Republic of China
| | - Tao Xi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
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23
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Khan MA, Srivastava SK, Zubair H, Patel GK, Arora S, Khushman M, Carter JE, Gorman GS, Singh S, Singh AP. Co-targeting of CXCR4 and hedgehog pathways disrupts tumor-stromal crosstalk and improves chemotherapeutic efficacy in pancreatic cancer. J Biol Chem 2020; 295:8413-8424. [PMID: 32358063 DOI: 10.1074/jbc.ra119.011748] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 04/17/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C-X-C motif chemokine receptor 4 (CXCR4) and hedgehog pathways cooperate in PC chemoresistance via bidirectional tumor-stromal crosstalk. We show that when PC cells are co-cultured with pancreatic stellate cells (PSCs) they are significantly more resistant to gemcitabine toxicity than those grown in monoculture. We also demonstrate that this co-culture-induced chemoresistance is abrogated by inhibition of the CXCR4 and hedgehog pathways. Similarly, the co-culture-induced altered expression of genes in PC cells associated with gemcitabine metabolism, antioxidant defense, and cancer stemness is also reversed upon CXCR4 and hedgehog inhibition. We have confirmed the functional impact of these genetic alterations by measuring gemcitabine metabolites, reactive oxygen species production, and sphere formation in vehicle- or gemcitabine-treated monocultures and co-cultured PC cells. Treatment of orthotopic pancreatic tumor-bearing mice with gemcitabine alone or in combination with a CXCR4 antagonist (AMD3100) or hedgehog inhibitor (GDC-0449) displays reduced tumor growth. Notably, we show that the triple combination treatment is the most effective, resulting in nearly complete suppression of tumor growth. Immunohistochemical analysis of Ki67 and cleaved caspase-3 confirm these findings from in vivo imaging and tumor measurements. Our findings provide preclinical and mechanistic evidence that a combination of gemcitabine treatment with targeted inhibition of both the CXCR4 and hedgehog pathways improves outcomes in a PC mouse model.
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Affiliation(s)
- Mohammad Aslam Khan
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Sanjeev Kumar Srivastava
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Haseeb Zubair
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Girijesh Kumar Patel
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Sumit Arora
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Moh'd Khushman
- Department of Medical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - James Elliot Carter
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama
| | | | - Seema Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Ajay Pratap Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama .,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
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24
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Ixazomib Improves Bone Remodeling and Counteracts sonic Hedgehog signaling Inhibition Mediated by Myeloma Cells. Cancers (Basel) 2020; 12:cancers12020323. [PMID: 32019102 PMCID: PMC7073172 DOI: 10.3390/cancers12020323] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 01/23/2020] [Accepted: 01/27/2020] [Indexed: 12/18/2022] Open
Abstract
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of plasma cells (PC) in the bone marrow (BM), leading to bone loss and BM failure. Osteolytic bone disease is a common manifestation observed in MM patients and represents the most severe cause of morbidity, leading to progressive skeletal damage and disabilities. Pathogenetic mechanisms of MM bone disease are closely linked to PCs and osteoclast (OCs) hyperactivity, coupled with defective osteoblasts (OBs) function that is unable to counteract bone resorption. The aim of the present study was to investigate the effects of Ixazomib, a third-generation proteasome inhibitor, on osteoclastogenesis and osteogenic differentiation. We found that Ixazomib was able to reduce differentiation of human monocytes into OCs and to inhibit the expression of OC markers when added to the OC medium. Concurrently, Ixazomib was able to stimulate osteogenic differentiation of human mesenchymal stromal cells (MSCs), increasing osteogenic markers, either alone or in combination with the osteogenic medium. Given the key role of Sonic Hedgehog (SHH) signaling in bone homeostasis, we further investigated Ixazomib-induced SHH pathway activation. This set of experiments showed that Ixazomib, but not Bortezomib, was able to bind the Smoothened (SMO) receptor leading to nuclear translocation of GLI1 in human MSCs. Moreover, we demonstrated that PCs act as GLI1 suppressors on MSCs, thus reducing the potential of MSCs to differentiate in OBs. In conclusion, our data demonstrated that Ixazomib regulates bone remodeling by decreasing osteoclastogenesis and prompting osteoblast differentiation via the canonical SHH signaling pathway activation, thus, representing a promising therapeutic option to improve the complex pathological condition of MM patients.
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25
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Zhu Q, Shen Y, Chen X, He J, Liu J, Zu X. Self-Renewal Signalling Pathway Inhibitors: Perspectives on Therapeutic Approaches for Cancer Stem Cells. Onco Targets Ther 2020; 13:525-540. [PMID: 32021295 PMCID: PMC6970631 DOI: 10.2147/ott.s224465] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 11/07/2019] [Indexed: 12/24/2022] Open
Abstract
The poor survival and prognosis of individuals with cancer are often attributed to tumour relapse and metastasis, which may be due to the presence of cancer stem cells (CSCs). CSCs have the characteristics of self-renewal, differentiation potential, high carcinogenicity, and drug resistance. In addition, CSCs exhibit many characteristics similar to those of embryonic or tissue stem cells while displaying persistent abnormal activation of self-renewal pathways associated with development and tissue homeostasis, including the Wnt, Notch, Hedgehog (Hh), TGF-β, JAK/STAT3, and NF-κB pathways. Therefore, we can eliminate CSCs by targeting these self-renewal pathways to constrain stem cell replication, survival and differentiation. At the same time, we cannot neglect the ping-pong effect of the tumour microenvironment, which releases cytokines and promotes self-renewal pathways in CSCs. Recently, meaningful progress has been made in the study of inhibitors of self-renewal pathways in tumours. This review primarily summarizes several representative and novel agents targeting these self-renewal signalling pathways and the tumour microenvironment and that represent a promising strategy for treating refractory and recurrent cancer.
