Vascular Endothelial Growth Factor as a Target for Cancer Gene Therapy
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VASCULAR ENDOTHELIAL GROWTH FACTOR AS A TARGET FOR CANCER GENE THERAPY Josephine Tuong Nguyen Department of Diagnostic Radiology Beth Israel Deaconess Medical Center Boston Massachusetts, 02115, U.S.A.
1. INTRODUCTION TO VASCULAR ENDOTHELIAL GROWTH FACTOR Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), has drawn increasing attention as a candidate biological target for cancer therapy because it is one of the most important factors promoting angiogenesis, the process by which tumors recruit and expand the blood supply necessary to support their growth (Dvorak, H. F., Brown, L. F., Detmar, Dvorak, 1995; Folkman, J., 1995). Besides being a potent angiogenic factor, VEGF is the only one which acts specifically on endothelial cells and which increases microvascular hyperpermeability (Connolly, Heuvelman, Nelson, Olander, Eppley, Delfino, Siegel, Leimgruber, and Feder, 1989), which can lead to significant morbidity in certain cancer settings and may facilitate tumor invasion. Abundant data exists that inhibiting VEGF leads to dose-dependent suppression of tumor growth and metastasis. That VEGF is expressed and secreted by almost all solid tumors underscores its fundamental role in neoplasia and implies the broad applicability of its inhibition as an anti-cancer strategy.
1.1. The Upregulation of VEGF in Neoplasia VEGF is a homodimer of two identical 23kDa subunits linked by disulfide bridges (reviewed by Neufeld, Cohen, Gitay-Goren, Poltorak,Tessler, Sharon, Gengrinovitch, and Levi, 1996). Alternative splicing of one mRNA transcript yields four products, leading to proteins of 121, 165, 189, and 206 amino acids (Tischer, Mitchell, Hartmann, Silva, Gosodarowicz, Tiddles, and Abraham, 1991). Isoforms 121 and 165 have mitogenic and permeabilizing activities and are secretable, the 165 isoform being more abundant, while the two larger isoforms, also mitogenic, remain mostly bound to cell surface heparan sulfate proteoglycans. The crystal structure of VEGF has recently been elucidated (Muller, Li, Christinger, Wells, Cunningham, and de Vos, 1997). Three Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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surface loops are situated symmetrically at either end of the dimeric molecule to form two receptor binding interfaces. Binding of VEGF to each of its tyrosine kinase receptors causes receptor dimerization and activation. Cell-surface heparan-sulfates may help VEGF-165 bind to its receptors, especially under oxidizing conditions, such as inflammation. VEGF is induced by the microenvironments caused by poor perfusion and acts primarily on postcapillary venules and small veins, but in other respects, the VEGF signalling system is distinctly different in benign as opposed to neoplastic conditions. In normal tissues, such as in kidney, heart, lung, and adrenal cortex, VEGF receptors are barely detectable, possibly all that is needed to carry out maintenance of the microvasculature (
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