Originally published as JCO Early Release 10.1200/JCO.2005.06.081 on December 7 2004
Journal of Clinical Oncology, Vol 23, No 5 (February 10), 2005: pp. 1011-1027
© 2005 American Society of Clinical Oncology.
Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis
Daniel J. Hicklin,
Lee M. Ellis
From the Department of Experimental Therapeutics, ImClone Systems Incorporated, New York, NY; and Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Address reprint requests to Daniel J. Hicklin, PhD, Department of Experimental Therapeutics, ImClone Systems Incorporated, New York, NY 10014; e-mail: dan.hicklin{at}imclone.com.
New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.
Supported, in part, by National Institutes of Health grants, and CA74821 and U54-CA90810 (L.M.E), the Lustgarten Foundation for Pancreatic Research (L.M.E), and the Lockton Fund for Pancreatic Cancer Research (L.M.E).
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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