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Affiliation(s)
- Qingyun Zhu
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Yingying Shen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Xiguang Chen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Jun He
- Department of Spine Surgery, The Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Jianghua Liu
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Xuyu Zu
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
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26
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Lu YB, Sun TJ, Chen YT, Cai ZY, Zhao JY, Miao F, Yang YN, Wang SX. Targeting the Epithelial-to-Mesenchymal Transition in Cancer Stem Cells for a Better Clinical Outcome of Glioma. Technol Cancer Res Treat 2020; 19:1533033820948053. [PMID: 33089751 PMCID: PMC7586027 DOI: 10.1177/1533033820948053] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 06/19/2020] [Accepted: 07/09/2020] [Indexed: 02/05/2023] Open
Abstract
Glioma is one of the most common malignant tumors of the central nervous system with a poor prognosis at present due to lack of effective treatment options. Its initiation, migration, and multipotency are affected by cancer stem cell's transition. Previous studies imply that changes in the cancer stem cells can affect the malignant differentiation of the tumor. We found that the epithelial-to-mesenchymal transition (EMT)-related regulatory pathway is an important target for tumor therapy. In this review, we discuss the transition factor of EMT and 3 specific pathways that affect the EMT of cancer stem cells during tumor development. We conclude that targeting the EMT process of cancer stem cells can be a feasible approach in the treatment of glioma.
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Affiliation(s)
- Yu-bao Lu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- *Both authors contributed equally to this study and share first authorship
| | - Tian-Jiao Sun
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- *Both authors contributed equally to this study and share first authorship
| | - Yu-tong Chen
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Zong-Yan Cai
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Jia-Yu Zhao
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Feng Miao
- Zhangye People's Hospital Affiliated to Hexi University, Zhangye, Gansu, China
| | - Yong-na Yang
- Department of Neurology, The First People’s Hospital of Lanzhou City, Lanzhou, Gansu, China
| | - Shi-Xin Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China
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27
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Repurposing Antibacterial AM404 as a Potential Anticancer Drug for Targeting Colorectal Cancer Stem-Like Cells. Cancers (Basel) 2019; 12:cancers12010106. [PMID: 31906201 PMCID: PMC7017077 DOI: 10.3390/cancers12010106] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/22/2019] [Accepted: 12/27/2019] [Indexed: 12/14/2022] Open
Abstract
Tumour-promoting inflammation is involved in colorectal cancer (CRC) development and therapeutic resistance. However, the antibiotics and antibacterial drugs and signalling that regulate the potency of anticancer treatment upon forced differentiation of cancer stem-like cell (CSC) are not fully defined yet. We screened an NIH-clinical collection of the small-molecule compound library of antibacterial/anti-inflammatory agents that identified potential candidate drugs targeting CRC-SC for differentiation. Selected compounds were validated in both in vitro organoids and ex vivo colon explant models for their differentiation induction, impediment on neoplastic cell growth, and to elucidate the mechanism of their anticancer activity. We initially focused on AM404, an anandamide uptake inhibitor. AM404 is a metabolite of acetaminophen with antibacterial activity, which showed high potential in preventing CRC-SC features, such as stemness/de-differentiation, migration and drug-resistance. Furthermore, AM404 suppressed the expression of FBXL5 E3-ligase, where AM404 sensitivity was mimicked by FBXL5-knockout. This study uncovers a new molecular mechanism for AM404-altering FBXL5 oncogene which mediates chemo-resistance and CRC invasion, thereby proposes to repurpose antibacterial AM404 as an anticancer agent.
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28
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Maier J, Elmenofi S, Taschauer A, Anton M, Sami H, Ogris M. Luminescent and fluorescent triple reporter plasmid constructs for Wnt, Hedgehog and Notch pathway. PLoS One 2019; 14:e0226570. [PMID: 31860685 PMCID: PMC6924688 DOI: 10.1371/journal.pone.0226570] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/29/2019] [Indexed: 12/11/2022] Open
Abstract
Tracking the activity of signalling pathways is a fundamental method for basic science, as well as in cancer- and pharmaceutical research. The developmental pathways Wnt, Hedgehog and Notch are frequently deregulated in cancers and represent a valuable target for the discovery of novel anticancer compounds. Here we present reporter systems for tracking activity of these pathways by using specific promoter elements driving the expression of either sensitive luciferases or fluorescent proteins. A high level of sensitivity was obtained using the luciferase reporter genes for firefly (FLuc), secreted Gaussia (GLuc) and synthetic NanoLuc (NLuc). As fluorescent reporter proteins, mTurqouise2, tdTomato and iRFP720 were chosen. Specificity of pathway activity was validated by co-transfection with pathway activating genes, showing significant response to induction. In addition, multi-gene plasmids were cloned, allowing the detection of all three pathways by one vector. By using the multi-gene vector 3P-Luc (wnt-NLuc, hedgehog-FLuc, Notch-GLuc), we could unambiguously demonstrate the crosstalk between pathways, while excluding cross reactivity of luciferase substrates. First studies with synthetic compounds confirmed the applicability of the system for future drug screening approaches.
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Affiliation(s)
- Julia Maier
- Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse, Vienna, Austria
| | - Salma Elmenofi
- Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse, Vienna, Austria
| | - Alexander Taschauer
- Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse, Vienna, Austria
| | - Martina Anton
- Institutes of Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Haider Sami
- Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse, Vienna, Austria
- * E-mail: (MO); (HS)
| | - Manfred Ogris
- Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse, Vienna, Austria
- * E-mail: (MO); (HS)
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29
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Kowolik CM, Lin M, Xie J, Overman LE, Horne DA. Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:431. [PMID: 31661013 PMCID: PMC6819529 DOI: 10.1186/s13046-019-1445-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 10/10/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Pancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer. METHODS We characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo. RESULTS NT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine. CONCLUSIONS Favorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease.
