Hindawi Publishing Corporation Journal of Nucleic Acids Volume 2012, Article ID 162692, 7 pages doi:10.1155/2012/162692 Review Article VEGF Spliced Variants: Possible Role of Anti-Angiogenesis Therapy Caroline Hilmi, Me´ lanie Guyot, and Gilles Page` s University of Nice Sophia Antipolis, Institute of Development and Cancer Research, UMR CNRS 6543, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice, France Correspondence should be addressed to Gilles Page`s, gpages@unice.fr Received 17 June 2011; Revised 27 July 2011; Accepted 29 July 2011 Academic Editor: Didier Auboeuf Copyright © 2012 Caroline Hilmi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Angiogenesis has been targeted in retinopathies, psoriasis, and a variety of cancers (colon, breast, lung, and kidney). Among these tumour types, clear cell renal cell carcinomas (RCCs) are the most vascularized tumours due to mutations of the von Hippel Lindau gene resulting in HIF-1 alpha stabilisation and overexpression of Vascular Endothelial Growth Factor (VEGF). Surgical nephrectomy remains the most eﬃcient curative treatment for patients with noninvasive disease, while VEGF targeting has resulted in varying degrees of success for treating metastatic disease. VEGF pre-mRNA undergoes alternative splicing generating pro-angiogenic isoforms. However, the recent identiﬁcation of novel splice variants of VEGF with anti-angiogenic properties has provided some insight for the lack of current treatment eﬃcacy. Here we discuss an explanation for the relapse to anti-angiogenesis treatment as being due to either an initial or acquired resistance to the therapy. We also discuss targeting angiogenesis via SR (serine/arginine-rich) proteins implicated in VEGF splicing. 1. Introduction Therapies targeting angiogenesis seek to either decrease VEGF levels or to block its receptors resulting in the inhibition of downstream signalling pathways such as RAS/RAF/MEK/ERK and PI3 Kinase. Thus, molecules used in the clinic block VEGF or inhibit the tyrosine kinase activ- ity of the VEGF receptors. These classical strategies evidently target endothelial cells and thus prevent angiogenesis but may also inhibit autocrine proliferative/survival pathways due to abnormal expression of VEGF receptors by tumour cells of diﬀerent origins [1–9]. The main treatment commonly used is Bevacizumab (BVZ), a humanized IgG1 monoclonal antibody against VEGF [10]. A phase II clinical trial has shown that BVZ can signiﬁcantly prolong the time to progression of disease in patients with metastatic renal-cell cancer [11]. However, only the BVZ plus interferon alpha (IFN) treatment has obtained approval by the Food and Drugs administration (FDA) in the United States of America and the European Medicines Agency (EMA) in Europe following phase III clinical assays [12, 13]. These clinical assays have demon- strated an increase in progression-free survival associated with the treatment combining IFN and BVZ compared to IFN alone. Unfortunately, BVZ plus IFN did not improve overall survival when compared to IFN monotherapy [14, 15]. Other treatments targeting the diﬀerent VEGF receptors are Receptor Tyrosine Kinase Inhibitors (RTKI) such as sunitinib targeting VEGFR2, PDGFR, FLT3, and c-Kit or sorafenib targeting B-Raf, c-Raf, VEGFR2/3, PDGFR, FLT3, and c-Kit. These compounds are used in cases of advanced RCC with good or intermediate prognosis. Two clinical trials showed the beneﬁt of using sunitinib for treating advanced RCC with a greater decrease in tumour size, an increase of progression-free survival of about nine months, and a better quality of life [16, 17]. Another phase III clinical trial has also demonstrated eﬃcacy of sorafenib on RCC [17]. However, as for the BVZ plus IFN combined treatment, sunitinib or sorafenib did not increase overall survival of RCC patients. Axitinib [18] and pazopanib [19] are new VEGFR-TKI compounds generated for the treatment of RCC but it is too early to evaluate their eﬃcacy compared to