The sVEGFR1-i13 splice variant regulates a β1 integrin/VEGFR autocrine loop involved in the progression and the response to anti-angiogenic therapies of squamous cell lung carcinoma

  • Br J Cancer. 2018 Jun;118(12):1596-1608. doi: 10.1038/s41416-018-0128-4.
Cherine Abou Faycal  1 ,  Elisabeth Brambilla  2 ,  Jackeline Agorreta  3  4 ,  Nina Lepeltier  1 ,  Thibault Jacquet  1 ,  Nicolas Lemaître  2 ,  Anouk Emadali  5 ,  Anthony Lucas  2 ,  Pedro M Lacal  6 ,  Luis Montuenga  3  4 ,  Ruben Pio  3  7 ,  Sylvie Gazzeri  1 ,  Beatrice Eymin  8
Affiliations
  • 1. Team RNA Splicing, Cell Signalling and Response to Therapies, Institute For Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000, Grenoble, France.
  • 2. Team Tumor Molecular Pathology and Biomarkers, Institute For Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000, Grenoble, France.
  • 3. Program in Solid Tumors (CIMA), CIBERONC and Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain.
  • 4. Department of Histology and Pathology, University of Navarra, School of Medicine, 31008, Pamplona, Spain.
  • 5. Team Genetics and Epigenetics of Lymphoid Cancers, Institute For Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000, Grenoble, France.
  • 6. Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy.
  • 7. Department of Biochemistry and Genetics, University of Navarra, School of Sciences, 31008, Pamplona, Spain.
  • 8. Team RNA Splicing, Cell Signalling and Response to Therapies, Institute For Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000, Grenoble, France. [email protected].
PMID: 29795310 DOI: 10.1038/s41416-018-0128-4
Abstract

Background: While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain. sVEGFR1-i13 is mainly viewed as an anti-angiogenic factor which counteracts VEGF-A/VEGFR signalling in endothelial cells. However, its role in tumour cells is poorly known.

Methods: mRNA and protein status were analysed by Real-Time qPCR, western blotting, ELISA assay, proximity ligation assay or immunohistochemistry in human tumour cell lines, murine tumourgrafts and non small cell lung carcinoma patients samples.

Results: We show that anti-angiogenic therapies specifically increase the levels of sVEGFR1-i13 in SQLC cell lines and chemically induced SQLC murine tumourgrafts. At the molecular level, we characterise a sVEGFR1-i13/β1 Integrin/VEGFR autocrine loop which determines whether SQLC cells proliferate or go into Apoptosis, in response to anti-angiogenic therapies. Furthermore, we show that high levels of both sVEGFR1-i13 and β1 Integrin mRNAs and proteins are associated with advanced stages in SQLC patients and with a poor clinical outcome in patients with early stage SQLC.

Conclusions: Overall, these results reveal an unexpected pro-tumoural function of sVEGFR1-i13 in SQLC tumour cells, which contributes to their progression and escape from anti-angiogenic therapies. These data might help to understand why some SQLC patients do not respond to anti-angiogenic therapies.

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