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Le phénotype mésenchymateux et la réponse aux agents anti-VEGF dans le cancer colorectal

Abstract : VEGF is a validated target for treatment of metastatic colorectal cancer (mCRC) with bevacizumab (avastin) and aflibercept (zaltrap) being approved for first and second line treatment, respectively. Despite intense efforts, no predictive biomarkers are available to identify patients likely to respond, or not, to VEGF-targeted therapies. Recently, different subtypes of CRC have been identified based on gene expression analysis including CMS4, a molecular subgroup with a mesenchymal phenotype, prominent angiogenesis and poor prognosis. We here wish to establish if the mesenchymal phenotype is predictive for the response to VEGF-targeted agents. CRC cell lines were examined for expression of epithelial (E-cadherin, gamma-catenin, cytokeratin 18) and mesenchymal (vimentin, N-cadherin, fibronectin) markers in vitro and in vivo by qRT-PCR and Western blot analysis and for the cellular distribution of E-cadherin and beta-catenin by ICC. Five CRC models were selected ranging from pronounced epithelial (HT-29, DLD-1), intermediate (HCT-116) to mesenchymal (HCT-116/5-FU, LS174T) and the tumor growth inhibitory activity of bevacizumab and aflibercept was established. VEGF-secretion was determined by ELISA and the microvascular density was characterized by quantitative IHC analysis. The mesenchymal phenotype was associated with higher microvascular density, but not with the expression of VEGF ligands. Two CRC xenograft models (DLD-1, HCT-116/5-FU) were sensitive to both bevacizumab and aflibercept, two models were more sensitive to aflibercept, compared to bevacizumab (HT-29, HCT-116), and one model (LS174T) was resistant to both agents. Aflibercept was more potent than bevacizumab in all CRC models. The mesenchymal phenotype was not predictive for the response to VEGF-targeted agents, neither positively nor negatively.
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https://tel.archives-ouvertes.fr/tel-01815285
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Submitted on : Thursday, June 14, 2018 - 1:01:32 AM
Last modification on : Tuesday, October 20, 2020 - 11:34:02 AM
Long-term archiving on: : Monday, September 17, 2018 - 12:30:01 PM

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  • HAL Id : tel-01815285, version 1

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Anaïs Bouygues. Le phénotype mésenchymateux et la réponse aux agents anti-VEGF dans le cancer colorectal. Physiologie [q-bio.TO]. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066463⟩. ⟨tel-01815285⟩

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