Similarly to VEGF-A, FGF signaling has been implicated in multiple aspects of tumor angiogenesis.235 In addition to promoting endothelial cell proliferation, survival and chemotaxis, FGF has been shown to upregulate protease activity and direct expression of uPAR to the leading edge of the endothelial cell migration front.256 FGF2 stimulation induces the reorganization of endothelial cells into capillary-like structures when plated in type 1 collagen; a process that involves upregulation of cell-matrix (integrins avb3) and cell-cell (cadherins) adhesion molecules.257,258 Whereas mice lacking FGFR1 die during gastrulation, prior to the appearance of blood vessels, expression of a dominant negative FGFR1 impairs vascular development and stabilization.259,260
In contrast to VEGF-A, endothelial cells coexpress both FGF ligands and receptors, permitting autocrine and paracrine pathway activation. Autocrine activation of the FGFR has been implicated in pathogenic endothelial lesions such as Kaposi's sarcoma and hemangioma; however, the role of FGFs in the normal angiogenenic process remains uncertain, as mice lacking the predominantly expressed forms do not display vascular abnormalities.261 One explanation for this apparent lack of an overt phenotype is the redundancy and cross-talk that occurs between the FGFand VEGF-A signaling pathways. FGFs stimulate VEGF-A and VEGFR expression, and inhibitors of VEGFR-1 and VEGFR-2 antagonize FGF-induced angiogenesis.262 Conversely, there is evidence that some of VEGFs effects on angiogenesis are dependent on expression of endogenous FGF2.263-265
Multiple studies have documented expression of FGF ligands, particularly FGF2, within tumors. Abrogation of FGF signaling has been shown to inhibit neovascularization and growth of experimental tumors, while a synergistic effect on tumor vessel density is observed upon administration of VEGF-A and FGF.266,267 However, whereas a consistent correlation between tumor microvessel density and VEGF-A expression has been documented, there appears to be marked heterogeneity when FGF levels are examined. One notable exception is melanoma, in which FGF2 levels and microvessel density are clearly correlated.268
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