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Theranostics 2019; 9(3):661-675. doi:10.7150/thno.27794 This issue Cite

Research Paper

VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness

Papa Diogop Ndiaye1, Maeva Dufies2, Sandy Giuliano2, Laetitia Douguet1, Renaud Grépin2, Jérôme Durivault2, Philippe Lenormand1, Natacha Glisse1, Janita Mintcheva1, Valérie Vouret-Craviari1, Baharia Mograbi1, Maud Wurmser3, Damien Ambrosetti4, Nathalie Rioux-Leclercq5, Pascal Maire3, Gilles Pagès1,2✉

1. University of Nice Sophia Antipolis, Institute for research on cancer and aging of Nice, CNRS UMR 7284; INSERM U1081, Centre Antoine Lacassagne, France
2. Centre Scientifique de Monaco, Biomedical Department, 8 Quai Antoine Ier, MC-98000 Monaco, Principality of Monaco.
3. Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Institut Cochin, Paris, 75014 France; CNRS UMR 8104, Paris, 75014 France, Paris, 75014 France.
4. Nice University Hospital, Central laboratory of Pathology.
5. Rennes University, Rennes University Hospital, Department of Pathology, Rennes, France.

✉ Corresponding author: Gilles Pagès: gpagesfr

Citation:
Ndiaye PD, Dufies M, Giuliano S, Douguet L, Grépin R, Durivault J, Lenormand P, Glisse N, Mintcheva J, Vouret-Craviari V, Mograbi B, Wurmser M, Ambrosetti D, Rioux-Leclercq N, Maire P, Pagès G. VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness. Theranostics 2019; 9(3):661-675. doi:10.7150/thno.27794. https://www.thno.org/v09p0661.htm
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Abstract

Graphic abstract

Hypoxic zones are common features of metastatic tumors. Due to inactivation of the von Hippel-Lindau gene (VHL), renal cell carcinomas (RCC) show constitutive stabilization of the alpha subunit of the hypoxia-inducible factor (HIF). Thus, RCC represents a model of chronic hypoxia. Development of the lymphatic network is dependent on vascular endothelial growth factor C (VEGFC) and lies at the front line of metastatic spreading. Here, we addressed the role of VEGFC in RCC aggressiveness and the regulation of its expression in hypoxia.

Methods: Transcriptional and post transcriptional regulation of VEGFC expression was evaluated by qPCR and with reporter genes. The involvement of HIF was evaluated using a siRNA approach. Experimental RCC were performed with immuno-competent/deficient mice using human and mouse cells knocked-out for the VEGFC gene by a CRISPR/Cas9 method. The VEGFC axis was analyzed with an online available data base (TCGA) and using an independent cohort of patients.

Results: Hypoxia induced VEGFC protein expression but down-regulated VEGFC gene transcription and mRNA stability. Increased proliferation, migration, over-activation of the AKT signaling pathway and enhanced expression of mesenchymal markers characterized VEGFC-/- cells. VEGFC-/- cells did not form tumors in immuno-deficient mice but developed aggressive tumors in immuno-competent mice. These tumors showed down-regulation of markers of activated lymphocytes and M1 macrophages, and up-regulation of M2 macrophages markers and programmed death ligand 1 (PDL1). Over-expression of lymphangiogenic genes including VEGFC was linked to increased disease-free and overall survival in patients with non-metastatic tumors, whereas its over-expression correlated with decreased progression-free and overall survival of metastatic patients.

Conclusion: Our study revisited the admitted dogma linking VEGFC to tumor aggressiveness. We conclude that targeting VEGFC for therapy must be considered with caution.

Keywords: VEGFC, lymphangiogenesis, sunitinib, angiogenesis, renal cell carcinoma, metastasis, CRISPR/Cas9

Citation styles

APA
Ndiaye, P.D., Dufies, M., Giuliano, S., Douguet, L., Grépin, R., Durivault, J., Lenormand, P., Glisse, N., Mintcheva, J., Vouret-Craviari, V., Mograbi, B., Wurmser, M., Ambrosetti, D., Rioux-Leclercq, N., Maire, P., Pagès, G. (2019). VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness. Theranostics, 9(3), 661-675. https://doi.org/10.7150/thno.27794.

ACS
Ndiaye, P.D.; Dufies, M.; Giuliano, S.; Douguet, L.; Grépin, R.; Durivault, J.; Lenormand, P.; Glisse, N.; Mintcheva, J.; Vouret-Craviari, V.; Mograbi, B.; Wurmser, M.; Ambrosetti, D.; Rioux-Leclercq, N.; Maire, P.; Pagès, G. VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness. Theranostics 2019, 9 (3), 661-675. DOI: 10.7150/thno.27794.

NLM
Ndiaye PD, Dufies M, Giuliano S, Douguet L, Grépin R, Durivault J, Lenormand P, Glisse N, Mintcheva J, Vouret-Craviari V, Mograbi B, Wurmser M, Ambrosetti D, Rioux-Leclercq N, Maire P, Pagès G. VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness. Theranostics 2019; 9(3):661-675. doi:10.7150/thno.27794. https://www.thno.org/v09p0661.htm

CSE
Ndiaye PD, Dufies M, Giuliano S, Douguet L, Grépin R, Durivault J, Lenormand P, Glisse N, Mintcheva J, Vouret-Craviari V, Mograbi B, Wurmser M, Ambrosetti D, Rioux-Leclercq N, Maire P, Pagès G. 2019. VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness. Theranostics. 9(3):661-675.

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