Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti-cancer strategies

// Melanie Guyot 1 , Caroline Hilmi 1, 2 , Damien Ambrosetti 3 , Marco Merlano 4 , Cristiana Lo Nigro 4 , Jerome Durivault 5 , Renaud Grepin 5 , Gilles Pages 1 1 University of Nice Sophia Antipolis, UMR CNRS 7284/U INSERM 1081, France 2 Bayer S.A.S, Crop Science Division, BCS Fr-BCSF-RDFR-DVPT-TOX-TOXR, Toxicology Research, France 3 Centre Hospitalier Universitaire (CHU) de Nice, Hopital Pasteur, Central laboratory of Pathology, France 4 Medical Oncology Department, S. Croce and Carle Teaching Hospital Cancer Genetics and Translational Oncology Laboratory Cuneo, Italy 5 Centre Scientifique de Monaco, Monaco Principality Correspondence to: Gilles Pages, email: gpages@unice.fr Keywords: VEGF/VEGFxxxb, angiogenesis, renal cell carcinoma, splicing, SRSF1 Received: October 13, 2016      Accepted: December 05, 2016      Published: December 15, 2016 ABSTRACT Tumor growth relies on oxygen and blood supply depending on neo-vascularization. This process is mediated by the Vascular Endothelial Growth Factor (VEGF) in many tumors. This paradigm has led to the development of specific therapeutic approaches targeting VEGF or its receptors. Despite their promising effects, these strategies have not improved overall survival of patients suffering from different cancers compared to standard therapies. We hypothesized that the existence of anti-angiogenic forms of VEGF VEGFxxxb which are still present in many tumors limit the therapeutic effects of the anti-VEGF antibodies bevacizumab/Avastin (BVZ). To test this hypothesis, we generated renal cell carcinoma cells (RCC) expressing VEGF165b. The incidence of tumors xenografts generated in nude mice and their growth were inferior to those obtained with control cells. Whereas BVZ had no effect on control tumors, it slowed-down the growth of tumor generated with VEGF165b expressing cells. A prophylactic immunization against the domain discriminating VEGF from VEGFxxxb isoforms inhibited the growth of tumor generated with two different syngenic tumor cell lines (melanoma (B16 cells) and RCC (RENCA cells)). Purified immunoglobulins from immunized mice also slowed-down tumor growth of human RCC xenografts in nude mice, producing a potent effect compared to BVZ in this model. Furthermore, down-regulating the serine-arginine-rich splicing factor 1 (SRSF1) or masking SRSF1 binding sites by 2’O-Methyl RNA resulted in the increase of the VEGFxxxb/VEGF ratio. Therefore, a vaccine approach, specific antibodies against pro-angiogenic forms of VEGF, or increasing the VEGFxxxb/VEGF ratio may represent new prophylactic or pro-active anti-cancer strategies.