title: Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti-cancer strategies.
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.
authors.affiliation: University of Nice Sophia Antipolis, UMR CNRS 7284/U INSERM 1081, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Guyot
authors.affiliation: University of Nice Sophia Antipolis, UMR CNRS 7284/U INSERM 1081, France.|Bayer S.A.S, Crop Science Division, BCS Fr-BCSF-RDFR-DVPT-TOX-TOXR, Toxicology Research, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hilmi
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Pasteur, Central laboratory of Pathology, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Ambrosetti
authors.affiliation: Medical Oncology Department, S. Croce and Carle Teaching Hospital Cancer Genetics and Translational Oncology Laboratory Cuneo, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Merlano
authors.affiliation: Medical Oncology Department, S. Croce and Carle Teaching Hospital Cancer Genetics and Translational Oncology Laboratory Cuneo, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
authors.affiliation: Centre Scientifique de Monaco, Monaco Principality.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Durivault
authors.affiliation: Centre Scientifique de Monaco, Monaco Principality.
authors.forename: Renaud
authors.initials: R
authors.lastname: Grépin
authors.affiliation: University of Nice Sophia Antipolis, UMR CNRS 7284/U INSERM 1081, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D019496:Cancer Vaccines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab
keywords: SRSF1; VEGF/VEGFxxxb; angiogenesis; renal cell carcinoma; splicing