IntroductionAngiogenesis is a complex process that leads to the formation of new blood vessels from existing ones. During embryogenesis, angiogenesis complements vasculogenesis, the production of new blood vessels from hematopoietic precursors. In the adult organism, angiogenesis takes place under normal conditions during the female reproductive cycle or under pathologic conditions, such as in tumor growth and wound healing. Secretion of angiogenic factors from the tumor mass induces the formation of blood vessels, which feed cancer cells with oxygen and nutrients. These vessels will eventually be used as a route for the spreading of metastases. 1 Several angiogenic factors have been described, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-␣ (TGF-␣), TGF-, hepatocyte growth factor (HGF), tumor necrosis factor, angiogenin, interleukin-8, and the angiopoietins. 2 The most prominent angiogenic factor is VEGF-A, a member of the VEGF family of growth factors also including placental growth factor and VEGF-B, -C, -D, and -E. 3 VEGFs bind to 3 related members of the VEGFR family, VEGFR-1, -2, and -3. The importance of VEGFs and their receptors is demonstrated by the phenotypes of the respective knockout mice. Indeed, Vegf-A and Vegfr-2 knockout mice show a failure in vasculature formation and die during embryogenesis, whereas Vegfr-1-deficient mice die of an overgrowth of blood vessels. 3 Fighting angiogenesis has become an attractive aim of cancer therapy. Indeed, targeting angiogenesis rather than directly addressing the tumor cells has the advantage that the same reagents can be applied to many different types of tumors. In addition, because of the low turnover rate of endothelial cells (ECs), they are less susceptible to become resistant to chemotherapy. 4 Several anti-VEGF treatment regimens already exist that can be combined with chemotherapy or radiotherapy. These treatments make use of VEGF inhibitors, such as antibodies against VEGF (bevacizumab), several small molecules inhibiting VEGFR-2 signaling, as well as soluble VEGF receptors that compete with the endogenous receptor for binding to VEGF. 5 However, because all these treatments have a relatively modest benefit for most cancer patients, there is still plenty of room for improvement.HGF is another potent angiogenic factor: the expression of HGF and its receptor c-Met correlates with tumor vascularization, 6 the production of VEGF in a variety of cells and tissues is induced by HGF, 7 and HGF can potentiate the activity of VEGF. [8][9][10] Furthermore, HGF leads to mobilization of endothelial progenitor cells, 11 and the expression of a soluble c-Met receptor (decoy Met) impairs tumor angiogenesis. 12 We have previously shown that HGF depends on a CD44 exon v6 containing isoform for the activation of c-Met on epithelial cells. 13 CD44 isoforms containing the variant exon v6 have been shown to be metastatic determinants. 14 The role of CD44v6 in metastasis results most probably from its coop...
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