Antiangiogenic Therapy Targeting Factors That Enhance Endothelial Cell Survival Wenbiao Liu, Niels Reinmuth, Oliver Stoeltzing, Alexander A. Parikh, Fan Fan, Syed A. Ahmad, Young D. Jung, and Lee M. Ellis The process of angiogenesis involves the formation of new blood vessels from established vasculature and the maintenance of the fragile neovascular network. Re- cent studies have shown that several angiogenic factors not only induce angiogenesis but also act as endothelial cell (EC) survival factors. Vascular endothelial growth factor, a potent angiogenic factor, is also an EC survival factor via activation of EC-specific tyrosine kinase re- ceptors. Angiopoietin-1 has recently been shown to stabilize EC networks by binding to the EC-specific tyrosine kinase receptor Tie-2; in contrast, angiopoi- etin-2 is antagonistic to angiopoietin-1 and destabilizes EC networks. Integrins may function as EC survival factors by preventing apoptosis by numerous mecha- nisms mediated by binding to the extracellular matrix. Integrins may also function in concert with vascular endothelial growth factor to promote EC survival. Lastly, pericytes contribute to EC stabilization by cell- cell contact and/or secretion of survival factors, such as vascular endothelial growth factor. Targeting EC sur- vival factors may provide a novel antineoplastic strat- egy for cancer. Semin Oncol 29 (suppl 11):96-103. Copyright 2002, Elsevier Science (USA). All rights reserved. A NGIOGENESIS is essential for tumor pro- gression and metastasis. This complicated process is regulated by numerous proangiogenic factors and antiangiogenic factors in a coordi- nated fashion. The process of angiogenesis also requires that endothelial cells (EC) detach from pericytes and the extracellular matrix (ECM), proliferate, invade the surrounding tissues, mi- grate, and differentiate to form capillary tubes that connect to other newly developed vascular networks. To maintain the integrity of these fragile neovascular networks, specific factors that assure EC survival must be secreted. 1 Re- cently, several factors have been found to func- tion as EC survival factors. These factors include vascular endothelial growth factor (VEGF), an- giopoietin-1 (Ang-1), integrins, and pericytes. This review will summarize the biologic charac- teristics of these factors that prevent ECs from undergoing apoptosis. Understanding the factors that enhance EC survival provides novel targets for antineoplastic therapy (Fig 1). VASCULAR ENDOTHELIAL GROWTH FACTOR AS AN ENDOTHELIAL CELL SURVIVAL FACTOR Vascular endothelial growth factor, also known as vascular permeability factor or VEGF-A, is the predominant angiogenic factor in a variety of hu- man cancers. 2 Vascular endothelial growth factor is a 34- to 50-kd homodimeric glycoprotein pro- duced by both malignant and normal cells. Vascu- lar endothelial growth factor is expressed as at least four different molecular species: VEGF-121, -165, -189, and -206 amino acids in length because of alternative splicing of mRNA. 3 The smaller isoforms, VEGF-121 and VEGF-165, are secreted from cells, whereas the two larger isoforms, VEGF-189 and VEGF-206, remain cell-associated. The functions of the larger isoforms are not well characterized at this time. VEGF-165 is the most abundant, best- characterized, and most potent biologically active isoform. Because of the possession of a hepa- rin-binding basic region absent in VEGF-121, VEGF-165 has 10- to 100-fold higher biological activity than VEGF-121. 4 It is possible that each VEGF isoform contributes differently to the pro- cess of tumor vascularization. 4-6 Overexpression of VEGF is associated with an- giogenesis in both primary and metastatic tumors. 7 Vascular endothelial growth factor exerts its ef- From the Departments of Cancer Biology and Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Hous- ton, TX. Supported in part by National Institutes of Health training grant T32 09599-08 (A.A.P., S.A.); German Foundation for Cancer Research-Mildred Scheel (N.R.); the Gillson Longenbaugh Foundation (L.M.E.); the Jon and Suzie Hall Fund for Colon Cancer Research (L.M.E.); the RGK Foundation (L.M.E.); and National Institutes of Health grant CA74821 (L.M.E.). Dr Ellis serves as a consultant to Genentech, ImClone Systems, and Attenuon LLC. He receives research grant support from Im- Clone Systems, Attenuon LLC, and Pharmacia Oncology. Address reprint requests to Lee M. Ellis, MD, Department of Surgical Oncology, Box 444, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2903-1113$35.00/0 doi:10.1053/sonc.2002.34061 96 Seminars in Oncology, Vol 29, No 3, Suppl 11 (June), 2002: pp 96-103