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Affiliation(s)
- Claudia M Kowolik
- Department of Molecular Medicine, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Min Lin
- Department of Molecular Medicine, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Jun Xie
- Department of Molecular Medicine, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Larry E Overman
- Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA, 92697-2025, USA
| | - David A Horne
- Department of Molecular Medicine, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
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30
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Herms F, Lambert J, Grob JJ, Haudebourg L, Bagot M, Dalac S, Dutriaux C, Guillot B, Jeudy G, Mateus C, Monestier S, Mortier L, Poulalhon N, Prey S, Robert C, Vabres P, Lebbe C, Meyer N, Basset-Seguin N. Follow-Up of Patients With Complete Remission of Locally Advanced Basal Cell Carcinoma After Vismodegib Discontinuation: A Multicenter French Study of 116 Patients. J Clin Oncol 2019; 37:3275-3282. [PMID: 31609670 DOI: 10.1200/jco.18.00794] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Vismodegib is a hedgehog pathway inhibitor indicated for the treatment of locally advanced basal cell carcinoma (laBCC), with an objective response rate of 65%, including a 32% complete response (CR). However, adverse effects often lead to drug discontinuation. The objective of our study was to evaluate long-term responses, predictive factors, and management of relapse after vismodegib discontinuation. METHODS An observational retrospective study was conducted in nine French oncodermatology units. We included patients with laBCC with CR on vismodegib who discontinued treatment between March 2012 and January 2016; we reviewed charts up to June 2016. The primary objective was to evaluate median relapse-free survival (RFS). Secondary objectives were risk factors associated with RFS, relapse, and death and treatment modalities after relapse and their efficacy. RESULTS One hundred sixteen patients with laBCC were included. The median RFS was 18.4 months (95% CI, 13.5 to 24.8 months). The RFS rate at 36 months was 35.4% (95% CI, 22.5% to 47.9%) for the total population and 40.0% (95% CI, 25.7% to 53.7%) for patients without Gorlin syndrome. LaBCC to the limbs and trunk was the only variable independently associated with a higher risk of relapse (hazard ratio, 2.77; 95% CI, 1.23 to 6.22; P = .019). Twenty-seven patients (50%) who experienced relapse during follow-up were retreated with vismodegib, with an objective response in 23 (objective response rate, 85%; CR rate, 37%; partial response rate, 48%) and eligibility for surgery in 24 (42%). CONCLUSION Long-term response after vismodegib discontinuation is frequent. Most patients who experience a relapse still respond to vismodegib rechallenge.
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Affiliation(s)
- Florian Herms
- Hôpital Saint-Louis, Paris, France.,Université Paris Diderot, Paris, France
| | - Jerome Lambert
- Hôpital Saint-Louis, Paris, France.,Université Paris Diderot, Paris, France
| | | | - Luc Haudebourg
- Hôpital Saint-Louis, Paris, France.,Université Paris Diderot, Paris, France
| | - Martine Bagot
- Hôpital Saint-Louis, Paris, France.,Université Paris Diderot, Paris, France
| | | | - Caroline Dutriaux
- University of Bordeaux, Bordeaux, France.,CHU Bordeaux, Bordeaux, France
| | | | | | | | | | | | | | - Sorilla Prey
- University of Bordeaux, Bordeaux, France.,CHU Bordeaux, Bordeaux, France
| | | | | | - Celeste Lebbe
- Hôpital Saint-Louis, Paris, France.,Université Paris Diderot, Paris, France
| | - Nicolas Meyer
- Institut Universitaire du Cancer et CHU de Toulouse, Toulouse, France
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31
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Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production. Cell Death Dis 2019; 10:626. [PMID: 31427566 PMCID: PMC6700102 DOI: 10.1038/s41419-019-1840-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 06/12/2019] [Accepted: 06/26/2019] [Indexed: 12/23/2022]
Abstract
Lung adenocarcinoma (LUAD), which comprises over 50% of all cases of non-small-cell lung cancer, has a poor prognosis and requires novel therapeutic approaches. The sonic Hedgehog (Shh) pathway, which plays a crucial role in differentiation, proliferation, and survival of cancer cells, is likely to be activated in LUADs, suggesting the Shh pathway as a potential therapeutic target for LUAD treatment. In this study, we reported that vismodegib, an inhibitor of the Shh pathway, only elicited minor antitumor efficacy in A549 and NCI-H1975 LUAD cells as well as in the xenograft tumors, with overexpressed GLI2 and increased autophagic activity. The aberrant autophagy in LUAD cells was further confirmed by the three main stages of autophagic flux, including the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Furthermore, inhibition of autophagy by siRNA against ATG5 or ATG7 rescued the sensitivity of A549 and NCI-H1975 LUAD cells to vismodegib in vitro. Meanwhile, administration of the pharmaceutical inhibitor of autophagy, chloroquine, contributed to the enhanced anti-LUAD efficacy of vismodegib in vivo, probably through overproduction of ROS, acceleration of apoptosis, and suppression of GLI2 in LUAD tissues. In summary, our research revealed that downregulating autophagy facilitated the anti-LUAD efficacy of the Shh pathway suppression, thus highlighting a potential approach for LUAD therapy via simultaneously targeting the Shh signaling and autophagy pathway.
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32
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Carpenter RL, Ray H. Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer. Drug Saf 2019; 42:263-279. [PMID: 30649745 DOI: 10.1007/s40264-018-0777-5] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The hedgehog pathway, for which sonic hedgehog (Shh) is the most prominent ligand, is highly conserved and is tightly associated with embryonic development in a number of species. This pathway is also tightly associated with the development of several types of cancer, including basal cell carcinoma (BCC) and acute promyelocytic leukemia, among many others. Inactivating mutations in Patched-1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types, but most prominent in BCC. This has led to the development of several compounds targeting this pathway as a cancer therapeutic. These compounds target the inducers of this pathway in Smoothened (SMO) and the GLI transcription factors, although targeting SMO has had the most success. Despite the many attempts at targeting this pathway, only three US FDA-approved drugs for cancers affect the Shh pathway. Two of these compounds, vismodegib and sonidegib, target SMO to suppress signaling from either PTCH1 or SMO mutations that lead to upregulation of the pathway. The other approved compound is arsenic trioxide, which can suppress this pathway at the level of the GLI proteins, although current evidence suggests it also has other targets. This review focuses on the safety and tolerability of these clinically approved drugs targeting the Shh pathway, along with a discussion on other Shh pathway inhibitors being developed.
