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Palazzo C, Mastrantonio R, Gioelli N, Testa E, Recco F, Lucchetti D, Villari G, D'Alessio A, Sgambato A, Mignone F, Serini G, Viscomi MT, Tamagnone L. Neuropilin1-dependent paracrine signaling of cancer cells mediated by miRNA exosomal cargo. Cell Commun Signal 2025; 23:54. [PMID: 39875894 PMCID: PMC11776261 DOI: 10.1186/s12964-025-02061-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 01/20/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Neuropilin-1 (NRP1) is a transmembrane protein involved in surface receptor complexes for a variety of extracellular signals. NRP1 expression in human cancers is associated with prominent angiogenesis and advanced progression stage. However, the molecular mechanisms underlying NRP1 activity in the tumor microenvironment remain unclear. Notably, diffusible forms of NRP1 in the extracellular space have been reported, but their functional role is poorly understood. METHODS Extracellular vesicles (EV) were isolated from conditioned media of diverse cancer cells. The quality of exosome-enriched preparations was validated by the presence of specific markers in western blotting, as well as by light scattering and nanoparticle tracking analysis. Wound healing, transwell, and digital real-time migration assays were carried out to assess the activity of cancer cell-derived exosomes in the regulation of endothelial cells. RNA interference was applied to obtain NRP1 knock-down, and cDNA transfer to achieve its overexpression, in exosome-releasing cells. The micro-RNA profile carried by exosomes was investigated by Next Generation Sequencing. miRNA-Scope in situ hybridization was used to assess the transfer of miRNA exosome cargo to target cells, and immunofluorescence analysis revealed expression regulation of targeted proteins. miRNA activity was blocked by the use of specific antago-miRs. RESULTS In this study, we show that diverse human cancer cells release NRP1 embedded in exosome-like small extracellular vesicles, which mediate a previously unknown NRP1-dependent paracrine signaling mechanism regulating endothelial cell migration. By transcriptomic analysis of the cargo of NRP1-loaded exosomes, we found a significant enrichment of miR-210-3p, known to promote tumor angiogenesis. Gene knock-down and overexpression experiments demonstrated that the loading of miR-210-3p into exosomes is dependent on NRP1. Data furthermore indicate that the exosomes released through this NRP1-driven mechanism effectively transfer miR-210-3p to human endothelial cells, causing paracrine downregulation of the regulatory cue ephrin-A3 and promotion of cell migration. The mechanistic involvement of miR-210-3p in this pathway was confirmed by applying a specific antago-miR. CONCLUSIONS In sum, we unveiled a previously unknown NRP1-dependent paracrine signaling mechanism, mediated by the loading of pro-angiogenic miR-210-3p in exosomes released by cancer cells, which underscores the relevance of NRP1 in controlling the tumor microenvironment.
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Affiliation(s)
- Claudia Palazzo
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Roberta Mastrantonio
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario "Agostino Gemelli" - IRCCS, Rome, Italy
| | - Noemi Gioelli
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, TO, Italy
| | - Erika Testa
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario "Agostino Gemelli" - IRCCS, Rome, Italy
| | | | - Donatella Lucchetti
- Fondazione Policlinico Universitario "Agostino Gemelli" - IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giulia Villari
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, TO, Italy
- Department of Oncology, University of Torino School of Medicine, Candiolo, TO, Italy
| | - Alessio D'Alessio
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario "Agostino Gemelli" - IRCCS, Rome, Italy
| | - Alessandro Sgambato
- Fondazione Policlinico Universitario "Agostino Gemelli" - IRCCS, Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Guido Serini
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Candiolo, TO, Italy
- Department of Oncology, University of Torino School of Medicine, Candiolo, TO, Italy
| | - Maria Teresa Viscomi
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario "Agostino Gemelli" - IRCCS, Rome, Italy
| | - Luca Tamagnone
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy.
- Fondazione Policlinico Universitario "Agostino Gemelli" - IRCCS, Rome, Italy.
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Miranda I, Jahan N, Shevde LA. The metastatic cascade through the lens of therapeutic inhibition. Cell Rep Med 2025; 6:101872. [PMID: 39706193 PMCID: PMC11866422 DOI: 10.1016/j.xcrm.2024.101872] [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: 06/19/2024] [Revised: 10/21/2024] [Accepted: 11/18/2024] [Indexed: 12/23/2024]
Abstract
Metastasis is a main cause of cancer-related death, and a deeper understanding of the metastatic process will inform more targeted and mechanistic approaches that can abrogate challenges in treatment efficacy and toxicity. Several steps throughout the metastatic cascade, from angiogenesis to secondary tumor formation, offer specific vulnerabilities to therapies that can lead to the decline or cessation of metastatic progression. A deeper understanding of the metastatic cascade also allows combination systemic therapies to be used synergistically. In this review, we describe current treatment modalities in the context of multiple steps of the metastatic cascade. We highlight their mechanisms and present their efficacy across multiple cancers. This work also presents targets within the metastatic cascade in need of more research that can advance the landscape of treatments and lead to the goal of metastatic cancer remission.
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Affiliation(s)
- Ian Miranda
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nusrat Jahan
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lalita A Shevde
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
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Obaidur Rab S, Altalbawy FMA, Chandra M, Ariffin IA, Kaur P, Rathore G, Rizaev J, Aloraibi F, Najeeb MA, Abdulhussain MA, Zwamel AH. Targeting the lung tumor microenvironment by phytochemicals and their nanoformulations. Pathol Res Pract 2024; 264:155679. [PMID: 39500198 DOI: 10.1016/j.prp.2024.155679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/15/2024] [Accepted: 10/25/2024] [Indexed: 11/30/2024]
Abstract
Lung malignancies are among the most prevalent and foremost causes of tumor-related deaths. Despite significant advancements in the understanding and management of lung cancer, resistance to traditional treatments remains a significant challenge. Understanding and targeting tumor microenvironment (TME) have attracted interest in the recent decade for eliminating various solid tumors. The lung TME has a crucial position in tumor expansion and therapy failure, driving it an engaging target for novel medicinal interventions. Plant-derived products offer a promising avenue for targeting TME due to their diverse chemical structures and biological activities. However, their clinical use is hindered by insufficient bioavailability and also possible systemic toxicity. The use of nanoparticles as delivery vehicles for natural products can overcome these challenges and enhance their therapeutic efficacy. This review article explores the potential of plant-derived products as medicinal agents for targeting lung TME. We provide an outline of the present knowledge of lung TME and explain the mechanisms by which plant-derived products can modulate key components of this microenvironment. The promising impacts and properties of nanoparticles for the delivery of these derivatives into lung tumors will also be discussed. We also review the preclinical and clinical findings for supporting the usefulness of these agents in targeting lung TME. Additionally, we highlight the challenges and forthcoming trends in the development of plant-derived products as targeted therapies for lung cancer, with a particular focus on combination therapies.
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Affiliation(s)
- Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia.
| | - Muktesh Chandra
- Department of Bioinformatics, Marwadi University Research Center, Faculty of Engineering and Technology, Marwadi University, Rajkot, Gujarat 360003, India
| | - I A Ariffin
- Management and Science University, Shah Alam, Selangor, Malaysia
| | - Parjinder Kaur
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab 140307, India
| | - Gulshan Rathore
- Department of Pharmaceutics, NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - Jasur Rizaev
- Department of Public health and Healthcare management, Rector, Samarkand State Medical University, 18, Amir Temur Street, Samarkand, Uzbekistan
| | - Farah Aloraibi
- Department of Density, Al-Manara College for Medical Sciences, Maysan, Iraq
| | - Maryam Ali Najeeb
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | | | - Ahmed Hussein Zwamel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq; Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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Sánchez-Martínez C, Grueso E, Calvo-López T, Martinez-Ortega J, Ruiz A, Almendral JM. VEGF-Virus Interactions: Pathogenic Mechanisms and Therapeutic Applications. Cells 2024; 13:1815. [PMID: 39513922 PMCID: PMC11545703 DOI: 10.3390/cells13211815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Many types of viruses directly or indirectly target the vascular endothelial growth factor (VEGF) system, which is a central regulator of vasculogenesis and angiogenesis in physiological homeostasis, causing diverse pathologies. Other viruses have been developed into effective therapeutic tools for VEGF modulation in conditions such as cancer and eye diseases. Some viruses may alter the levels of VEGF in the pathogenesis of respiratory syndromes, or they may encode VEGF-like factors, promoting vascular disruption and angiogenesis to enable viruses' systemic spread. Oncogenic viruses may express interactive factors that perturb VEGF's functional levels or downstream signaling, which increases the neovascularization and metastasis of tumors. Furthermore, many viruses are being developed as therapeutic vectors for vascular pathologies in clinical trials. Major examples are those viral vectors that inhibit the role of VEGF in the neovascularization required for cancer progression; this is achieved through the induction of immune responses, by exposing specific peptides that block signaling or by expressing anti-VEGF and anti-VEGF receptor-neutralizing antibodies. Other viruses have been engineered into effective pro- or anti-angiogenesis multitarget vectors for neovascular eye diseases, paving the way for therapies with improved safety and minimal side effects. This article critically reviews the large body of literature on these issues, highlighting those contributions that describe the molecular mechanisms, thus expanding our understanding of the VEGF-virus interactions in disease and therapy. This could facilitate the clinical use of therapeutic virus vectors in precision medicine for the VEGF system.
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Affiliation(s)
- Cristina Sánchez-Martínez
- Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (C.S.-M.); (E.G.)
| | - Esther Grueso
- Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (C.S.-M.); (E.G.)
| | - Tania Calvo-López
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
- Department of Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Jorge Martinez-Ortega
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
| | - Ana Ruiz
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
| | - José M. Almendral
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
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Coursier D, Calvo F. CAFs vs. TECs: when blood feuds fuel cancer progression, dissemination and therapeutic resistance. Cell Oncol (Dordr) 2024; 47:1091-1112. [PMID: 38453816 PMCID: PMC11322395 DOI: 10.1007/s13402-024-00931-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2024] [Indexed: 03/09/2024] Open
Abstract
Neoplastic progression involves complex interactions between cancer cells and the surrounding stromal milieu, fostering microenvironments that crucially drive tumor progression and dissemination. Of these stromal constituents, cancer-associated fibroblasts (CAFs) emerge as predominant inhabitants within the tumor microenvironment (TME), actively shaping multiple facets of tumorigenesis, including cancer cell proliferation, invasiveness, and immune evasion. Notably, CAFs also orchestrate the production of pro-angiogenic factors, fueling neovascularization to sustain the metabolic demands of proliferating cancer cells. Moreover, CAFs may also directly or indirectly affect endothelial cell behavior and vascular architecture, which may impact in tumor progression and responses to anti-cancer interventions. Conversely, tumor endothelial cells (TECs) exhibit a corrupted state that has been shown to affect cancer cell growth and inflammation. Both CAFs and TECs are emerging as pivotal regulators of the TME, engaging in multifaceted biological processes that significantly impact cancer progression, dissemination, and therapeutic responses. Yet, the intricate interplay between these stromal components and the orchestrated functions of each cell type remains incompletely elucidated. In this review, we summarize the current understanding of the dynamic interrelationships between CAFs and TECs, discussing the challenges and prospects for leveraging their interactions towards therapeutic advancements in cancer.
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Affiliation(s)
- Diane Coursier
- Instituto de Biomedicina y Biotecnología de Cantabria (Consejo Superior de Investigaciones Científicas, Universidad de Cantabria), Santander, Spain
| | - Fernando Calvo
- Instituto de Biomedicina y Biotecnología de Cantabria (Consejo Superior de Investigaciones Científicas, Universidad de Cantabria), Santander, Spain.
