1. Cancer-associated fibroblasts in renal cell carcinoma: implication in prognosis and resistance to anti-angiogenic therapy
- Author
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Christopher Montemagno, Gilles Pagès, Renaud Grépin, Arnaud Borderie, Michael Coutts, Delphine Borchiellini, Damien Ambrosetti, Charlotte Paoli, Matthieu Durand, Jean-Christophe Bernhard, Nathalie Rioux-Leclercq, Olivia Rastoin, Maeva Dufies, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Laboratoire International Associé Réponse des Organismes et Populations face au Stress Environnemental - Université Côte d’Azur - Centre Scientifique de Monaco (LIA ROPSE), Université Côte d’Azur - Centre Scientifique de Monaco, Centre Scientifique de Monaco (CSM), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Bordeaux [Bordeaux], Fondation de France, Ligue Nationale contre le Cancer (Equipe Labellisee 2019), French National Institute for Cancer Research (INCA), Cordon de vie Foundation, l'Institut National du Cancer (INCa) Institut National du Cancer (INCA) France, Government of the Principality of Monaco, FX Mora Foundation, Université Nice Sophia Antipolis (... - 2019) (UNS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Fondation de FranceFondation de France, and l'Institut National du Cancer (INCa)Institut National du Cancer (INCA) France
- Subjects
Male ,#uroonc ,anti-angiogenic treatment ,[SDV]Life Sciences [q-bio] ,Angiogenesis Inhibitors ,clear cell renal cell carcinoma ,Nephrectomy ,Metastasis ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Renal cell carcinoma ,Cell Movement ,Sunitinib ,Medicine ,Cytotoxic T cell ,Lymphangiogenesis ,Aged, 80 and over ,0303 health sciences ,Neovascularization, Pathologic ,Cell migration ,Cell Differentiation ,Middle Aged ,Kidney Neoplasms ,Neoadjuvant Therapy ,3. Good health ,Vascular endothelial growth factor ,Survival Rate ,030220 oncology & carcinogenesis ,Lymphatic Metastasis ,Female ,cancer-associated fibroblasts ,Adult ,Urology ,Antineoplastic Agents ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Disease-Free Survival ,resistance ,03 medical and health sciences ,Cell Line, Tumor ,Endopeptidases ,Biomarkers, Tumor ,Animals ,Humans ,Carcinoma, Renal Cell ,030304 developmental biology ,Aged ,Retrospective Studies ,#kcsm ,business.industry ,Membrane Proteins ,medicine.disease ,Actins ,Capillaries ,Clear cell renal cell carcinoma ,chemistry ,Drug Resistance, Neoplasm ,fibroblast-associated protein ,#KidneyCancer ,Cancer research ,Cancer-Associated Fibroblasts ,business ,Transcriptome ,prognostic marker - Abstract
International audience; Objectives: To investigate the role of cancer-associated fibroblasts (CAFs) in clear cell renal cell carcinoma (ccRCC) with respect to tumour aggressiveness, metastasis development, and resistance to anti-angiogenic therapy (vascular endothelial growth factor receptor-tyrosine kinase inhibitors [VEGFR-TKI]).Patients and methods: Our study involved tissue samples from three distinct and independent cohorts of patients with ccRCC. The presence of CAFs and tumour lymphangiogenesis was investigated, respectively, by transcriptional signatures and then correlated with tumour development and prognosis. The effect of these CAFs on tumour cell migration and VEGFR-TKI resistance was analysed on co-cultures of ccRCC cells with CAFs.Results: Results from our cohorts and from in silico investigations showed that VEGFR-TKI significantly increase the number of CAFs in tumours. In the same populations of patients with ccRCC, the proportion of intra-tumoral CAFs correlated to shorter disease-free and overall survival. The presence of CAFs was also correlated with lymphangiogenesis and lymph node metastasis. CAFs increased the migration and decreased the VEGFR-TKI-dependent cytotoxic effect of tumour cells.Conclusions: Our results show that VEGFR-TKI promote the development of CAFs, and CAFs favour tumour aggressiveness, metastatic dissemination, and resistance to treatment in ccRCC. CAFs could represent a new therapeutic target to fight resistance to treatment of ccRCC. Targeting CAF and immunotherapies combination are emerging as efficient treatments in many types of solid tumours. Our results highlight their relevance in ccRCC.
- Published
- 2022
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