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Affiliation(s)
- Richard L Carpenter
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN, 47405, USA. .,Medical Sciences, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN, 47405, USA. .,Simon Cancer Center, Indiana University School of Medicine, 535 Barnhill Dr., Indianapolis, IN, 46202, USA.
| | - Haimanti Ray
- Medical Sciences, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN, 47405, USA
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Lakkakula BVKS, Farran B, Lakkakula S, Peela S, Yarla NS, Bramhachari PV, Kamal MA, Saddala MS, Nagaraju GP. Small molecule tyrosine kinase inhibitors and pancreatic cancer-Trials and troubles. Semin Cancer Biol 2019; 56:149-167. [PMID: 30314681 DOI: 10.1016/j.semcancer.2018.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 09/18/2018] [Accepted: 09/29/2018] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer (PC) is an aggressive carcinoma and the fourth cause of cancer deaths in Western countries. Although surgery is the most effective therapeutic option for PC, the management of unresectable, locally advanced disease is highly challenging. Our improved understanding of pancreatic tumor biology and associated pathways has led to the development of various treatment modalities that can control the metastatic spread of PC. This review intends to present trials of small molecule tyrosine kinase inhibitors (TKIs) in PC management and the troubles encountered due to inevitable acquired resistance to TKIs.
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Affiliation(s)
| | - Batoul Farran
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA
| | - Saikrishna Lakkakula
- Department of Zoology, Visvodaya Government Degree College, Venkatagiri, AP-524132, India
| | - Sujatha Peela
- Department of Biotechnology, Dr.B.R.Ambedkar University, Srikakulam, Andhra Pradesh, India
| | - Nagendra Sastry Yarla
- Dr. LV Prasad Diagnostics and Research Laboratory, Khairtabad, Hyderabad, AP- 500004, India
| | | | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia; Novel Global Community Educational Foundation, Australia
| | | | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA.
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Jin M, Yin Z, Wei K, Xie Y, Bai X, Fu B, Feng Z, Li Q, Chen X. Metanephric mesenchyme-derived Foxd1 + mesangial precursor cells alleviate mesangial proliferative glomerulonephritis. J Mol Med (Berl) 2019; 97:553-561. [PMID: 30810761 DOI: 10.1007/s00109-019-01749-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/16/2019] [Accepted: 01/23/2019] [Indexed: 01/04/2023]
Abstract
Mesangial proliferative glomerulonephritis (MsPGN) is a glomerular disease characterized by the proliferation of mesangial cells and the accumulation of mesangial matrix. No effective treatment is currently able to stop or reverse the disease process. Here, we isolated metanephric mesenchyme-derived Foxd1+ mesangial precursor cells from E13.5 Foxd1Cre; DTRflox double transgenic embryo mice. The Foxd1+ cells showed the cell-specific expression of high levels of Foxd1 without Six2 and manifested specific cell surface markers of mesenchymal stem cells while retaining their differentiation potential. Next, an anti-Thy1 MsPGN rat model was established, and the Foxd1+ cells were injected into the tail veins 24 h later. We found that the Foxd1+ cells could improve the pathological changes to the kidney and significantly reduce proteinuria by inhibiting the sonic hedgehog pathway. Moreover, the Foxd1+ cells could inhibit PDGF-BB-induced activation of mesangial cells by secreting multiple cytokines, including hepatocyte growth factor. Our study uncovered the novel function of Foxd1+ mesangial precursor cells in repairing the damaged mesangium, stabilizing the structure and function of mesangial cells, and restoring their therapeutic effect on the MsPGN. KEY MESSAGES: It is viable to isolate highly purified metanephric mesenchyme-derived Foxd1+ mesangial precursor cells using transgenic mice. Foxd1+ cells could alleviate experimental mesangial proliferative glomerulonephritis and PDGF-induced mesangial cell proliferation through a variety of mechanisms including inhibiting the sonic hedgehog pathway and secreting multiple cytokines. As the progenitor cells of mesangial cells, Foxd1+ cells could stabilize the structure and function of mesangial cells that had undergone pathological changes.
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Affiliation(s)
- Meiling Jin
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
- Department of Nephrology, Beijing Chao-Yang Hospital, Beijing, China
- Medical College, Nankai University, Tianjin, 300071, China
| | - Zhong Yin
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
| | - Kai Wei
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
- Medical College, Nankai University, Tianjin, 300071, China
| | - Yuansheng Xie
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
| | - Xueyuan Bai
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
| | - Bo Fu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
| | - Zhe Feng
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
| | - Qinggang Li
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China.
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China.
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The Importance of the Hedgehog Signaling Pathway in Tumorigenesis of Spinal and Cranial Chordoma. J Clin Med 2019; 8:jcm8020248. [PMID: 30769952 PMCID: PMC6406847 DOI: 10.3390/jcm8020248] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/06/2019] [Accepted: 02/12/2019] [Indexed: 12/20/2022] Open
Abstract
Chordomas is rare malignant bone tumors thought to arise from remnants of embryonic notochord along the spine, frequently at the skull base and sacrum. Although chordoma is slow growing tumors, while are extremely recurrent, and aggressive, as well as the rate of prognosis remains poorly. Radical surgery and high-dose radiation are the most used treatments. Currently, there is no effective chemotherapeutic standard for chordomas. The Hedgehog (HH) pathway adjusts various processes included in expansion and differentiation of tissues and organs throughout the fetus’s life, furthermore cell growth and differentiation in the adult organism, of the cell in an adult organism, in which acute anesthesia is involved in multiple cancers. To study the role of signaling the hedgehog in the base of the skull and sacrum chordomas, the expression of SHH and GLI-1 levels were detected immuno histochemically, Additionally, PTCH-1 and GLI-1 expressions were distinguished by in- Situ- hybridization. Based on the findings presented herein, it is likely that the HH signal cascade was revealed even in cranial, where consecoently spinal chordoma and their recurrences play an important role. Our staining exhibited a canonical, ligand- dependent and autocrine Hedgehog signaling in skull base and sacrum chordomas including relapse. Due to the high levels of SHH and GLI-1 expression in all investigated chordoma samples, the study suggests a possible autocrine ligand-dependent activation of the canonical HH signaling cascade. A paracrine or non-canonical pathway cannot be excluded. Our results suggest that Hedgehog-inhibitors, like SHH-, GLI- and SMO- inhibitors, might serve as a potential and effective target for the treatment of chordomas.