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6
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Melo Bisneto AVD, Fernandes AS, Silva LDC, Silva LS, Araújo DPD, Santos ICD, Melo MDR, Silva RRDS, Franchi LP, Cardoso CG, Silveira-Lacerda EDP, Carneiro CC, Teixeira CS, Chen-Chen L. Dioclea violacea lectin inhibits tumorigenesis and tumor angiogenesis in vivo. Biochimie 2024; 222:18-27. [PMID: 38395337 DOI: 10.1016/j.biochi.2024.02.007] [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: 06/30/2023] [Revised: 01/08/2024] [Accepted: 02/20/2024] [Indexed: 02/25/2024]
Abstract
Dioclea violacea seed mannose-binding lectin (DvL) has attracted considerable attention because of its interesting biological activities, including antitumor, antioxidant, and anti-inflammatory activities. This study evaluated the cytotoxic effect of DvL on tumor and normal cells using the mitochondrial activity reduction (MTT) assay, the carcinogenic and anti-carcinogenic activity by the epithelial tumor test (ETT) in Drosophila melanogaster, and the anti-angiogenic effect by the chick embryo chorioallantoic membrane (CAM) assay. Data demonstrated that DvL promoted strong selective cytotoxicity against tumor cell lines, especially A549 and S180 cells, whereas normal cell lines were weakly affected. Furthermore, DvL did not promote carcinogenesis in D. melanogaster at any concentration tested, but modulated DXR-induced carcinogenesis at the highest concentrations tested. In the CAM and immunohistochemical assays, DvL inhibited sarcoma 180-induced angiogenesis and promoted the reduction of VEGF and TGF-β levels at all concentrations tested. Therefore, our results demonstrated that DvL is a potent anticancer, anti-angiogenic, and selective cytotoxic agent for tumor cells, suggesting its potential application as a prototype molecule for the development of new drugs with chemoprotective and/or antitumor effects.
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Affiliation(s)
- Abel Vieira de Melo Bisneto
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Amanda Silva Fernandes
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Lívia do Carmo Silva
- Laboratory of Molecular Genetics and Cytogenetics, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Luana Santos Silva
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Diego Pereira de Araújo
- Laboratory of Molecular Genetics and Cytogenetics, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Ivan Cerqueira Dos Santos
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Marcella da Rocha Melo
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | | | - Leonardo Pereira Franchi
- Department of Biochemistry and Molecular Biology of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Clever Gomes Cardoso
- Department of Morphology of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Elisangela de Paula Silveira-Lacerda
- Laboratory of Molecular Genetics and Cytogenetics, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil
| | - Cristiene Costa Carneiro
- Institute of Health Sciences, Universidade Paulista - Campus Flamboyant, 74845-090, Goiânia, Brazil
| | - Claudener Souza Teixeira
- Center for Agrarian Sciences and Biodiversity, Federal University of Cariri, 63130-025, Crato, Brazil
| | - Lee Chen-Chen
- Laboratory of Radiobiology and Mutagenesis, Department of Genetics of Institute of Biological Sciences, Federal University of Goiás, 74690-900, Goiânia, Brazil.
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Li QQ, Guo M, He GH, Xi KH, Zhou MY, Shi RY, Chen GQ. VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement membrane. Oncogene 2024; 43:1836-1851. [PMID: 38654108 DOI: 10.1038/s41388-024-03038-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 04/12/2024] [Accepted: 04/15/2024] [Indexed: 04/25/2024]
Abstract
Vascular endothelial cells (VECs) are key players in the formation of neovessels and tumor metastasis, the ultimate cause of the majority of cancer-related human death. However, the crosstalk between VECs and metastasis remain greatly elusive. Based on our finding that tumor-associated VECs present significant decrease of Nrdp1 protein which is closely correlated with higher metastatic probability, herein we show that the conditional medium from hypoxia-incubated cancer cells induces extensive Nrdp1 downregulation in human and mouse VECs by vascular endothelial growth factor (VEGF), which activates CHIP, followed by Nrdp1 degradation in ubiquitin-proteasome-dependent way. More importantly, lung metastases of cancer cells significantly increase in conditional VECs Nrdp1 knockout mice. Mechanically, Nrdp1 promotes degradation of Fam20C, a secretory kinase involved in phosphorylating numerous secreted proteins. Reciprocally, deficiency of Nrdp1 in VECs (ecNrdp1) results in increased secretion of Fam20C, which induces degradation of extracellular matrix and disrupts integrity of vascular basement membrane, thus driving tumor metastatic dissemination. In addition, specific overexpression of ecNrdp1 by Nrdp1-carrying adeno-associated virus or chemical Nrdp1 activator ABPN efficiently mitigates tumor metastasis in mice. Collectively, we explore a new mechanism for VEGF to enhance metastasis and role of Nrdp1 in maintaining the integrity of vascular endothelium, suggesting that ecNrdp1-mediated signaling pathways might become potential target for anti-metastatic therapies.
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Affiliation(s)
- Qing-Qing Li
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China
| | - Meng Guo
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China.
| | - Guang-Huan He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China
| | - Kai-Hua Xi
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China
| | - Mei-Yi Zhou
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China
| | - Rong-Yi Shi
- Hainan Academy of Medical Sciences and School of Basic Medicine, Hainan Medical University, Hainan, 570000, China.
- Key Laboratory of Pediatric Hematology and Oncology in National Health Commission, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, SJTU-SM, Shanghai, 200127, China.
| | - Guo-Qiang Chen
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China.
- Hainan Academy of Medical Sciences and School of Basic Medicine, Hainan Medical University, Hainan, 570000, China.
- Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer, Research Units of Stress and Tumor (2019RU043), Chinese Academy of Medical Sciences, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
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Miao H, Wu Y, Ouyang H, Zhang P, Zheng W, Ma X. Screening and construction of nanobodies against human CD93 using phage libraries and study of their antiangiogenic effects. Front Bioeng Biotechnol 2024; 12:1372245. [PMID: 38751868 PMCID: PMC11094214 DOI: 10.3389/fbioe.2024.1372245] [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: 01/17/2024] [Accepted: 04/11/2024] [Indexed: 05/18/2024] Open
Abstract
Background Cluster of Differentiation 93 (CD93) plays an important role in angiogenesis and is considered an important target for inhibiting tumor angiogenesis, but there are currently no therapeutic antibodies against CD93 in the clinic. Thus, we describe the screening of novel nanobodies (Nbs) targeting human CD93 from a phage library of shark-derived Nbs. Methods Screening and enrichment of phage libraries by enzyme-linked immunosorbent assay (ELISA). Anti-CD93 Nbs were purified by expression in E. coli. The binding affinity of anti-CD93 Nbs NC81/NC89 for CD93 was examined by flow cytometry (FC) and ELISA. The thermal stability of NC81/NC89 was examined by ELISA and CD spectroscopy. Afterward, the anti-angiogenic ability of NC81/NC89 was examined by MTT, wound healing assay, and tube formation assay. The expression level of VE-cadherin (VE-Ca) and CD93 was detected by Western Blot (WB). The binding sites and binding forms of NC81/NC89 to CD93 were analyzed by molecular docking. Results The anti-CD93 Nbs were screened in a phage library, expressed in E. coli, and purified to >95% purity. The results of FC and ELISA showed that NC81/NC89 have binding ability to human umbilical vein endothelial cells (HUVECs). The results of ELISA and CD spectroscopy showed that NC81/NC89 retained the ability to bind CD93 at 80°C and that the secondary structure remained stable. In vitro, the results showed that NC81 and NC89 significantly inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVECs) as well as tube formation on Matrigel. Western Blot showed that NC81 and NC89 also inhibited the expression of VE-Ca thereby increasing vascular permeability. It was found during molecular docking that the CDR regions of NC81 and NC89 could be attached to CD93 by strong hydrogen bonds and salt bridges, and the binding sites were different. Conclusion We have successfully isolated NC81 and NC89, which bind CD93, and both Nbs significantly inhibit angiogenesis and increase vascular permeability. These results suggest that NC81 and NC89 have potential clinical applications in angiogenesis-related therapies.
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Affiliation(s)
- Hui Miao
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Yiling Wu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Hao Ouyang
- Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Peiwen Zhang
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Wenyun Zheng
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Xingyuan Ma
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
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Min T, Lee SH, Lee S. Angiogenesis and Apoptosis: Data Comparison of Similar Microenvironments in the Corpus Luteum and Tumors. Animals (Basel) 2024; 14:1118. [PMID: 38612357 PMCID: PMC11011057 DOI: 10.3390/ani14071118] [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: 02/29/2024] [Revised: 03/20/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024] Open
Abstract
The corpus luteum is a temporary endocrine gland formed in the ovary after ovulation, and it plays a critical role in animal reproductive processes. Tumors rely on the development of an adequate blood supply to ensure the delivery of nutrients and oxygen and the removal of waste products. While angiogenesis occurs in various physiological and pathological contexts, the corpus luteum and tumors share similarities in terms of the signaling pathways that promote angiogenesis. In the corpus luteum and tumors, apoptosis plays a crucial role in controlling cell numbers and ensuring proper tissue development and function. Interestingly, there are similarities between the apoptotic-regulated signaling pathways involved in apoptosis in the corpus luteum and tumors. However, the regulation of apoptosis in both can differ due to their distinct physiological and pathological characteristics. Thus, we reviewed the biological events of the corpus luteum and tumors in similar microenvironments of angiogenesis and apoptosis.
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Affiliation(s)
| | | | - Seunghyung Lee
- College of Animal Life Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea
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Teichmann T, Malacarne P, Zehr S, Günther S, Pflüger-Müller B, Warwick T, Brandes RP. NCoR1 limits angiogenic capacity by altering Notch signaling. J Mol Cell Cardiol 2024; 188:65-78. [PMID: 38359551 DOI: 10.1016/j.yjmcc.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/15/2024] [Accepted: 02/06/2024] [Indexed: 02/17/2024]
Abstract
Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), silencing mediator of retinoid and thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCOR1 promotes RBPJk activity. Furthermore, NCoR1 depletion prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCOR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
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Affiliation(s)
- Tom Teichmann
- Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main 60590, Germany; German Center for Cardiovascular Research (DZHK), Partner site Rhein Main, Frankfurt am Main, Germany
| | - Pedro Malacarne
- Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main 60590, Germany; German Center for Cardiovascular Research (DZHK), Partner site Rhein Main, Frankfurt am Main, Germany
| | - Simonida Zehr
- Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main 60590, Germany; German Center for Cardiovascular Research (DZHK), Partner site Rhein Main, Frankfurt am Main, Germany
| | - Stefan Günther
- Max-Planck-Institute for Heart- and Lung Research (MPI-HLR), Bad Nauheim 61231, Germany
| | - Beatrice Pflüger-Müller
- Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main 60590, Germany; German Center for Cardiovascular Research (DZHK), Partner site Rhein Main, Frankfurt am Main, Germany
| | - Timothy Warwick
- Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main 60590, Germany; German Center for Cardiovascular Research (DZHK), Partner site Rhein Main, Frankfurt am Main, Germany.
| | - Ralf P Brandes
- Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main 60590, Germany; German Center for Cardiovascular Research (DZHK), Partner site Rhein Main, Frankfurt am Main, Germany.
