Journal Article

VEGF165b, a splice variant of VEGF-A, promotes lung tumor progression and escape from anti-angiogenic therapies through a β1 integrin/VEGFR autocrine loop

Boudria, Asma, Didier, Chloé, Josserand, Véronique, Faurobert, Eva, Brambilla, Christian, Jia, Tao, Moro-Sibilot, Denis, Albiges-Rizo, Corinne, Lemaître, Nicolas, Eymin, Beatrice, Manet, Sandra, Abou Faycal, Cherine, Gazzeri, Sylvie, Keramidas, Michelle, Toffart, Anne-Claire, Coll, Jean-Luc, Brambilla, Elisabeth, Gout, Stephanie

2019

Overview

Vascular endothelial growth factor-A (VEGF-A) is highly subjected to alternative pre-mRNA splicing that generates several splice variants. The VEGF xxx and VEGF xxx b families encode splice variants of VEGF-A that differ only at the level of six amino acids in their C-terminal part. The expression level of VEGF xxx splice variants and their function as pro-angiogenic factors during tumor neo-angiogenesis have been well-described. The role of VEGF xxx b isoforms is less well known, but they have been shown to inhibit VEGF xxx -mediated angiogenesis, while being partial or weak activators of VEGFR receptors in endothelial cells. On the opposite, their role on tumor cells expressing VEGFRs at their surface remains largely unknown. In this study, we find elevated levels of VEGF 165 b, the main VEGF xxx b isoform, in 36% of non-small cell lung carcinoma (NSCLC), mainly lung adenocarcinoma (46%), and show that a high VEGF 165 b/VEGF 165 ratio correlates with the presence of lymph node metastases. At the molecular level, we demonstrate that VEGF 165 b stimulates proliferation and invasiveness of two lung tumor cell lines through a VEGFR/β1 integrin loop. We further provide evidence that the isoform-specific knockdown of VEGF 165 b reduces tumor growth, demonstrating a tumor-promoting autocrine role for VEGF 165 b in lung cancer cells. Importantly, we show that bevacizumab, an anti-angiogenic compound used for the treatment of lung adenocarcinoma patients, increases the expression of VEGF 165 b and activates the invasive VEGFR/β1 integrin loop. Overall, these data highlight an unexpected role of the VEGF 165 b splice variant in the progression of lung tumors and their response to anti-angiogenic therapies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Publishing Group [1987-....]
• Subject: 13/1 / 13/109 / 13/31 / 13/89 / 13/95 / 14/63 / 631/67/1059/2326 / 631/67/1612/1350 / 631/80/86/2368 / 82/80 / Adenocarcinoma / Alternative splicing / Angiogenesis / Apoptosis / Autocrine signalling / Bevacizumab / Cancer / Cell Biology / Cellular Biology / Endothelial cells / Human Genetics / Internal Medicine / Invasiveness / Isoforms / Life Sciences / Lung cancer / Lung carcinoma / Lymph nodes / Medicine / Medicine & Public Health / Metastases / Monoclonal antibodies / mRNA / Non-small cell lung carcinoma / Oncology / Small cell lung carcinoma / Targeted cancer therapy / Tumor cell lines / Tumor cells / Tumors / Vascular endothelial growth factor / Vascular endothelial growth factor receptors