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Ma Y, Yu W, Shrivastava A, Srivastava RK, Shankar S. Inhibition of pancreatic cancer stem cell characteristics by α-Mangostin: Molecular mechanisms involving Sonic hedgehog and Nanog. J Cell Mol Med 2019; 23:2719-2730. [PMID: 30712329 PMCID: PMC6433724 DOI: 10.1111/jcmm.14178] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 12/31/2018] [Accepted: 01/02/2019] [Indexed: 12/21/2022] Open
Abstract
The current investigation was intended to elucidate the molecular mechanism of α‐Mangostin in the regulation of pancreatic cancer stem cell (CSC) characteristics. Here, we demonstrate that α‐Mangostin inhibited cell proliferation in pancreatic CSCs and cancer cell lines while it showed no effect on human pancreatic normal ductal epithelial cells. Also, α‐Mangostin inhibited colony formation and induced apoptosis in these cells. Further, α‐Mangostin inhibited the self‐renewal capacity of CSCs isolated from human primary tumours and KrasG12D mice. Furthermore, α‐Mangostin inhibited the invasive and metastatic ability of pancreatic CSCs by suppressing the epithelial‐to‐mesenchymal transition (EMT) via up‐regulation of E‐cadherin and down‐regulation of mesenchymal phenotype by inhibiting N‐cadherin, Snail and Slug expression. Interestingly, the pluripotency maintaining factors and CSC markers were inhibited by α‐Mangostin thus suggesting that α‐Mangostin can target CSCs to inhibit pancreatic cancer effectively. Gli signalling plays a crucial role in the self‐renewal and pluripotency of CSCs. α‐Mangostin inhibited the Gli transcription and the expression of Gli target genes (Nanog, Oct4, c‐Myc, Sox‐2 and KLF4) in CSCs. Using ChIP assay, we demonstrated that Nanog could directly bind to promoters of Cdk2, Cdk6, FGF4, c‐Myc and α‐Mangostin inhibited Nanog binding to these promoters. Conversely, the inhibitory effects of the α‐Mangostin on CSC proliferation and Gli or Nanog transcription and their targets were abrogated by either enforced activation of sonic hedgehog (Shh) or by the overexpression of Nanog. Taken together, our studies suggest that α‐Mangostin may act as Gli inhibitor and establishes the pre‐clinical significance of α‐Mangostin for the prevention and treatment of pancreatic cancer.
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Affiliation(s)
- Yiming Ma
- Kansas City VA Medical Center, Kansas City, Missouri
| | - Wei Yu
- Kansas City VA Medical Center, Kansas City, Missouri
| | - Anju Shrivastava
- Department of Oncology, St. Joseph's Hospital and Medical Center, Phoenix, Arizona
| | - Rakesh K Srivastava
- Kansas City VA Medical Center, Kansas City, Missouri.,Department of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, Missouri
| | - Sharmila Shankar
- Kansas City VA Medical Center, Kansas City, Missouri.,Department of Pathology, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri
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Fu J, Shrivastava A, Shrivastava SK, Srivastava RK, Shankar S. Triacetyl resveratrol upregulates miRNA‑200 and suppresses the Shh pathway in pancreatic cancer: A potential therapeutic agent. Int J Oncol 2019; 54:1306-1316. [PMID: 30720134 DOI: 10.3892/ijo.2019.4700] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 01/07/2019] [Indexed: 11/06/2022] Open
Abstract
Trans‑3,4',5‑trihydroxystilbene (resveratrol) is a naturally occurring polyphenolic phytoalexin with marked anticancer activities, and is mainly found in grapes, berries and peanuts. However, due to a low bioavailability, it has not progressed to clinical practice for cancer treatment. Therefore, the aims of the present study were to examine the anticancer activities of the resveratrol derivative, triacetyl resveratrol (TCRV), in pancreatic cancer cells. Apoptosis was measured by fluorescence‑activated cell sorting and terminal deoxynucleotidyl transferase (TdT)‑mediated dUTP nick‑end labeling assays. Gene expression was measured by reverse transcription‑quantitative polymerase chain reaction. TCRV inhibited colony formation and induced apoptosis through caspase‑3 activation in human pancreatic cancer AsPC‑1 and PANC‑1 cells, whereas it exerted no effect on human pancreatic normal ductal epithelial cells (HPNE). TCRV inhibited epithelial‑mesenchymal transition (EMT) by upregulating the expression of E‑cadherin and suppressing the expression of N‑cadherin and the transcription factors, Snail, Slug and Zeb1. TCRV inhibited Zeb1 3'UTR‑luciferase activity through the upregulation of microRNA (miR)‑200 family members. The inhibitory effects of TCRV on pancreatic cancer cell migration and invasion were counteracted by anti‑miR‑200 family members. The inhibitory effects of TCRV on EMT and the induction of apoptosis were exerted through the suppression of the sonic hedgehog (Shh) pathway, and through the modulation of cyclin D1 and Bcl‑2 expression. The hyperactivation of the Shh pathway by either Shh protein or Gli1 overexpression abrogated the biological effects of TCRV. Taken together, the results of this study demonstrate that TCRV inhibits pancreatic cancer growth and EMT by targeting the Shh pathway and its downstream signaling mediators. TCRV inhibited EMT through the upregulation of miR‑200 family members. Since TCRV effectively inhibited the growth of human pancreatic cancer cells by modulating the Shh pathway, without affecting the growth of HPNE cells, our findings suggest the possible use of TCRV as a promising candidate for the treatment and/or prevention of pancreatic cancer.
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Affiliation(s)
- Junsheng Fu
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| | - Anju Shrivastava
- St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Sushant K Shrivastava
- Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India
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Diab M, Azmi A, Mohammad R, Philip PA. Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges. Expert Opin Pharmacother 2018; 20:535-546. [PMID: 30592647 DOI: 10.1080/14656566.2018.1561869] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease. AREAS COVERED This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease. EXPERT OPINION Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemcitabine (GEM) and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). PDAC has a number of genetic mutations that may explain its biological behavior, such as KRAS, p53 and CDK2NA, which occur in more than 90% of cases. Unfortunately, to this day, a specific targeting agent to any of those frequent gene mutations is lacking. Emerging areas of targeted therapies include the DNA repair, stroma, metabolism, and stem cells. Immunotherapy with either vaccines or immune checkpoint inhibitors has not produced any significant improvements in outcome of PDAC. Incorporating different approaches in therapy, including conventional, immunological, and others, is key in offering patients with the best possible care.