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11
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Pawlik VE, Sonntag SR, Grisanti S, Tura A, Kakkassery V, Ranjbar M. Impact of Nintedanib and Anti-Angiogenic Agents on Uveal Melanoma Cell Behavior. Invest Ophthalmol Vis Sci 2024; 65:30. [PMID: 38381412 PMCID: PMC10893901 DOI: 10.1167/iovs.65.2.30] [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: 06/30/2023] [Accepted: 01/21/2024] [Indexed: 02/22/2024] Open
Abstract
Purpose The purpose of this study was to investigate the direct impact of the combined angiokinase inhibitor nintedanib as well as the anti-angiogenic agents ranibizumab, bevacizumab, and aflibercept on the primary uveal melanoma (UM) cell line Mel270 and liver metastasis UM cell line OMM2.5. Methods The metabolic activity, viability, and oxidative stress levels were analyzed by the Thiazolyl Blue Tetrazolium Bromide (MTT), LIVE/DEAD, and reactive oxygen species (ROS) assays. Expression of intracellular VEGF-A165 and VEGF receptor-2 was detected by immunofluorescent staining. The secretion of VEGF-A165 into the cell culture supernatants was evaluated by VEGF-A165 ELISA. Results Nintedanib, at a concentration of 1 µg/mL, resulted in a median reduction of metabolic activity (for Mel270 of approximately 38% and for OMM2.5 of 46% compared to the untreated control) without exerting toxicity in either cell line, whereas the other 3 substances did not result in any changes (which also means that none of the 4 substances led to an increased cell death). Moreover, nintedanib (1 µg/mL) induced oxidative stress in the Mel270 by approximately 1.2 to 1.5-fold compared to the untreated control, but not the OMM2.5 cells. Conclusions Nintedanib could suppress the growth of UM cells in a concentration-dependent manner. The metastatic UM cell line OMM2.5 was not sensitive to the pro-oxidant activity of nintedanib. This study was the first to investigate nintedanib in the context of UM. We propose further investigation of this substance to elucidate its effects on this tumor entity with the hope of identifying advantageous therapeutic options for future adjuvant tumor therapies.
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Affiliation(s)
- Vera E. Pawlik
- Department of Ophthalmology, University of Lübeck, Lübeck, Germany
| | | | | | - Aysegül Tura
- Department of Ophthalmology, University of Lübeck, Lübeck, Germany
| | | | - Mahdy Ranjbar
- Department of Ophthalmology, University of Lübeck, Lübeck, Germany
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12
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Horchler SN, Hancock PC, Sun M, Liu AT, Massand S, El-Mallah JC, Goldenberg D, Waldron O, Landmesser ME, Agrawal S, Koduru SV, Ravnic DJ. Vascular persistence following precision micropuncture. Microcirculation 2024; 31:e12835. [PMID: 37947797 PMCID: PMC10842157 DOI: 10.1111/micc.12835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 10/16/2023] [Accepted: 10/27/2023] [Indexed: 11/12/2023]
Abstract
OBJECTIVE The success of engineered tissues continues to be limited by time to vascularization and perfusion. Recently, we described a simple microsurgical approach, termed micropuncture (MP), which could be used to rapidly vascularize an adjacently placed scaffold from the recipient macrovasculature. Here we studied the long-term persistence of the MP-induced microvasculature. METHODS Segmental 60 μm diameter MPs were created in the recipient rat femoral artery and vein followed by coverage with a simple Type 1 collagen scaffold. The recipient vasculature and scaffold were then wrapped en bloc with a silicone sheet to isolate intrinsic vascularization. Scaffolds were harvested at 28 days post-implantation for detailed analysis, including using a novel artificial intelligence (AI) approach. RESULTS MP scaffolds demonstrated a sustained increase of vascular density compared to internal non-MP control scaffolds (p < 0.05) secondary to increases in both vessel diameters (p < 0.05) and branch counts (p < 0.05). MP scaffolds also demonstrated statistically significant increases in red blood cell (RBC) perfused lumens. CONCLUSIONS This study further highlights that the intrinsic MP-induced vasculature continues to persist long-term. Its combination of rapid and stable angiogenesis represents a novel surgical platform for engineered scaffold and graft perfusion.
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Affiliation(s)
- Summer N. Horchler
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
| | - Patrick C. Hancock
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
| | - Mingjie Sun
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
- Department of Surgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Alexander T. Liu
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
- Department of Surgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Sameer Massand
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
- Department of Surgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Jessica C. El-Mallah
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
- Department of Surgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Dana Goldenberg
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
| | - Olivia Waldron
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
| | - Mary E. Landmesser
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
- Department of Surgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Shailaja Agrawal
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
- Department of Surgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Srinivas V. Koduru
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
- Department of Surgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
| | - Dino J. Ravnic
- Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA
- Department of Surgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802
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13
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Sweeney PL, Suri Y, Basu A, Koshkin VS, Desai A. Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:858-873. [PMID: 38239394 PMCID: PMC10792482 DOI: 10.20517/cdr.2023.89] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 11/20/2023] [Accepted: 12/21/2023] [Indexed: 01/22/2024]
Abstract
Renal cell carcinoma (RCC), the most prevalent type of kidney cancer, is a significant cause of cancer morbidity and mortality worldwide. Antiangiogenic tyrosine kinase inhibitors (TKIs), in combination with immune checkpoint inhibitors (ICIs), are among the first-line treatment options for patients with advanced RCC. These therapies target the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase pathway and other kinases crucial to cancer proliferation, survival, and metastasis. TKIs have yielded substantial improvements in progression-free survival (PFS) and overall survival (OS) for patients with advanced RCC. However, nearly all patients eventually progress on these drugs as resistance develops. This review provides an overview of TKI resistance in RCC and explores different mechanisms of resistance, including upregulation of alternative proangiogenic pathways, epithelial-mesenchymal transition (EMT), decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration, alterations in the tumor microenvironment including bone marrow-derived cells (BMDCs) and tumor-associated fibroblasts (TAFs), and genetic factors such as single nucleotide polymorphisms (SNPs). A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKI resistance, thereby improving outcomes for patients with advanced RCC.
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Affiliation(s)
- Patrick L. Sweeney
- Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Yash Suri
- University of Arizona College of Medicine, Tucson, AZ 85724, USA
| | - Arnab Basu
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA
| | - Vadim S. Koshkin
- Division of Hematology and Oncology, Department of Medicine, University of California at San Francisco School of Medicine, San Francisco, CA 94143, USA
| | - Arpita Desai
- Division of Hematology and Oncology, Department of Medicine, University of California at San Francisco School of Medicine, San Francisco, CA 94143, USA
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14
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Ni Y, Liang Y, Li M, Lin Y, Zou X, Han F, Cao J, Li L. The updates on metastatic mechanism and treatment of colorectal cancer. Pathol Res Pract 2023; 251:154837. [PMID: 37806170 DOI: 10.1016/j.prp.2023.154837] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/20/2023] [Accepted: 09/30/2023] [Indexed: 10/10/2023]
Abstract
Colorectal cancer (CRC) is a main cause of cancer death worldwide. Metastasis is a major cause of cancer-related death in CRC. The treatment of metastatic CRC has progressed minimally. However, the potential molecular mechanisms involved in CRC metastasis have remained to be comprehensively clarified. An improved understanding of the CRC mechanistic determinants is needed to better prevent and treat metastatic cancer. In this review, based on evidence from a growing body of research in metastatic cancers, we discuss the cellular and molecular mechanisms involved in CRC metastasis. This review reveals both the molecular mechanisms of metastases and identifies new opportunities for developing more effective strategies to target metastatic relapse and improve CRC patient outcomes.
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Affiliation(s)
- Yunfei Ni
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - You Liang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Mingzhou Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yang Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Xin Zou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Fangyi Han
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Jianing Cao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Liang Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China.
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15
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Zhao Z, Li T, Sun L, Yuan Y, Zhu Y. Potential mechanisms of cancer-associated fibroblasts in therapeutic resistance. Biomed Pharmacother 2023; 166:115425. [PMID: 37660643 DOI: 10.1016/j.biopha.2023.115425] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/30/2023] [Accepted: 08/30/2023] [Indexed: 09/05/2023] Open
Abstract
Despite continuous improvements in research and new cancer therapeutics, the goal of eradicating cancer remains elusive because of drug resistance. For a long time, drug resistance research has been focused on tumor cells themselves; however, recent studies have found that the tumor microenvironment also plays an important role in inducing drug resistance. Cancer-associated fibroblasts (CAFs) are a main component of the tumor microenvironment. They cross-talk with cancer cells to support their survival in the presence of anticancer drugs. This review summarizes the current knowledge of the role of CAFs in tumor drug resistance. An in-depth understanding of the mechanisms underlying the cross-talk between CAFs and cancer cells and insight into the importance of CAFs in drug resistance can guide the development of new anticancer strategies.
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Affiliation(s)
- Zehua Zhao
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Tianming Li
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China
| | - Liping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
| | - Yanmei Zhu
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), Shenyang, China.
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16
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Penco-Campillo M, Pages G, Martial S. Angiogenesis and Lymphangiogenesis in Medulloblastoma Development. BIOLOGY 2023; 12:1028. [PMID: 37508458 PMCID: PMC10376362 DOI: 10.3390/biology12071028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
Medulloblastoma (MB) is the most prevalent brain tumor in children. Although the current cure rate stands at approximately 70%, the existing treatments that involve a combination of radio- and chemotherapy are highly detrimental to the patients' quality of life. These aggressive therapies often result in a significant reduction in the overall well-being of the patients. Moreover, the most aggressive forms of MB frequently relapse, leading to a fatal outcome in a majority of cases. However, MB is highly vascularized, and both angiogenesis and lymphangiogenesis are believed to play crucial roles in tumor development and spread. In this context, our objective is to provide a comprehensive overview of the current research progress in elucidating the functions of these two pathways.
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Affiliation(s)
- Manon Penco-Campillo
- Institute for Research on Cancer and Aging (IRCAN), Université Côte d'Azur, CNRS UMR 7284 and INSERM U1081, 33 Avenue de Valombrose, 06107 Nice, France
| | - Gilles Pages
- Institute for Research on Cancer and Aging (IRCAN), Université Côte d'Azur, CNRS UMR 7284 and INSERM U1081, 33 Avenue de Valombrose, 06107 Nice, France
| | - Sonia Martial
- Institute for Research on Cancer and Aging (IRCAN), Université Côte d'Azur, CNRS UMR 7284 and INSERM U1081, 33 Avenue de Valombrose, 06107 Nice, France
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17
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Tang H, Xu W, Lu J, Anwaier A, Ye D, Zhang H. Heterogeneity and function of cancer-associated fibroblasts in renal cell carcinoma. JOURNAL OF THE NATIONAL CANCER CENTER 2023; 3:100-105. [PMID: 39035728 PMCID: PMC11256550 DOI: 10.1016/j.jncc.2023.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/14/2023] [Accepted: 04/14/2023] [Indexed: 07/23/2024] Open
Abstract
With the advancement of anticancer therapy, there is increasing interest in understanding the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) play a pivotal role in the TME and have been the focus of much research in recent years. CAFs play an active role in cancer progression through complex interactions with other cells in the TME, releasing regulatory factors, synthesizing and remodeling the extracellular matrix. However, research on the role of CAFs in renal cell carcinoma (RCC) is still in its nascent stages. Here, we describe the origins and subgroups of CAFs, the roles of CAFs in the development and progression of RCC, the impact of CAFs on RCC prognosis, and the potential of CAFs as treatment targets in RCC. By analyzing CAF subsets, biomarkers, and targeted therapies, we present the significance and contribution of CAFs in RCC research. Furthermore, we highlight the distinct contribution of CAFs in advanced RCC through horizontal comparison with other cancers. This paper provides a comprehensive perspective of recent and foundational studies on the role of CAFs in RCC and other types of cancers and new insights for further study of CAFs in RCC.
