Vascular endothelial growth factor--a positive and negative regulator of tumor growth.
Over the past decade, the well-documented role of vascular endothelial growth factor (VEGF) in tumor angiogenesis has led it to become one of the leading therapeutic targets for the treatment of cancer. Emerging evidence from genetically modified animal models, however, suggests that elevated levels of VEGF, or a proangiogenic phenotype, may impede, rather than promote, early tumor development and progression. For example, hypermorph VEGF transgenic mice display delayed progression of a retroviral-induced murine leukemia, and knockdown of VEGF expression within the myeloid compartment accelerates tumor progression. Several mechanisms have been proposed to explain this paradox, whereby VEGF induces changes within the hematopoietic compartment and tumor microenvironment through recruitment of tumor inhibitory monocytic cells and the negative regulation of tumor angiogenesis. Thus, it is apparent that the levels of VEGF expression in both tumor and nontumor tissues, as well as the context and timing of its modulation relative to cancer induction, play an important role in determining the effects of VEGF expression on tumorigenicity. In light of these recent findings, the various mechanisms underlying the negative role of VEGF during early tumor development, progression, and metastasis will be discussed.
Vecchiarelli-Federico
Laura M
LM
Department of Medical Biophysics, Division of Molecular and Cellular Biology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
Cervi
David
D
Haeri
Mehran
M
Li
Yanmei
Y
Nagy
Andras
A
Ben-David
Yaacov
Y
D000818:Animals; D018450:Disease Progression; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D011485:Protein Binding; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor