Anti-tumor angiogenesis therapy using soluble receptors: enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor

Abstract

We have shown that a soluble receptor for vascular endothelial growth factor ( sVEGFR ), which adsorbs VEGF and may function as a dominant -negative receptor, suppresses tumor angiogenesis and enhances apoptosis of cancer cells, thereby inhibiting tumor growth [ Cancer Res 60 ( 2000 ) 2169 -2177. In the present study, using as many as 11 cancer cell lines, we tested two hypotheses: ( a ) that a soluble fibroblast growth factor receptor -1 ( sFGFR1 ) might inhibit tumor angiogenesis and growth in sVEGFR -resistant cancers, and ( b ) that combining sFGFR1 with sVEGFR might produce an enhanced inhibitory effect. In two cell lines derived from human lung cancer, H460 and A549, both of which produce a considerable amount of FGF -2, sVEGFR and a soluble receptor for angiopoietin -1 were both ineffective; however, sFGFR1 inhibited tumor angiogenesis and growth, demonstrating the critical role that FGFs play in some cancers. In three cell lines ( QG56 from lung cancer, T3M4 and Panc1 from pancreatic cancer ), which produced both VEGF and FGF -2 at detectable levels, combined sVEGFR and sFGFR1 produced an enhanced inhibitory effect compared to their individual effects. The combined usage of sVEGFR plus sFGFR1 suppressed tumor growth in all cancer cell lines tested, suggesting possible effectiveness of this strategy against a wide range of cancers.

The tyrp1 -Tag/ tyrp1 -FGFR1-DN Bigenic Mouse

“…Blockade of the FGF pathway in mice by FGF-2 or FGFR1 antisense molecules or by FGF-2 neutralizing antibody inhibits tumor angiogenesis and growth (17,18). Adenoviral expression of soluble FGFRs does not inhibit tumor growth in vitro but decreases the number of capillaries in tumors in vivo, which suggests that in vivo tumor growth is impaired through an angiogenesis-dependent mechanism and is in agreement with the present study (19,20). However, work from our laboratory has also demonstrated that in C6 tumors, FGFs may have a dual mode of action (8).…”

Identification of a Fibroblast Growth Factor Receptor 1 Splice Variant That Inhibits Pancreatic Cancer Cell Growth

“…Our hypothesis that FGFR1-IIIc promotes, whereas FGFR1-IIIb inhibits, the transformed phenotype of epithelial cells is further supported by the following findings. Inhibition of FGFR1-IIIc signaling using dominant-negative strategies or soluble forms of the receptor resulted in significant growth inhibition of several cancer cell lines, including pancreas and prostate (17,(31)(32)(33). Moreover, similar possible counteracting functions have been described for the Ig domain III variants of FGFR2 (9)(10)(11)(12)(13)(14)(15).…”

Targeting the Extracellular Domain of Fibroblast Growth Factor Receptor 3 with Human Single-Chain Fv Antibodies Inhibits Bladder Carcinoma Cell Line Proliferation

“…Previous results have shown that secreted soluble, extracellular ligand-binding domains of the native FGFRs play an inhibitory effect on cell proliferation, mopping up the ligand binding to the receptor (35). The antibody fragments may mimic this capability of the secreted extracellular domains.…”