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Affiliation(s)
- Maria Diab
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Asfar Azmi
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Ramzi Mohammad
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Philip A Philip
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA.,b Department of Pharmacology, School of Medicine , Wayne State University , Detroit , MI , USA
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Toledo-Guzmán ME, Bigoni-Ordóñez GD, Ibáñez Hernández M, Ortiz-Sánchez E. Cancer stem cell impact on clinical oncology. World J Stem Cells 2018; 10:183-195. [PMID: 30613312 PMCID: PMC6306557 DOI: 10.4252/wjsc.v10.i12.183] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/15/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023] Open
Abstract
Cancer is a widespread worldwide chronic disease. In most cases, the high mortality rate from cancer correlates with a lack of clear symptoms, which results in late diagnosis for patients, and consequently, advanced tumor disease with poor probabilities for cure, since many patients will show chemo- and radio-resistance. Several mechanisms have been studied to explain chemo- and radio-resistance to anti-tumor therapies, including cell signaling pathways, anti-apoptotic mechanisms, stemness, metabolism, and cellular phenotypes. Interestingly, the presence of cancer stem cells (CSCs), which are a subset of cells within the tumors, has been related to therapy resistance. In this review, we focus on evaluating the presence of CSCs in different tumors such as breast cancer, gastric cancer, lung cancer, and hematological neoplasias, highlighting studies where CSCs were identified in patient samples. It is evident that there has been a great drive to identify the cell surface phenotypes of CSCs so that they can be used as a tool for anti-tumor therapy treatment design. We also review the potential effect of nanoparticles, drugs, natural compounds, aldehyde dehydrogenase inhibitors, cell signaling inhibitors, and antibodies to treat CSCs from specific tumors. Taken together, we present an overview of the role of CSCs in tumorigenesis and how research is advancing to target these highly tumorigenic cells to improve oncology patient outcomes.
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Affiliation(s)
- Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | | | - Miguel Ibáñez Hernández
- Departamento de Bioquímica, Laboratorio de Terapia Génica, Escuela Nacional de Ciencias Biológicas, Posgrado de Biomedicina y Biotecnología Molecular, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico.
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Barati Bagherabad M, Afzaljavan F, ShahidSales S, Hassanian SM, Avan A. Targeted therapies in pancreatic cancer: Promises and failures. J Cell Biochem 2018; 120:2726-2741. [PMID: 28703890 DOI: 10.1002/jcb.26284] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 07/11/2018] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incidence rate nearly equal to its mortality rate. The poor prognosis of the disease can be explained by the absence of effective biomarkers for screening and early detection, together with the aggressive behavior and resistance to the currently available chemotherapy. The therapeutic failure can also be attributed to the inter-/intratumor genetic heterogeneity and the abundance of tumor stroma that occupies the majority of the tumor mass. Gemcitabine is used in the treatment of PDAC; however, the response rate is less than 12%. A recent phase III trial revealed that the combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin could be an option for the treatment of metastatic PDAC patients with good performance status, although these approaches can result in high toxicity level. Further investigations are required to develop innovative anticancer agents that either improve gemcitabine activity, within novel combinatorial approaches or acts with a better efficacy than gemcitabine. The aim of the current review is to give an overview of preclinical and clinical studies targeting key dysregulated signaling pathways in PDAC.
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Affiliation(s)
- Matineh Barati Bagherabad
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fahimeh Afzaljavan
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soodabeh ShahidSales
- Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Molecular Medicine group, Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Nimmakayala RK, Batra SK, Ponnusamy MP. Unraveling the journey of cancer stem cells from origin to metastasis. Biochim Biophys Acta Rev Cancer 2018; 1871:50-63. [PMID: 30419314 DOI: 10.1016/j.bbcan.2018.10.006] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 09/27/2018] [Accepted: 10/09/2018] [Indexed: 02/08/2023]
Abstract
Cancer biology research over recent decades has given ample evidence for the existence of self-renewing and drug-resistant populations within heterogeneous tumors, widely recognized as cancer stem cells (CSCs). However, a lack of clear understanding about the origin, existence, maintenance, and metastatic roles of CSCs limit efforts towards the development of CSC-targeted therapy. In this review, we describe novel avenues of current CSC biology. In addition to cell fusion and horizontal gene transfer, CSCs are originated by mutations in somatic or differentiated cancer cells, resulting in de-differentiation and reprogramming. Recent studies also provided evidence for the existence of distinct or heterogeneous CSC populations within a single heterogeneous tumor. Our analysis of the literature also opens the doors for a novel hypothesis that CSC populations with specific phenotypes, metabolic profiles, and clonogenic potential metastasize to specific organs.
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Affiliation(s)
- Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
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42
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Role of tumor microenvironment in cancer stem cell chemoresistance and recurrence. Int J Biochem Cell Biol 2018; 103:115-124. [DOI: 10.1016/j.biocel.2018.08.011] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 08/16/2018] [Accepted: 08/18/2018] [Indexed: 12/13/2022]
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43
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Zeng X, Ju D. Hedgehog Signaling Pathway and Autophagy in Cancer. Int J Mol Sci 2018; 19:E2279. [PMID: 30081498 PMCID: PMC6121518 DOI: 10.3390/ijms19082279] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 07/29/2018] [Accepted: 07/31/2018] [Indexed: 12/19/2022] Open
Abstract
Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities.
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Affiliation(s)
- Xian Zeng
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery MOE, School of Pharmacy, Fudan University, Shanghai 201203, China.
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
| | - Dianwen Ju
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery MOE, School of Pharmacy, Fudan University, Shanghai 201203, China.