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Affiliation(s)
- Haijia Tang
- Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenhao Xu
- Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Jiahe Lu
- Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
| | - Aihetaimujiang Anwaier
- Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
| | - Hailiang Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, China
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18
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Zhang Q, Wu G, Zhang X, Zhang J, Jiang M, Zhang Y, Ding L, Wang Y. Vascular endothelial growth factor and risk of malignant brain tumor: A genetic correlation and two-sample Mendelian randomization study. Front Oncol 2023; 13:991825. [PMID: 36910644 PMCID: PMC9995857 DOI: 10.3389/fonc.2023.991825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 02/14/2023] [Indexed: 02/25/2023] Open
Abstract
Objective The relationship between vascular endothelial growth factor (VEGF) and the risk of malignant brain tumors has always been a concern in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders, coinheritability and reverse causality. We aimed to investigate the causal relationship between VEGF and different types of malignant brain tumors. Methods Using publicly available summary data from genome-wide association studies (GWAS) of VEGF (n=16,112) and different types of malignant brain tumors (n=174,097-174,646), we adopted a standard two-sample bidirectional Mendelian randomization (MR) to estimate potential causal associations of circulating VEGF levels and the risk of malignant brain tumors. Inverse variance weighted (IVW) was used as the primary analysis method to estimate causality. MR-Egger regression, weighted median (WM), penalty weighted median (PWM), MR robust adjusted profile score (MR.RAPS) and causal analysis using summary effect estimates (CAUSE) methods were used in sensitivity analyses to verify the robustness of the findings. Meanwhile, we applied the MR pleiotropy residual sum and outlier (MR-PRESSO) test and PhenoScanner tool to identify and remove potential horizontal pleiotropic single nucleotide polymorphisms (SNPs). Additionally, linkage disequilibrium score regression (LDSC) analysis was conducted to assess the coinheritability of exposure and outcome. Results A total of 6 (VEGF), 12 (malignant brain tumor), 13 (brain glioblastoma) and 12 (malignant neoplasm of meninges) SNPs were identified as valid instrumental variables. No evidence supported a causal relationship between circulating VEGF levels and the risk of malignant brain tumors (forwards: odds ratio (OR) = 1.277, 95% confidence interval (CI), 0.812~2.009; reversed: β = 0.005, 95% CI, -0.029~0.038), brain glioblastoma (forwards: OR (95% CI) = 1.278(0.463~3.528); reversed: β = 0.010, 95% CI, -0.002~0.022) and malignant neoplasm of meninges (forwards: OR (95% CI) = 0.831(0.486~1.421); reversed: β = 0.010, 95% CI, -0.030~0.050) using the main IVW method. Outliers and pleiotropy bias were not detected by sensitivity analyses and pleiotropy-robust methods in any estimates. LDSC failed to identify genetic correlations between VEGF and different types of malignant brain tumors. Conclusions Our findings reported no coinheritability and failed to provide evidence for causal associations between VEGF and the risk of different types of malignant brain tumors. However, certain subtypes of VEGF for which genetic predictors have not been identified may play a role and need to be further investigated.
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Affiliation(s)
- Qiaoyun Zhang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China.,Department of Anesthesiology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Guangheng Wu
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Xiaoyu Zhang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China.,Department of Anesthesiology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Jie Zhang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Mengyang Jiang
- Department of Anesthesiology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Yiqiang Zhang
- Department of Anesthesiology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Lixiang Ding
- Department of Spine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Youxin Wang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
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19
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The VEGF/VEGFR Axis Revisited: Implications for Cancer Therapy. Int J Mol Sci 2022; 23:ijms232415585. [PMID: 36555234 PMCID: PMC9779738 DOI: 10.3390/ijms232415585] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/04/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
The vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) axis is indispensable in the process of angiogenesis and has been implicated as a key driver of tumor vascularization. Consequently, several strategies that target VEGF and its cognate receptors, VEGFR-1 and VEGFR-2, have been designed to treat cancer. While therapies targeting full-length VEGF have resulted in an improvement in both overall survival and progression-free survival in various cancers, these benefits have been modest. In addition, the inhibition of VEGFRs is associated with undesirable off-target effects. Moreover, VEGF splice variants that modulate sprouting and non-sprouting angiogenesis have been identified in recent years. Cues within the tumor microenvironment determine the expression patterns of these variants. Noteworthy is that the mechanisms of action of these variants challenge the established norm of VEGF signaling. Furthermore, the aberrant expression of some of these variants has been observed in several cancers. Herein, developments in the understanding of the VEGF/VEGFR axis and the splice products of these molecules, as well as the environmental cues that regulate these variants are reviewed. Furthermore, strategies that incorporate the targeting of VEGF variants to enhance the effectiveness of antiangiogenic therapies in the clinical setting are discussed.
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20
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González-Moles MÁ, Keim-del Pino C, Ramos-García P. Hallmarks of Cancer Expression in Oral Lichen Planus: A Scoping Review of Systematic Reviews and Meta-Analyses. Int J Mol Sci 2022; 23:13099. [PMID: 36361889 PMCID: PMC9658487 DOI: 10.3390/ijms232113099] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 09/05/2023] Open
Abstract
Oral lichen planus (OLP) is a common chronic inflammatory disease of unknown etiology and likely autoimmune nature that is currently considered an oral potentially malignant disorder, implying that patients suffering from this process are at risk of developing oral cancer in their lifetime. The molecular alterations that develop in OLP and that make the affected oral epithelium predisposed to malignancy are unknown, although, as in other autoimmune diseases (ulcerative colitis, primary biliary cirrhosis, etc.), they may be linked to oncogenesis-promoting effects mediated by the inflammatory infiltrate. So far there is no in-depth knowledge on how these hallmarks of cancer are established in the cells of the oral epithelium affected by OLP. In this scoping review of systematic reviews and meta-analyses the state of evidence based knowledge in this field is presented, to point out gaps of evidence and to indicate future lines of research. MEDLINE, Embase, Cochrane Library and Dare were searched for secondary-level studies published before October 2022. The results identified 20 systematic reviews and meta-analyses critically appraising the hallmarks tumor-promoting inflammation (n = 17, 85%), sustaining proliferative signaling (n = 2, 10%), and evading growth suppressors (n = 1, 5%). No evidence was found for the other hallmarks of cancer in OLP. In conclusion, OLP malignization hypothetically derives from the aggressions of the inflammatory infiltrate and a particular type of epithelial response based on increased epithelial proliferation, evasion of growth-suppressive signals and lack of apoptosis. Future evidence-based research is required to support this hypothesis.
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Affiliation(s)
- Miguel Ángel González-Moles
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Carmen Keim-del Pino
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Pablo Ramos-García
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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21
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Targhazeh N, Hutt KJ, Winship AL, Reiter R, Yousefi B. Melatonin as an oncostatic agent: Review of the modulation of tumor microenvironment and overcoming multidrug resistance. Biochimie 2022; 202:71-84. [PMID: 36116742 DOI: 10.1016/j.biochi.2022.09.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/01/2022] [Accepted: 09/12/2022] [Indexed: 11/25/2022]
Abstract
Multi drug resistance (MDR) generally limits the efficacy of chemotherapy in cancer patients and can be categorized into primary or acquired resistance. Melatonin (MLT), a lipophilic hormone released from pineal gland, is a molecule with oncostatic effects. Here, we will briefly review the contribution of different microenvironmental components including fibroblasts, immune and inflammatory cells, stem cells and vascular endothelial cells in tumor initiation, progression and development. Then, the mechanisms by which MLT can potentially affect these elements and regulate drug resistance will be presented. Finally, we will explain how different studies have used novel strategies incorporating MLT to suppress cancer resistance against therapeutics.
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Affiliation(s)
- Niloufar Targhazeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karla J Hutt
- Development and Stem Cell Program and Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Amy L Winship
- Development and Stem Cell Program and Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Russel Reiter
- Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA.
| | - Bahman Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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González-Moles MÁ, Warnakulasuriya S, López-Ansio M, Ramos-García P. Hallmarks of Cancer Applied to Oral and Oropharyngeal Carcinogenesis: A Scoping Review of the Evidence Gaps Found in Published Systematic Reviews. Cancers (Basel) 2022; 14:3834. [PMID: 35954497 PMCID: PMC9367256 DOI: 10.3390/cancers14153834] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 02/07/2023] Open
Abstract
In 2000 and 2011, Hanahan and Weinberg published two papers in which they defined the characteristics that cells must fulfil in order to be considered neoplastic cells in all types of tumours that affect humans, which the authors called "hallmarks of cancer". These papers have represented a milestone in our understanding of the biology of many types of cancers and have made it possible to reach high levels of scientific evidence in relation to the prognostic impact that these hallmarks have on different tumour types. However, to date, there is no study that globally analyses evidence-based knowledge on the importance of these hallmarks in oral and oropharyngeal squamous cell carcinomas. For this reason, we set out to conduct this scoping review of systematic reviews with the aim of detecting evidence gaps in relation to the relevance of the cancer hallmarks proposed by Hanahan and Weinberg in oral and oropharyngeal cancer, and oral potentially malignant disorders, and to point out future lines of research in this field.
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Affiliation(s)
- Miguel Ángel González-Moles
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Saman Warnakulasuriya
- Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
- WHO Collaborating for Oral Cancer, King’s College London, London SE1 9RT, UK
| | - María López-Ansio
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Pablo Ramos-García
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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23
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Shen T, Wu Y, Cai W, Jin H, Yu D, Yang Q, Zhu W, Yu J. LncRNA Meg3 knockdown reduces corneal neovascularization and VEGF-induced vascular endothelial angiogenesis via SDF-1/CXCR4 and Smad2/3 pathway. Exp Eye Res 2022; 222:109166. [PMID: 35820465 DOI: 10.1016/j.exer.2022.109166] [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: 11/03/2021] [Revised: 06/10/2022] [Accepted: 06/23/2022] [Indexed: 11/04/2022]
Abstract
The crucial effect of vascular endothelial growth factor (VEGF)-induced vascular angiogenesis has been well known in corneal neovascularization (CNV). This research aimed to determine the underlying value and mechanism of Meg3 on CNV in vivo and in vitro. In an alkali-burned mouse model, length and area of new vessels were increased along with thinning of corneal epithelium, accompanied by the overexpression of Meg3. Notably, subconjunctival injection of shMeg3 suppressed the degree of injury in cornea, causing expression of the angiogenesis markers--VEGF-A and CD31 decreased. In VEGF-induced human umbilical vein endothelial cells (HUVECs), knockdown of Meg3 antagonized the enhancement of viability, proliferation, wound healing ability and angiogenesis by VEGF. The proteins expression of VEGF-A, CD31, SDF-1/CXCR4 as well as phosphoraylation-Smad2/3 pathways, which were related to angiogenesis, were reduced with Meg3 deficiency. Overall, knockdown of Meg3 alleviated formation of neovascularization in alkali-burned corneas and reduced VEGF-induced angiogenesis by inhibiting SDF-1/CXCR4 and Smad2/3 signaling in vitro.
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Affiliation(s)
- Tianyi Shen
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Yan Wu
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Wenting Cai
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Huizi Jin
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Donghui Yu
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Qian Yang
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China; Anhui Medical University, Hefei, China
| | - Wei Zhu
- Department of Ophthalmology, Changshu NO. 2 People's Hospital, Changshu, China.
| | - Jing Yu
- Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China; Department of Ophthalmology, The Third People's Hospital of Bengbu, Bengbu, China.
