Abstract
Fibroblast growth factor-1 (FGF1) and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels. Integrins are critically involved in FGF signaling through crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and induces FGF receptor-1 (FGFR1)-FGF1-integrin αvβ3 ternary complex. We previously generated an integrin binding defective FGF1 mutant (Arg-50 to Glu, R50E). R50E is defective in inducing ternary complex formation, cell proliferation, and cell migration, and suppresses FGF signaling induced by WT FGF1 (a dominant-negative effect) in vitro. These findings suggest that FGFR and αvβ3 crosstalk through direct integrin binding to FGF, and that R50E acts as an antagonist to FGFR. We studied if R50E suppresses tumorigenesis and angiogenesis. Here we describe that R50E suppressed tumor growth in vivo while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E. Since R50E did not affect proliferation of cancer cells in vitro, we hypothesized that R50E suppressed tumorigenesis indirectly through suppressing angiogenesis. We thus studied the effect of R50E on angiogenesis in several angiogenesis models. We found that excess R50E suppressed FGF1-induced migration and tube formation of endothelial cells, FGF1-induced angiogenesis in matrigel plug assays, and the outgrowth of cells in aorta ring assays. Excess R50E suppressed FGF1-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) assays. Interestingly, excess R50E suppressed FGF2-induced angiogenesis in CAM assays as well, suggesting that R50E may uniquely suppress signaling from other members of the FGF family. Taken together, our results suggest that R50E suppresses angiogenesis induced by FGF1 or FGF2, and thereby indirectly suppresses tumorigenesis, in addition to its possible direct effect on tumor cell proliferation in vivo. We propose that R50E has potential as an anti-cancer and anti-angiogenesis therapeutic agent (“FGF1 decoy”).
Highlights
The FGF family consists of 22 related polypeptides that are expressed in almost all tissues and are multifunctional
Suppression of Tumorigenesis in vivo by R50E We have reported that Fibroblast growth factor-1 (FGF1) binds to integrin avb3
Our results suggest that 1) R50E is a dominant-negative mutant, 2) ternary complex formation is involved in FGF signaling, and 3) the defect of R50E to bind to integrin may be directly related to the antagonistic action of R50E
Summary
The FGF family consists of 22 related polypeptides that are expressed in almost all tissues and are multifunctional. They can be subdivided in canonical (cFGFs, FGF7-10, FGF16-20, FGF22), intracellular (iFGFs, FGF11-14), and hormonelike (hFGFs, FGF19, 21 and 23) subfamilies [1]. The biological effects of FGFs are mediated by four structurally related receptor tyrosine kinases: FGFR1, FGFR2, FGFR3, and FGFR4. The binding of FGF to its receptor results in receptor dimerization and subsequent transphosphorylation of specific tyrosine residues within the cytoplasmic domain. This leads to the activation of intracellular signaling cascades. FGF1 binds to all known cell-surface FGFR isoforms (FGFR1b, 1c, 2b, 2c, 3b, 3c, and 4) [2,3,4]
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