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Yu W, Ma Y, Shankar S, Srivastava RK. Chronic ethanol exposure of human pancreatic normal ductal epithelial cells induces cancer stem cell phenotype through SATB2. J Cell Mol Med 2018; 22:3920-3928. [PMID: 29761897 PMCID: PMC6050497 DOI: 10.1111/jcmm.13666] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 03/31/2018] [Indexed: 12/13/2022] Open
Abstract
The incidence of pancreatic cancer is on the rise. Risk factors for pancreatic cancer include alcohol toxicity and metabolic conditions such as obesity, hypertension, dyslipidaemia, insulin resistance and type 2 diabetes. However, the molecular mechanism by which chronic alcohol consumption contributes to pancreatic cancer is not well understood. The purpose of the study was to demonstrate the effects of long-term chronic ethanol exposure on the transformation of human pancreatic normal ductal epithelial (HPNE) cells. Our data showed that ethanol-transformed HPNE cells were more progressively transformed exhibiting spheroids and colonies, and anchorage-independent growth. These transformed cells contained high levels of reactive oxygen species and induced SATB2 expression. Furthermore, during ethanol-induced cellular transformation, cells gained the phenotypes of cancer stem cells (CSCs) by expressing pluripotency maintaining factors (Oct4, Sox2, cMyc and KLF4) and stem cell markers (CD24, CD44 and CD133). Ethanol-induced SATB2 can bind to the promoters of KLF4, Oct4, cMyc, Sox2, Bcl-2 and XIAP genes. Suppression of SATB2 expression in ethanol-transformed HPNE cells inhibited cell proliferation, colony formation and markers of CSCs and pluripotency. These data suggest that chronic alcohol consumption may contribute toward the development of pancreatic cancer by converting HPNE cells to cancer stem-like cells.
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Affiliation(s)
- Wei Yu
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Yiming Ma
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Sharmila Shankar
- Kansas City VA Medical Center, Kansas City, MO, USA
- Department of Pathology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Rakesh K Srivastava
- Kansas City VA Medical Center, Kansas City, MO, USA
- Department of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO, USA
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45
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Emerging functional markers for cancer stem cell-based therapies: Understanding signaling networks for targeting metastasis. Semin Cancer Biol 2018; 53:90-109. [PMID: 29966677 DOI: 10.1016/j.semcancer.2018.06.006] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/20/2018] [Accepted: 06/28/2018] [Indexed: 12/18/2022]
Abstract
Metastasis is one of the most challenging issues in cancer patient management, and effective therapies to specifically target disease progression are missing, emphasizing the urgent need for developing novel anti-metastatic therapeutics. Cancer stem cells (CSCs) gained fast attention as a minor population of highly malignant cells within liquid and solid tumors that are responsible for tumor onset, self-renewal, resistance to radio- and chemotherapies, and evasion of immune surveillance accelerating recurrence and metastasis. Recent progress in the identification of their phenotypic and molecular characteristics and interactions with the tumor microenvironment provides great potential for the development of CSC-based targeted therapies and radical improvement in metastasis prevention and cancer patient prognosis. Here, we report on newly uncovered signaling mechanisms controlling CSC's aggressiveness and treatment resistance, and CSC-specific agents and molecular therapeutics, some of which are currently under investigation in clinical trials, gearing towards decisive functional CSC intrinsic or surface markers. One special research focus rests upon subverted regulatory pathways such as insulin-like growth factor 1 receptor signaling and its interactors in metastasis-initiating cell populations directly related to the gain of stem cell- and EMT-associated properties, as well as key components of the E2F transcription factor network regulating metastatic progression, microenvironmental changes, and chemoresistance. In addition, the study provides insight into systems biology tools to establish complex molecular relationships behind the emergence of aggressive phenotypes from high-throughput data that rely on network-based analysis and their use to investigate immune escape mechanisms or predict clinical outcome-relevant CSC receptor signaling signatures. We further propose that customized vector technologies could drastically enhance systemic drug delivery to target sites, and summarize recent progress and remaining challenges. This review integrates available knowledge on CSC biology, computational modeling approaches, molecular targeting strategies, and delivery techniques to envision future clinical therapies designed to conquer metastasis-initiating cells.
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Wefers C, Schreibelt G, Massuger LFAG, de Vries IJM, Torensma R. Immune Curbing of Cancer Stem Cells by CTLs Directed to NANOG. Front Immunol 2018; 9:1412. [PMID: 29971070 PMCID: PMC6018198 DOI: 10.3389/fimmu.2018.01412] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 06/06/2018] [Indexed: 12/15/2022] Open
Abstract
Cancer stem cells (CSCs) have been identified as the source of tumor growth and disease recurrence. Eradication of CSCs is thus essential to achieve durable responses, but CSCs are resistant to current anti-tumor therapies. Novel therapeutic approaches that specifically target CSCs will, therefore, be crucial to improve patient outcome. Immunotherapies, which boost the body's own immune system to eliminate cancerous cells, could be an alternative approach to target CSCs. Vaccines of dendritic cells (DCs) loaded with tumor antigens can evoke highly specific anti-tumor T cell responses. Importantly, DC vaccination also promotes immunological memory formation, paving the way for long-term cancer control. Here, we propose a DC vaccination that specifically targets CSCs. DCs loaded with NANOG peptides, a protein required for maintaining stem cell properties, could evoke a potent anti-tumor immune response against CSCs. We hypothesize that the resulting immunological memory will also control newly formed CSCs, thereby preventing disease recurrence.
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Affiliation(s)
- Christina Wefers
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, Netherlands
- Department of Obstetrics and Gynecology, Radboudumc, Nijmegen, Netherlands
| | - Gerty Schreibelt
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, Netherlands
| | | | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, Netherlands
| | - Ruurd Torensma
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, Netherlands
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Song L, Chen X, Wang P, Gao S, Qu C, Liu L. Effects of baicalein on pancreatic cancer stem cells via modulation of sonic Hedgehog pathway. Acta Biochim Biophys Sin (Shanghai) 2018; 50:586-596. [PMID: 29697746 DOI: 10.1093/abbs/gmy045] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Indexed: 12/27/2022] Open
Abstract
Recent studies have suggested that sonic Hedgehog (Shh) signaling pathway is aberrantly activated in cancer stem cells (CSCs). A seven-herb Chinese medicinal formula composed of Amorphophallus rivieri Durieu, Oldenlandia diffusa (Wild) Roxb, Scutellaria barbata D. Don, Gynostemma pentaphyllum (Thunb.) Mak and Amomum cardamomum L, i.e. Qingyihuaji (QYHJ) formula, has been shown to inhibit proliferation of pancreatic CSCs by inhibiting Shh signaling pathway and thereby prolong the overall survival of pancreatic cancer patients. Mass spectrometry analysis revealed that baicalein is one of the major compounds of QYHJ formula. The objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms of baicalein involved in pancreatic cancer treatment. We examined the effects of baicalein on pancreatic CSCs both in vivo and in vitro. The results indicated that baicalein attenuated the pluripotency of pancreatic CSCs. Then, we investigated the underlying mechanism and found that nuclear transcription factors, such as Sox-2 and Oct-4 as well as members in Shh signaling pathway, e.g. SHH, SMO, and Gli-2, were downregulated after baicalein treatment. Furthermore, silencing Gli-2 expression by small interfering RNA decreased Sox-2 expression and blocked the inhibitory effects of baicalein, suggesting that the effects of baicalein may be mediated through inhibition of Shh pathway. Our results suggested that baicalein, an active compound in QYHJ formula, could suppress the self-renewal of pancreatic CSCs through inhibition of Shh signaling pathway.