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24
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Qi S, Deng S, Lian Z, Yu K. Novel Drugs with High Efficacy against Tumor Angiogenesis. Int J Mol Sci 2022; 23:6934. [PMID: 35805939 PMCID: PMC9267017 DOI: 10.3390/ijms23136934] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 12/13/2022] Open
Abstract
Angiogenesis is involved in physiological and pathological processes in the body. Tumor angiogenesis is a key factor associated with tumor growth, progression, and metastasis. Therefore, there is great interest in developing antiangiogenic strategies. Hypoxia is the basic initiating factor of tumor angiogenesis, which leads to the increase of vascular endothelial growth factor (VEGF), angiopoietin (Ang), hypoxia-inducible factor (HIF-1), etc. in hypoxic cells. The pathways of VEGF and Ang are considered to be critical steps in tumor angiogenesis. A number of antiangiogenic drugs targeting VEGF/VEGFR (VEGF receptor) or ANG/Tie2, or both, are currently being used for cancer treatment, or are still in various stages of clinical development or preclinical evaluation. This article aims to review the mechanisms of angiogenesis and tumor angiogenesis and to focus on new drugs and strategies for the treatment of antiangiogenesis. However, antitumor angiogenic drugs alone may not be sufficient to eradicate tumors. The molecular chaperone heat shock protein 90 (HSP90) is considered a promising molecular target. The VEGFR system and its downstream signaling molecules depend on the function of HSP90. This article also briefly introduces the role of HSP90 in angiogenesis and some HSP90 inhibitors.
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Affiliation(s)
- Shiyu Qi
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
| | - Shoulong Deng
- National Health Commission (NHC) of China Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China;
| | - Zhengxing Lian
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
| | - Kun Yu
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
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25
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Wilczyński JR, Nowak M. Cancer Immunoediting: Elimination, Equilibrium, and Immune Escape in Solid Tumors. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:1-57. [PMID: 35165859 DOI: 10.1007/978-3-030-91311-3_1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Emphasizing the dynamic processes between cancer and host immune system, the initially discovered concept of cancer immunosurveillance has been replaced by the current concept of cancer immunoediting consisting of three phases: elimination, equilibrium, and escape. Solid tumors composed of both cancer and host stromal cells are an example how the three phases of cancer immunoediting functionally evolve and how tumor shaped by the host immune system gets finally resistant phenotype. The elimination, equilibrium, and escape have been described in this chapter in details, including the role of immune surveillance, cancer dormancy, disruption of the antigen-presenting machinery, tumor-infiltrating immune cells, resistance to apoptosis, as well as the function of tumor stroma, microvesicles, exosomes, and inflammation.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecologic Surgery and Gynecologic Oncology, Medical University of Lodz, Lodz, Poland.
| | - Marek Nowak
- Department of Operative Gynecology and Gynecologic Oncology, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
- Department of Operative and Endoscopic Gynecology, Medical University of Lodz, Lodz, Poland
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26
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Ando T, Tai-Nagara I, Sugiura Y, Kusumoto D, Okabayashi K, Kido Y, Sato K, Saya H, Navankasattusas S, Li DY, Suematsu M, Kitagawa Y, Seiradake E, Yamagishi S, Kubota Y. Tumor-specific inter-endothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness. J Clin Invest 2022; 132:153626. [PMID: 35104247 PMCID: PMC8920344 DOI: 10.1172/jci153626] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/28/2022] [Indexed: 11/17/2022] Open
Abstract
Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans, and that its expression correlates negatively with long-term survival. Endothelial-specific deletion of Flrt2 in mice selectively pruned abnormalized vessels, resulting in a unique metabolic state termed "oxygen-glucose uncoupling", which suppresses tumor metastasis. Moreover, Flrt2 deletion caused an increase in the number of mature vessels, resulting in a significant increase in the anti-tumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms non-canonical inter-endothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrate the existence of tumor-specific inter-endothelial adhesions that enable abnormalized vessels to facilitate cancer aggressiveness. Targeting this type of adhesion complex could be a safe and effective therapeutic option to suppress cancer progression.
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Affiliation(s)
- Tomofumi Ando
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Ikue Tai-Nagara
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
| | - Yuki Sugiura
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
| | - Dai Kusumoto
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Koji Okabayashi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yasuaki Kido
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
| | - Kohji Sato
- Department of Organ & Tissue Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hideyuki Saya
- Division of Gene Regulation, Keio University School of Medicine, Tokyo, Japan
| | - Sutip Navankasattusas
- Department of Medicine, University of Utah, Salt Lake City, United States of America
| | - Dean Y Li
- Department of Medicine, University of Utah, Salt Lake City, United States of America
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Elena Seiradake
- Department of Biochemistry, University of Oxford, Oxford, United Kingdom
| | - Satoru Yamagishi
- Department of Organ & Tissue Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yoshiaki Kubota
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
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27
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Kumari R, Dutta R, Ranjan P, Suleiman ZG, Goswami SK, Li J, Pal HC, Verma SK. ALKBH5 Regulates SPHK1-Dependent Endothelial Cell Angiogenesis Following Ischemic Stress. Front Cardiovasc Med 2022; 8:817304. [PMID: 35127873 PMCID: PMC8811170 DOI: 10.3389/fcvm.2021.817304] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/20/2021] [Indexed: 12/29/2022] Open
Abstract
Background Endothelial cells dysfunction has been reported in many heart diseases including acute myocardial infarction, and atherosclerosis. The molecular mechanism for endothelial dysfunction in the heart is still not clearly understood. We aimed to study the role of m6A RNA demethylase alkB homolog 5 (ALKBH5) in ECs angiogenesis during ischemic injury. Methods and Results ECs were treated with ischemic insults (lipopolysaccharide and 1% hypoxia) to determine the role of ALKBH5 in ECs angiogenesis. siRNA mediated ALKBH5 gene silencing was used for examining the loss of function. In this study, we report that ALKBH5 levels are upregulated following ischemia and are associated with maintaining ischemia-induced ECs angiogenesis. To decipher the mechanism of action, we found that ALKBH5 is required to maintain eNOS phosphorylation and SPHK1 protein levels. ALKBH5 silencing alone or with ischemic stress significantly increased SPHK1 m6A mRNA methylation. In contrast, METTL3 (RNA methyltransferase) overexpression resulted in the reduced expression of SPHK1. Conclusion We reported that ALKBH5 helps in the maintenance of angiogenesis in endothelial cells following acute ischemic stress via reduced SPHK1 m6A methylation and downstream eNOS-AKT signaling.
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Affiliation(s)
- Rajesh Kumari
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Roshan Dutta
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Prabhat Ranjan
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Zainab Gbongbo Suleiman
- Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Sumanta Kumar Goswami
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jing Li
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Harish Chandra Pal
- Department of Pathology, Molecular and Cellular Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Suresh Kumar Verma
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, United States
- *Correspondence: Suresh Kumar Verma
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28
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Yuan Y, Geng B, Xu X, Zhao H, Bai J, Dou Z, Jia S, Yu X, Luo W. Dual VEGF/PDGF knockdown suppresses vasculogenic mimicry formation in choroidal melanoma cells via the Wnt5a/β-catenin/AKT signaling pathway. Acta Histochem 2022; 124:151842. [PMID: 34995928 DOI: 10.1016/j.acthis.2021.151842] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE This study aimed to explore the effects of knocking down both vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) on vasculogenic mimicry (VM) formation in choroidal melanoma (CM) cells. METHODS Cell counting Kit (CCK)-8, monoclonal formation, wound healing, transwell and flow cytometry assays were used to observe the cell effects in CM cell line, ocular choroidal melanoma-1 cells (OCM-1) with respect to proliferation, migration, invasion and apoptosis. Three-dimensional (3D) cultures were also used to characterize VM tube structural effects in OCM-1 cells and western blotting was used to characterize protein expression changes in VM-related markers. RESULTS Dual VEGF/PDGF knockdown suppressed cell proliferation, migration and invasion, but promoted cell apoptosis. It also reduced VM tube structures in OCM-1 cells. VM associated markers including, VE-cadherin, EphA2 and MT1-MMP were also down-regulated in OCM-1 cells. Similarly, Wnt5a, β-catenin and phosphorylated-AKT levels were also down-regulated. Western blotting and 3D cultures further demonstrated that combined Wnt5a silencing with dual VEGF/PDGF knockdown significantly decreased VE-cadherin and EphA2 levels and reduced VM tube structures in OCM-1 cells. CONCLUSIONS Dual VEGF/PDGF knockdown suppressed cell growth and metastasis in OCM-1 cells, and blocked the Wnt5a/β-catenin/AKT signaling pathway thereby inhibiting VM formation.
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29
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Mukherjee S, Madamsetty VS. Nanomedicine: An Alternative Approach Towards Anti-angiogenic Cancer Therapy. SYNTHESIS LECTURES ON BIOMEDICAL ENGINEERING 2022:21-31. [DOI: 10.1007/978-3-031-11284-3_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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30
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Villani L, Rosti V, Massa M, Campanelli R, Catarsi P, Carolei A, Abbà C, de Silvstri A, Gale RP, Barosi G. VEGFA rs3025020 Polymorphism Contributes to CALR -Mutation Susceptibility and Is Associated with Low Risk of Deep Vein Thrombosis in Primary Myelofibrosis. TH OPEN 2021; 5:e513-e520. [PMID: 34778698 PMCID: PMC8577885 DOI: 10.1055/s-0041-1739293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/15/2021] [Indexed: 11/27/2022] Open
Abstract
Background
Single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (
VEGFA
) are associated with susceptibility to several diseases including cancer. Correlations between
VEGFA rs3025020
genotypes with clinical and laboratory features of primary myelofibrosis (PMF) are unstudied.
Methods
DNA was analyzed by real-time polymerase chain reaction for
VEGFA rs3025020
genotypes in a cohort of 844 subjects with PMF and in two cohorts of normal subjects (
N
= 247 and
N
= 107).
Results
Frequency of
rs3025020
minor allele (T) was not significantly different in subjects with PMF compared with normals; however, the T-allele was more frequent in PMF subjects with a calreticulin (
CALR
)-mutated genotype compared with normals (35 vs. 27%; OR = 1.47 [95% CI, 1.09, 1.98]
p
= 0.011), especially in subjects with a
CALR-
type 2/type 2-like mutation (43 vs. 27%; OR = 2.01 [1.25, 3.24]
p
= 0.004).
CALR
mutants with the
rs3025020
TT genotype had higher CXCR4 expression on CD34-positive blood cells, and those who carried CT/TT genotypes had lower platelet concentrations compared with other genotypes at diagnosis. Overall, subjects with the
rs3025020
CT/TT genotype had a lower cumulative incidence of deep vein thrombosis in typical sites (1.6 vs. 4.2%; OR = 0.37 [0.15, 0.90]
p
= 0.029) and longer interval from diagnosis to first thrombosis (HR = 0.37 [0.14, 0.95]
p
= 0.039).
Conclusion
Persons with PMF and the
VEGFA rs3025020
minor T-allele are more likely to have a
CALR
mutation compared with other somatic driver mutations and lower cumulative incidence and hazard for deep vein thrombosis in typical sites.
