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Cited by 53Angiogenesis and VEGF in CancerLymphatic System and DiseasesCancer, Hypoxia, and Metabolism

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

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Boudria, Asma, Abou Faycal, Cherine, Jia, Tao, Gout, Stephanie, Keramidas, Michelle, Didier, Chloé, Lemaître, Nicolas, Manet, Sandra +10 more·2019·Oncogene
DOI 10.1038/s41388-018-0486-7
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Abstract

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.

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Authors
Boudria, A., Abou Faycal, C., Jia, T., Gout, S., Keramidas, M., Didier, C., Lemaître, N., Manet, S., Coll, J.-L., Toffart, A.-C., Moro-Sibilot, D., Albiges-Rizo, C., Josserand, V., Faurobert, E., Brambilla, C., Brambilla, E., Gazzeri, S., & Eymin, B.
Affiliations
Centre National de la Recherche Scientifique (FR)
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2018-09-07
Volume
38
Issue
7
Pages
1050-1066
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/s41388-018-0486-7
OpenAlex
W2890124177
Cited by
53
References
51
Citations by year
2026: 1 · 2025: 7 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 11 · 2020: 8 · 2019: 9
FWCI
2.49
Type
journal article
Language
en
Update notices
correction (2023-07-05)
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • HAL (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
VEGF165b, VEGF splice variants, VEGF-A, non-small cell lung cancer, lung adenocarcinoma, beta1 integrin, VEGFR, autocrine loop, tumor progression, tumor invasion, lymph node metastasis, bevacizumab, anti-angiogenic therapy resistance, alternative splicing
MeSH terms
Bevacizumab, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Neoplasm Proteins, Neovascularization, Pathologic, Signal Transduction, Alternative Splicing, Integrin beta1, Autocrine Communication, Protein Isoforms, Angiogenesis Inhibitors, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A

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