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Affiliation(s)
- Libin Song
- Department of Integrative Oncology, Fudan University, Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiangyuan Chen
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Anesthesiology, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Peng Wang
- Department of Integrative Oncology, Fudan University, Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Song Gao
- Department of Integrative Oncology, Fudan University, Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Chao Qu
- Department of Integrative Oncology, Fudan University, Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Luming Liu
- Department of Integrative Oncology, Fudan University, Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Targeting GLI Transcription Factors in Cancer. Molecules 2018; 23:molecules23051003. [PMID: 29695137 PMCID: PMC6100584 DOI: 10.3390/molecules23051003] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 04/19/2018] [Accepted: 04/20/2018] [Indexed: 12/22/2022] Open
Abstract
Aberrant activation of hedgehog (Hh) signaling has been observed in a wide variety of tumors and accounts for more than 25% of human cancer deaths. Inhibitors targeting the Hh signal transducer Smoothened (SMO) are widely used and display a good initial efficacy in patients suffering from basal cell carcinoma (BCC); however, a large number of patients relapse. Though SMO mutations may explain acquired therapy resistance, a growing body of evidence suggests that the non-canonical, SMO-independent activation of the Hh pathway in BCC patients can also account for this adverse effect. In this review, we highlight the importance of glioma-associated oncogene (GLI) transcription factors (the main downstream effectors of the canonical and the non-canonical Hh cascade) and their putative role in the regulation of multiple oncogenic signaling pathways. Moreover, we discuss the contribution of the Hh signaling to malignant transformation and propose GLIs as central hubs in tumor signaling networks and thus attractive molecular targets in anti-cancer therapies.
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Gu J, Saiyin H, Fu D, Li J. Stroma - A Double-Edged Sword in Pancreatic Cancer: A Lesson From Targeting Stroma in Pancreatic Cancer With Hedgehog Signaling Inhibitors. Pancreas 2018; 47:382-389. [PMID: 29521941 DOI: 10.1097/mpa.0000000000001023] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Pancreatic cancer is a uniformly lethal malignancy with an abundant dense desmoplastic stroma. Because of its dense stroma, conventional drugs were considered to not penetrate this physical barrier, and this caused a systemic drug resistance. Thus, abolishing this barrier with targeted agents is considered to improve the efficiency of chemotherapeutic treatment. The Hedgehog (Hh) signaling pathway is a critical regulator of pancreas development and plays diversified roles in pancreatic cancer stroma and neoplastic cells. Increasing Hh expression in neoplastic cells added desmoplastic stroma accumulation in orthotopic tumors, and Hh inhibitors that target the stroma have an ability to prolong the overall survival of Pdx-1-Cre/KrasG12D/p53R172H mice models via deleting the stromal components and increasing vascularity in pancreatic tumor. However, the failure of translation from bench to bedside indicate the complexity of the relationship between Hh signaling and desmoplastic stroma, and more insights into the complex relationships between Hh signaling pathway and stroma, even tumor cells, might help redesign Hh-targeted therapy. In this review, we discuss the possible mechanism of translation of Hh inhibitor in the clinic from pathology to molecular mechanism.
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Tong W, Qiu L, Qi M, Liu J, Hu K, Lin W, Huang Y, Fu J. GANT-61 and GDC-0449 induce apoptosis of prostate cancer stem cells through a GLI-dependent mechanism. J Cell Biochem 2018; 119:3641-3652. [PMID: 29231999 DOI: 10.1002/jcb.26572] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 11/30/2017] [Indexed: 02/05/2023]
Abstract
Aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway promotes prostate cancer (PC) growth and progression by regulating cancer-related genes through its downstream effectors GLI1 and GLI2. Therefore, targeting the SHH-GLI pathway provides an alternative approach to avoid cancer progression. The aim of this study was to delineate the underlying molecular mechanisms by which GDC-0449 (a SMO receptor inhibitor) and GANT-61 (a GLI transcription factor inhibitor) regulate cellular proliferation and self-renewal in human PC stem cells (ProCSCs). Inhibition of the SHH signaling pathway by GANT-61 induced apoptosis with more efficacy than by GDC-0449 in ProCSCs and PC cell lines. GLI1 and GLI2 expression, promoter-binding activity and GLI-responsive luciferase reporter activity were all decreased with either GDC-0449 or GANT-61 treatment. Expression of Fas, DR4, DR5, and cleavage of caspase-3 and PARP were increased, whereas levels of PDGFR-α and Bcl-2 were reduced. Double knockout of GLI1 and GLI2 using shRNA abolished the effects observed with either GDC-0449 or GANT-61 treatment. Collectively, our results showed that GANT-61 and GDC-0449 induced ProCSC apoptosis by directly or indirectly inhibiting the activities of the GLI family transcription factors, may enhance the efficacy of PC treatment.
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Affiliation(s)
- Wangxia Tong
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian Province, P.R. China.,Department of Hepatology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, P.R. China
| | - Lei Qiu
- Division of Abdominal Cancer, West China Hospital, Sichuan University and National Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Meng Qi
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian Province, P.R. China
| | - Jianbing Liu
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian Province, P.R. China
| | - Kaihui Hu
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian Province, P.R. China
| | - Wenxiong Lin
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian Province, P.R. China.,Institute of Modern Seed Industrial Engineering, Fujian Agriculture and Forestry University, Fuzhou, Fujian Province, P.R. China
| | - Yan Huang
- Center for Nuclear Medicine, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Junsheng Fu
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian Province, P.R. China.,Institute of Modern Seed Industrial Engineering, Fujian Agriculture and Forestry University, Fuzhou, Fujian Province, P.R. China
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