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Affiliation(s)
- Laura Villani
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Vittorio Rosti
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Margherita Massa
- Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy
| | - Rita Campanelli
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Paolo Catarsi
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Adriana Carolei
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Carlotta Abbà
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Annalisa de Silvstri
- Biometry & Clinical Epidemiology, Scientific Direction, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy
| | - Robert Peter Gale
- Department of Immunology and Inflammation, Centre for Haematology Research, Imperial College London, London SW7 2BU, United Kingdom
| | - Giovanni Barosi
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
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31
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Villani L, Rosti V, Massa M, Campanelli R, Catarsi P, Carolei A, Abbà C, De Silvestri A, Gale RP, Barosi G. Primary myelofibrosis: rs2010963 VEGFA polymorphism favors a prefibrotic phenotype and is associated with higher risk of thrombosis. Leuk Res 2021; 111:106730. [PMID: 34700050 DOI: 10.1016/j.leukres.2021.106730] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 09/24/2021] [Accepted: 10/02/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Laura Villani
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Vittorio Rosti
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Margherita Massa
- Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy
| | - Rita Campanelli
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Paolo Catarsi
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Adriana Carolei
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Carlotta Abbà
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy
| | - Annalisa De Silvestri
- Biometry & Clinical Epidemiology, Scientific Direction, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy
| | - Robert Peter Gale
- Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, SW7 2BU, UK
| | - Giovanni Barosi
- Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy.
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Campanelli R, Massa M, Rosti V, Barosi G. New Markers of Disease Progression in Myelofibrosis. Cancers (Basel) 2021; 13:5324. [PMID: 34771488 PMCID: PMC8582535 DOI: 10.3390/cancers13215324] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 12/30/2022] Open
Abstract
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm due to the clonal proliferation of a hematopoietic stem cell. The vast majority of patients harbor a somatic gain of function mutation either of JAK2 or MPL or CALR genes in their hematopoietic cells, resulting in the activation of the JAK/STAT pathway. Patients display variable clinical and laboratoristic features, including anemia, thrombocytopenia, splenomegaly, thrombotic complications, systemic symptoms, and curtailed survival due to infections, thrombo-hemorrhagic events, or progression to leukemic transformation. New drugs have been developed in the last decade for the treatment of PMF-associated symptoms; however, the only curative option is currently represented by allogeneic hematopoietic cell transplantation, which can only be offered to a small percentage of patients. Disease prognosis is based at diagnosis on the classical International Prognostic Scoring System (IPSS) and Dynamic-IPSS (during disease course), which comprehend clinical parameters; recently, new prognostic scoring systems, including genetic and molecular parameters, have been proposed as meaningful tools for a better patient stratification. Moreover, new biological markers predicting clinical evolution and patient survival have been associated with the disease. This review summarizes basic concepts of PMF pathogenesis, clinics, and therapy, focusing on classical prognostic scoring systems and new biological markers of the disease.
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Affiliation(s)
- Rita Campanelli
- Center for the Study of Myelofibrosis, General Medicine 2—Center for Systemic Amyloidosis and High-Complexity Diseases, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (V.R.); (G.B.)
| | - Margherita Massa
- General Medicine 2—Center for Systemic Amyloidosis and High-Complexity Diseases, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy;
| | - Vittorio Rosti
- Center for the Study of Myelofibrosis, General Medicine 2—Center for Systemic Amyloidosis and High-Complexity Diseases, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (V.R.); (G.B.)
| | - Giovanni Barosi
- Center for the Study of Myelofibrosis, General Medicine 2—Center for Systemic Amyloidosis and High-Complexity Diseases, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (V.R.); (G.B.)
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Tagai N, Goi T, Shimada M, Kurebayashi H. Plasma Prokineticin 1, a prognostic biomarker in colorectal cancer patients with curative resection: a retrospective cohort study. World J Surg Oncol 2021; 19:302. [PMID: 34657605 PMCID: PMC8522247 DOI: 10.1186/s12957-021-02421-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 10/07/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Prokineticin 1 (PROK1) was reported as an angiogenic factor, which is associated with tumor progression, cell invasion, and metastasis in colorectal cancer. Although the association between PROK1 expression in primary cancer lesion and patient prognosis was reported, it is unclear whether plasma PROK1 concentration may be a predictive factor in colorectal cancer patients. This study investigated the association between PROK1 concentration in plasma and prognosis in colorectal cancer patients. METHODS We measured preoperative PROK1 plasma levels using ELISA method, while PROK1 expression in primary cancer lesion was evaluated using immunohistochemistry (IHC). The association between plasma PROK1 levels and cancer-related survival rate (CRS) was evaluated. Additionally, we examined whether simultaneous PROK1 expression in both primary cancer lesions and plasma was correlated with CRS. The cancer-related survival rate was calculated using the Kaplan-Meier method, and survival estimates were compared using the log-rank test. RESULTS We have gathered eligible 130 CRC patients retrospectively. Out of 130 patients, 61 (46.9%) were positive on IHC in primary cancer, and 69 (53.1%) were negative, while 43 (33.1%) had high-value PROK1 in plasma. Out of these 43, 30 (25.4%) also had concomitant higher IHC expression in primary cancer. The plasma PROK1 levels tended to increase with advancing stages. The plasma PROK1-positive group had a lower 5-year CRS than the negative group (63.6% vs. 88.2%; P = 0.006). Additionally, simultaneous PROK1 expression was associated with a more significant decrease of 5-year CRS than both negative groups in all stages (76.2% vs. 92.5%; P = 0.003) and stage III (59.3% vs. 84.5%; P = 0.047). Multivariate analysis showed simultaneous PROK1 expression was independently associated with worse CRS (HR, 1.97; 95% CI 1.20‑3.24, P < 0.01). CONCLUSION PROK1 expression in preoperative plasma reflects poor prognosis in patients undergoing curative resection for colorectal cancer. The plasma PROK1 level may be a potential predictive marker, especially in stage III colorectal cancer patients.
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Affiliation(s)
- Noriyuki Tagai
- Department of Surgery 1, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-Cho, Yoshida-gun, Fukui, 910-1193, Japan.
| | - Takanori Goi
- Department of Surgery 1, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-Cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Michiaki Shimada
- Department of Surgery 1, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-Cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Hidetaka Kurebayashi
- Department of Surgery 1, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-Cho, Yoshida-gun, Fukui, 910-1193, Japan
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Fang JS, Hultgren NW, Hughes CCW. Regulation of Partial and Reversible Endothelial-to-Mesenchymal Transition in Angiogenesis. Front Cell Dev Biol 2021; 9:702021. [PMID: 34692672 PMCID: PMC8529039 DOI: 10.3389/fcell.2021.702021] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/22/2021] [Indexed: 12/11/2022] Open
Abstract
During development and in several diseases, endothelial cells (EC) can undergo complete endothelial-to-mesenchymal transition (EndoMT or EndMT) to generate endothelial-derived mesenchymal cells. Emerging evidence suggests that ECs can also undergo a partial EndoMT to generate cells with intermediate endothelial- and mesenchymal-character. This partial EndoMT event is transient, reversible, and supports both developmental and pathological angiogenesis. Here, we discuss possible regulatory mechanisms that may control the EndoMT program to dictate whether cells undergo complete or partial mesenchymal transition, and we further consider how these pathways might be targeted therapeutically in cancer.
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Affiliation(s)
- Jennifer S. Fang
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States
| | - Nan W. Hultgren
- Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
| | - Christopher C. W. Hughes
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States
- Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, United States
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Ngema LM, Adeyemi SA, Marimuthu T, Choonara YE. A review on engineered magnetic nanoparticles in Non-Small-Cell lung carcinoma targeted therapy. Int J Pharm 2021; 606:120870. [PMID: 34245844 DOI: 10.1016/j.ijpharm.2021.120870] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/25/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023]
Abstract
There are growing appeals forthe design of efficacious treatment options for non-small-cell lung carcinoma (NSCLC) as it accrues to ~ 85% cases of lung cancer. Although platinum-based doublet chemotherapy has been the main therapeutic intervention in NSCLC management, this leads to myriad of problems including intolerability to the doublet regimens and detrimental side effects due to high doses. A new approach is therefore needed and warrants the design of targeted drug delivery systems that can halt tumor proliferation and metastasis by targeting key molecules, while exhibiting minimal side effects and toxicity. This review aims to explore the rational design of magnetic nanoparticles for the development of tumor-targeting systems for NSCLC. In the review, we explore the anticancer merits of conjugated linoleic acid (CLA) and provide a concise incursion into its application for the invention of functionalized magnetic nanoparticles in the targeted treatment of NSCLC. Recent nanoparticle-based targeted chemotherapies for targeting angiogenesis biomarkers in NSCLC will also be reviewed to further highlight versatility of magnetic nanoparticles. These developments through molecular tuning at the nanoscale and supported by comprehensive pre-clinical studies could lead to the establishment of precise nanosystems for tumor-homing cancer therapy.
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Affiliation(s)
- Lindokuhle M Ngema
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
| | - Samson A Adeyemi
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
| | - Thashree Marimuthu
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
| | - Yahya E Choonara
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa.
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Desbois M, Wang Y. Cancer-associated fibroblasts: Key players in shaping the tumor immune microenvironment. Immunol Rev 2021; 302:241-258. [PMID: 34075584 DOI: 10.1111/imr.12982] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/14/2021] [Accepted: 04/30/2021] [Indexed: 12/18/2022]
Abstract
Cancer immunotherapies have rapidly changed the therapeutic landscape for cancer. Nevertheless, most of the patients show innate or acquired resistance to these therapies. Studies conducted in recent years have highlighted an emerging role of cancer-associated fibroblasts (CAFs) in immune regulation that shapes the tumor immune microenvironment (TIME) and influences response to cancer immunotherapies. In this review, we outline recent advances in the understanding of phenotypic and functional heterogeneity of CAFs. We will focus on emerging roles of CAFs in shaping the TIME, especially under a framework of tumor immunity continuum, and discuss current and future CAF-targeting therapeutic strategies in particular in the context of optimizing the success of immunotherapies.
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Affiliation(s)
- Mélanie Desbois
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA
| | - Yulei Wang
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA
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Mettu PS, Allingham MJ, Cousins SW. Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities. Prog Retin Eye Res 2021; 82:100906. [PMID: 33022379 PMCID: PMC10368393 DOI: 10.1016/j.preteyeres.2020.100906] [Citation(s) in RCA: 219] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/13/2022]
Abstract
Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs. In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.
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Affiliation(s)
- Priyatham S Mettu
- Duke Center for Macular Diseases, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, NC.
| | - Michael J Allingham
- Duke Center for Macular Diseases, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, NC
| | - Scott W Cousins
- Duke Center for Macular Diseases, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, NC; Department of Immunology, Duke University School of Medicine, Durham, NC, USA
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Zhang JY, Xue WJ, Wang M, Li W, Dong R, Li MT, Sun LP. Discovery of 4,6-Disubstituted Pyrimidine Derivatives as Novel Dual VEGFR2/FGFR1 Inhibitors. Chem Biodivers 2021; 18:e2100095. [PMID: 33829649 DOI: 10.1002/cbdv.202100095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/06/2021] [Indexed: 11/08/2022]
Abstract
Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies have shown that the up-regulation of FGF-2 is closely related to the resistance of VEGFR2 inhibitors. Activation of the FGFRs signal is a signal of compensatory angiogenesis after VEGFR2 resistance. Dual VEGFR2/FGFR1 inhibitors contribute to overcoming the resistance of VEGFR2 inhibitors and inhibit tumor growth significantly. Based on this, we designed and synthesized a series of 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors by the molecular hybridization strategy. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea (8b) had the best inhibitory activities against VEGFR2 and FGFR1 at 10 μM (82.2 % and 101.0 %, respectively), it showed moderate antiproliferative activities against A549 and KG-1 cell lines as well. Besides, molecular docking was also carried out to study the binding mode of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)-amino]-pyrimidin-4-yl}-1-methylurea (8b) with VEGFR2 and FGFR1. These studies reveal that this series of compounds deserve further optimization.
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Affiliation(s)
- Jin-Yang Zhang
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Wen-Jun Xue
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Min Wang
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Wen Li
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Ru Dong
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Ming-Tao Li
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
| | - Li-Ping Sun
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
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Derakhshani A, Rostami Z, Safarpour H, Shadbad MA, Nourbakhsh NS, Argentiero A, Taefehshokr S, Tabrizi NJ, Kooshkaki O, Astamal RV, Singh PK, Taefehshokr N, Alizadeh N, Silvestris N, Baradaran B. From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy. Molecules 2021; 26:2278. [PMID: 33920054 PMCID: PMC8071039 DOI: 10.3390/molecules26082278] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/09/2021] [Accepted: 04/09/2021] [Indexed: 12/19/2022] Open
Abstract
Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.
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Affiliation(s)
- Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
| | - Zeinab Rostami
- Student Research Committee, Birjand University of Medical Sciences, Birjand 97178-53577, Iran; (Z.R.); (O.K.)
| | - Hossein Safarpour
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand 97178-53577, Iran;
| | - Mahdi Abdoli Shadbad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz 51666-14766, Iran
| | | | | | - Sina Taefehshokr
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
| | - Neda Jalili Tabrizi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
| | - Omid Kooshkaki
- Student Research Committee, Birjand University of Medical Sciences, Birjand 97178-53577, Iran; (Z.R.); (O.K.)
| | - Reza Vaezi Astamal
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
| | - Pankaj Kumar Singh
- Principal Research Technologist, Department of Radiation Oncology, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224, USA;
| | - Nima Taefehshokr
- Department of Microbiology and Immunology, Center for Human Immunology, The University of Western Ontario, London, ON N6A 5C1, Canada;
| | - Nazila Alizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
| | - Nicola Silvestris
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 51666-14766, Iran
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In vitro angiogenesis inhibition with selective compounds targeting the key glycolytic enzyme PFKFB3. Pharmacol Res 2021; 168:105592. [PMID: 33813027 DOI: 10.1016/j.phrs.2021.105592] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 03/27/2021] [Accepted: 03/28/2021] [Indexed: 11/22/2022]
Abstract
Abnormal glycolytic metabolism contributes to angiogenic sprouting involved in atherogenesis. We investigated the potential anti-angiogenic properties of specific 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) inhibitors in endothelial cells (ECs). ECs were treated with PFKFB3 inhibitors (named PA-1 and PA-2) and their effects on metabolic and functional characteristics of ECs were investigated. The anti-glycolytic compound 3-(pyridinyl)- 1-(4-pyridinyl)- 2-propen-1-one (3PO) was used as reference compound. PFKFB3 expression and activity (IC50 about 3-21 nM) was inhibited upon treatment with both compounds. Glucose uptake and lactate export were measured using commercial assays and showed a partial reduction up to 40%. PFKFB3 inhibition increased intracellular lactate accumulation, and reduced expression of monocarboxylate transporters-1 (MCT1) and MCT4. Furthermore, endothelial cell migration and proliferation assays demonstrated significant reduction upon treatment with both compounds. Matrix- metalloproteinase (MMP) activity, measured by gelatin zymography, and expression was significantly reduced (up to 25%). In addition, PA compounds downregulated the expression of VCAM-1, VE-cadherin, VEGFa, VEGFR2, TGF-β, and IL-1β, in inflamed ECs. Finally, PA-1 and PA-2 treatment impaired the formation of angiogenic sprouts measured by both morphogenesis and spheroid-based angiogenesis assays. Our data demonstrate that the anti-glycolytic PA compounds may affect several steps involved in angiogenesis. Targeting the key glycolytic enzyme PFKFB3 might represent an attractive therapeutic strategy to improve the efficacy of cancer treatments, or to be applied in other pathologies where angiogenesis is a detrimental factor.
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Naderi S, Roshan R, Behdani M, Kazemi-Lomedasht F. Inhibition of neovascularisation in human endothelial cells using anti NRP-1 nanobody fused to truncated form of diphtheria toxin as a novel immunotoxin. Immunopharmacol Immunotoxicol 2021; 43:230-238. [PMID: 33657977 DOI: 10.1080/08923973.2021.1888114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neuropilin-1 (NRP-1) regulates a range of physiological and pathological processes, including angiogenesis. Targeting of NRP1 is considered a significant approach in cancer therapy. In the present study, a novel antiNRP1 immunotoxin (αNRP1 IT) was developed by genetic fusion of a single domain (VHH) anti-NRP-1 antibody fragment to a truncated diphtheria toxin. The αNRP1 IT was expressed into bacterial cells as an inclusion body (IB). Expression of αNRP1 IT was confirmed by SDS-PAGE and western blotting. Recombinant αNRP1 IT was purified using nickel affinity chromatography. Toxicity and antiangiogenesis effect of αNRP1 IT was investigated both in vitro and in vivo. Results showed that αNRP1 IT significantly reduced the viability of human umbilical vein endothelial cell line (HUVEC) (p < .05). The αNRP1 IT significantly inhibited tube formation of HUVEC cells (p < .001). Furthermore, αNRP1 IT inhibited angiogenesis in Chick Chorioallantoic Membrane (CAM) Assay. These data suggest the potential of αNRP1 IT as a novel therapeutic in targeted cancer therapy.
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Affiliation(s)
- Shamsi Naderi
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Islamic Republic of Iran
| | - Reyhaneh Roshan
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Islamic Republic of Iran
| | - Mahdi Behdani
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Islamic Republic of Iran
| | - Fatemeh Kazemi-Lomedasht
- Venom and Biotherapeutics Molecules Laboratory, Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Islamic Republic of Iran
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Yu Q, Li K, Zhao A, Wei M, Huang Z, Zhang Y, Chen Y, Lian T, Wang C, Xu L, Zhang Y, Xu C, Liu F. Sorafenib not only impairs endothelium-dependent relaxation but also promotes vasoconstriction through the upregulation of vasoconstrictive endothelin type B receptors. Toxicol Appl Pharmacol 2021; 414:115420. [PMID: 33503445 DOI: 10.1016/j.taap.2021.115420] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 01/06/2021] [Accepted: 01/21/2021] [Indexed: 01/01/2023]
Abstract
As a VEGF-targeting agent, sorafenib has been used to treat a number of solid tumors but can easily lead to adverse vascular effects. To elucidate the underlying mechanism, rat mesenteric arteries were subjected to organ cultured in the presence of different concentrations of sorafenib (0, 3, 6 and 9 mg/L) with or without inhibitors (U0126, 10-5 M; SB203580, 10-5 M; SP200126, 10-5 M) of MAPK kinases, and then acetylcholine- or sodium nitroprusside-induced vasodilation and sarafotoxin 6c-induced vasoconstriction were monitored by a sensitive myograph. The NO synthetases, the nitrite levels, the endothelial marker CD31,the ETB and ETA receptors and the phosphorylation of MAPK kinases were studied. Next, rats were orally administrated by sorafenib for 4 weeks (7.5 and 15 mg/kg/day), and their blood pressure, plasma ET-1, the ETB and ETA receptors and the phosphorylation of MAPK kinases in the mesenteric arteries were investigated. The results showed that sorafenib impairs endothelium-dependent vasodilation due to decreased NO levels and the low expression of eNOS and iNOS. Weak staining for CD31 indicated that sorafenib induced endothelial damage. Moreover, sorafenib caused the upregulation of vasoconstrictive ETB receptors, the enhancement of ETB receptor-mediated vasoconstriction and the activation of JNK/MAPK. Blocking the JNK, ERK1/2 and p38/MAPK signaling pathways by using the inhibitors significantly abolished ETB receptor-mediated vasoconstriction. Furthermore, it was observed that the oral administration of sorafenib caused an increase in blood pressure and plasma ET-1, upregulation of the ETB receptor and the activation of JNK in the mesenteric arteries. In conclusion, sorafenib not only impairs endothelium-dependent vasodilatation but also enhances ETB receptor-mediated vasoconstriction, which may be the causal factors for hypertension and other adverse vascular effects in patients treated with sorafenib.
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MESH Headings
- Angiogenesis Inhibitors/toxicity
- Animals
- Blood Pressure/drug effects
- Cell Proliferation/drug effects
- Cells, Cultured
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Hypertension/chemically induced
- Hypertension/metabolism
- Hypertension/physiopathology
- JNK Mitogen-Activated Protein Kinases/metabolism
- Male
- Mesenteric Artery, Superior/drug effects
- Mesenteric Artery, Superior/metabolism
- Mesenteric Artery, Superior/physiopathology
- Nitric Oxide/metabolism
- Rats, Sprague-Dawley
- Receptor, Endothelin B/genetics
- Receptor, Endothelin B/metabolism
- Signal Transduction
- Sorafenib/toxicity
- Tissue Culture Techniques
- Up-Regulation
- Vasoconstriction/drug effects
- Vasodilation/drug effects
- p38 Mitogen-Activated Protein Kinases/metabolism
- Rats
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Affiliation(s)
- Qi Yu
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China; Department of Histology and Embryology, Xi'an Medical University, Xi'an 710021, China; Department of Pharmacology, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China.
| | - Kun Li
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Andong Zhao
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Mengqian Wei
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Zhenhao Huang
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Yunting Zhang
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Ying Chen
- School of Computer Science and Technology, Xi'an University of Posts and Telecommunications, Xi'an 710121, China.
| | - Ting Lian
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Chuan Wang
- Department of Pharmacology, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Li Xu
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Yaping Zhang
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Cangbao Xu
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Fuqiang Liu
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China; Cardiovascular Department, Shaanxi Provincial People's Hospital, Xi'an 710010, China.
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Naderi S, Roshan R, Ghaderi H, Behdani M, Mahmoudi S, Habibi-Anbouhi M, Shokrgozar MA, Kazemi-Lomedasht F. Selection and characterization of specific nanobody against neuropilin-1 for inhibition of angiogenesis. Mol Immunol 2020; 128:56-63. [DOI: 10.1016/j.molimm.2020.10.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 07/08/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
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Recent Advances and Challenges in Controlling the Spatiotemporal Release of Combinatorial Anticancer Drugs from Nanoparticles. Pharmaceutics 2020; 12:pharmaceutics12121156. [PMID: 33261219 PMCID: PMC7759840 DOI: 10.3390/pharmaceutics12121156] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/21/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022] Open
Abstract
To overcome cancer, various chemotherapeutic studies are in progress; among these, studies on nano-formulated combinatorial drugs (NFCDs) are being actively pursued. NFCDs function via a fusion technology that includes a drug delivery system using nanoparticles as a carrier and a combinatorial drug therapy using two or more drugs. It not only includes the advantages of these two technologies, such as ensuring stability of drugs, selectively transporting drugs to cancer cells, and synergistic effects of two or more drugs, but also has the additional benefit of enabling the spatiotemporal and controlled release of drugs. This spatial and temporal drug release from NFCDs depends on the application of nanotechnology and the composition of the combination drug. In this review, recent advances and challenges in the control of spatiotemporal drug release from NFCDs are provided. To this end, the types of combinatorial drug release for various NFCDs are classified in terms of time and space, and the detailed programming techniques used for this are described. In addition, the advantages of the time and space differences in drug release in terms of anticancer efficacy are introduced in depth.
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Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment. Cancers (Basel) 2020; 12:cancers12092652. [PMID: 32957515 PMCID: PMC7564346 DOI: 10.3390/cancers12092652] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/11/2020] [Accepted: 09/13/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Cancer-associated fibroblasts (CAFs) are key players in the tumor microenvironment. They are responsible for potentiating growth and metastasis through versatile functions, including maintenance of the extracellular matrix, blood vessel formation, modulation of tumor metabolism, suppression of antitumor immunity, and promotion of chemotherapy resistance. As such, CAFs are associated with poor prognosis and have emerged as a focus of anticancer research. In this review, we discuss the origins of CAFs, their heterogenous subtypes and their properties. We then detail the current state of preclinical and clinical research targeting CAF activities. We believe the limited efficacy of current cancer therapeutic approaches is driven by an incomplete understanding of CAF functions and by a nonstandardized CAF classification system. Therefore, we suggest a unified CAF classification based on specific functions to develop a new class of therapies that will focus on targeting the pro-tumorigenic properties of CAFs during tumor progression. Abstract Cancer-associated fibroblasts (CAFs) are indispensable architects of the tumor microenvironment. They perform the essential functions of extracellular matrix deposition, stromal remodeling, tumor vasculature modulation, modification of tumor metabolism, and participation in crosstalk between cancer and immune cells. In this review, we discuss our current understanding of the principal differences between normal fibroblasts and CAFs, the origin of CAFs, their functions, and ultimately, highlight the intimate connection of CAFs to virtually all of the hallmarks of cancer. We address the remarkable degree of functional diversity and phenotypic plasticity displayed by CAFs and strive to stratify CAF biology among different tumor types into practical functional groups. Finally, we summarize the status of recent and ongoing trials of CAF-directed therapies and contend that the paucity of trials resulting in Food and Drug Administration (FDA) approvals thus far is a consequence of the failure to identify targets exclusive of pro-tumorigenic CAF phenotypes that are mechanistically linked to specific CAF functions. We believe that the development of a unified CAF nomenclature, the standardization of functional assays to assess the loss-of-function of CAF properties, and the establishment of rigorous definitions of CAF subpopulations and their mechanistic functions in cancer progression will be crucial to fully realize the promise of CAF-targeted therapies.
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Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C. Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet 2020; 58:1131-1147. [PMID: 31016670 PMCID: PMC6719436 DOI: 10.1007/s40262-019-00766-0] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Nintedanib is an oral, small-molecule tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis and patients with advanced non-small cell cancer of adenocarcinoma tumour histology. Nintedanib competitively binds to the kinase domains of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF). Studies in healthy volunteers and in patients with advanced cancer have shown that nintedanib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of nintedanib are reached approximately 2–4 h after oral administration and thereafter decline at least bi-exponentially. Over the investigated dose range of 50–450 mg once daily and 150–300 mg twice daily, nintedanib exposure increases are dose proportional. Nintedanib is metabolised via hydrolytic ester cleavage, resulting in the formation of the free acid moiety that is subsequently glucuronidated and excreted in the faeces. Less than 1% of drug-related radioactivity is eliminated in urine. The terminal elimination half-life of nintedanib is about 10–15 h. Accumulation after repeated twice-daily dosing is negligible. Sex and renal function have no influence on nintedanib pharmacokinetics, while effects of ethnicity, low body weight, older age and smoking are within the inter-patient variability range of nintedanib exposure and no dose adjustments are required. Administration of nintedanib in patients with moderate or severe hepatic impairment is not recommended, and patients with mild hepatic impairment should be monitored closely and the dose adjusted accordingly. Nintedanib has a low potential for drug–drug interactions, especially with drugs metabolised by cytochrome P450 enzymes. Concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of nintedanib. At an investigated dose of 200 mg twice daily, nintedanib does not have proarrhythmic potential.
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Affiliation(s)
- Sven Wind
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany.
| | - Ulrike Schmid
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
| | - Matthias Freiwald
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
| | - Kristell Marzin
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
| | - Ralf Lotz
- Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
| | - Thomas Ebner
- Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
| | - Peter Stopfer
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
| | - Claudia Dallinger
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany
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Joo JI, Choi M, Jang SH, Choi S, Park SM, Shin D, Cho KH. Realizing Cancer Precision Medicine by Integrating Systems Biology and Nanomaterial Engineering. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2020; 32:e1906783. [PMID: 32253807 DOI: 10.1002/adma.201906783] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/19/2019] [Indexed: 06/11/2023]
Abstract
Many clinical trials for cancer precision medicine have yielded unsatisfactory results due to challenges such as drug resistance and low efficacy. Drug resistance is often caused by the complex compensatory regulation within the biomolecular network in a cancer cell. Recently, systems biological studies have modeled and simulated such complex networks to unravel the hidden mechanisms of drug resistance and identify promising new drug targets or combinatorial or sequential treatments for overcoming resistance to anticancer drugs. However, many of the identified targets or treatments present major difficulties for drug development and clinical application. Nanocarriers represent a path forward for developing therapies with these "undruggable" targets or those that require precise combinatorial or sequential application, for which conventional drug delivery mechanisms are unsuitable. Conversely, a challenge in nanomedicine has been low efficacy due to heterogeneity of cancers in patients. This problem can also be resolved through systems biological approaches by identifying personalized targets for individual patients or promoting the drug responses. Therefore, integration of systems biology and nanomaterial engineering will enable the clinical application of cancer precision medicine to overcome both drug resistance of conventional treatments and low efficacy of nanomedicine due to patient heterogeneity.
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Affiliation(s)
- Jae Il Joo
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Minsoo Choi
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Seong-Hoon Jang
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Sea Choi
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Sang-Min Park
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Dongkwan Shin
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Kwang-Hyun Cho
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
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Zhong L, Xie L, Yang Z, Li L, Song S, Cao D, Liu Y. Prognostic value of S1PR1 and its correlation with immune infiltrates in breast and lung cancers. BMC Cancer 2020; 20:766. [PMID: 32799825 PMCID: PMC7429796 DOI: 10.1186/s12885-020-07278-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 08/09/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Sphingosine-1-phosphate receptor (S1PR1) is involved in vascular development, a key process in tumorigenesis. This study aimed to evaluate its roles in tumor development and prognosis. METHODS S1PR1 expression levels were analyzed using TIMER and Oncomine database, and the prognostic significance of S1PR1 was assessed using PrognoScan and Kaplan-Meier plotter databases. The relationship between S1PR1 and tumor-infiltrated immune cells was analyzed using TIMER. RESULTS S1PR1 expression was remarkably lower in breast and lung cancer tissues than in the corresponding normal tissues. Lower expression was related to poor overall survival and disease-free survival in breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). A functional network analysis confirmed the function of S1PR1 in regulating vasculogenesis. In addition, S1PR1 levels were significantly negative with regard to the tumor purity of BRCA (r = - 0.508, P = 1.76e-66), LUAD (r = - 0.353, P = 6.05e-16), and LUSC (r = - 0.402, P = - 5.20e-20). Furthermore, S1PR1 levels were significantly positive with regard to infiltrating CD8+ (r = 0.38, P = 5.91e-35) and CD4+ T cells (r = 0.335, P = 1.03e-26), macrophages (r = 0.219, P = 3.67e-12), neutrophils (r = 0.168, P = 2.03e-7), and dendritic cells (DCs) (r = 0.208, P = 9.14e-11) in BRCA; S1PR1 levels were significantly positive with regard to CD8+ T cells (r = 0.308, P = 3.61e-12), macrophages (r = 0.376, P = 1.01e-17), neutrophils (r = 0.246, P = 4.15e-8), and DCs (r = 0.207, P = 4.16e-6) in LUAD; and positive with regard to B cells (r = 0.356, P = 1.57e-15), CD8+ (r = 0.459, P = 3.83e-26) and CD4+ T cells (r = 0.338, P = 3.98e-14), macrophages (r = 0.566, P = 2.61e-45), neutrophils (r = 0.453, P = 1.79e-25), and DCs (r = 0.56, P = 2.12e-40) in LUSC. CONCLUSIONS S1PR1 levels are positively correlated with multiple immune markers in breast and lung cancer. These observed correlations between S1PR1 and the prognosis and immune cell infiltration provide a foundation for further research on its immunomodulatory role in cancer.
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Affiliation(s)
- Limei Zhong
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Linling Xie
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou, 510407, China
| | - Zhiyong Yang
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Lijuan Li
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Shaohua Song
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Donglin Cao
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China.
| | - Yufeng Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou, 510407, China.
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510407, China.
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He W, Pang L, Gong S, Wang X, Hou L. Nei Endonuclease VIII-like 2 Gene rs8191670 Polymorphism affects the Sensitivity of Non-small Cell Lung Cancer to Cisplatin by binding with MiR-548a. J Cancer 2020; 11:4801-4809. [PMID: 32626527 PMCID: PMC7330683 DOI: 10.7150/jca.47495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 05/25/2020] [Indexed: 11/05/2022] Open
Abstract
Background: Nei endonuclease VIII-like 2 (NEIL2) is a gene encoding DNA repair enzyme, which is involved in the base excision repair (BER) pathway in mammalian cells. Cisplatin is a common cytotoxic anti-tumor agent in clinic by destroying normal structure of DNA and inducing cell apoptosis. However, how NEIL2 affects the sensitivity of NSCLC to cisplatin is still unclear. Methods: The clinical data from 206 patients diagnosed pathologically were collected. The DNA sequencing of NEIL2 gene 3'UTR and the PFS curve of NSCLC patients receiving cisplatin-based chemotherapy were performed. Western blot analysis and immunohistochemistry were used to detect NEIL2 protein expression. Human NSCLC cell lines A549 and H1299 were cultured and evaluated for cell viability. RT-PCR was performed for quantitative detection of miR-548a. 3'UTR reporter plasmid was constructed and luciferase reporter assay was used to verify the target gene regulated by miR-548a. Results: In this study, we found that the Neil2 gene had the polymorphism (T/C) in rs8191670 and it is associated with the PFS of advanced NSCLC patients. MiR-548a targets NEIL2 3'UTR to suppress its expression. Upregulation of NEIL2 expression or downregulation of miR-548a could reduce the sensitivity of NSCLC cells to cisplatin. Conclusion: Our results demonstrated that NEIL2 gene rs8191670 polymorphism affects the PFS of advanced NSCLC patients, and the underlying molecular mechanisms may be that miR-548a can regulate NEIL2 expression by binding to its 3'UTR seed region containing rs8191670.
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Affiliation(s)
- Wei He
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Lina Pang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Shuai Gong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xin Wang
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Lixia Hou
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Huo D, Jiang X, Hu Y. Recent Advances in Nanostrategies Capable of Overcoming Biological Barriers for Tumor Management. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2020; 32:e1904337. [PMID: 31663198 DOI: 10.1002/adma.201904337] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 09/27/2019] [Indexed: 05/22/2023]
Abstract
Engineered nanomaterials have been extensively employed as therapeutics for tumor management. Meanwhile, the complex tumor niche along with multiple barriers at the cellular level collectively hinders the action of nanomedicines. Here, the advanced strategies that hold promise for overcoming the numerous biological barriers facing nanomedicines are summarized. Starting from tumor entry, methods that promote tissue penetration of nanomedicine and address the hypoxia issue are also highlighted. Then, emphasis is given to the significance of overcoming both physical barriers, such as membrane-associated efflux pumps, and biological features, such as resistance to apoptosis. The pros and cons for an individual approach are presented. In addition, the associated technical problems are discussed, along with the importance of balancing the therapeutic merits and the additional cost of sophisticated nanomedicine designs.
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Affiliation(s)
- Da Huo
- College of Engineering and Applied Sciences, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Xiqun Jiang
- Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Yong Hu
- College of Engineering and Applied Sciences, Nanjing University, Nanjing, Jiangsu, 210093, China
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