Beyond VEGF: inhibition of the fibroblast growth factor pathway and antiangiogenesis

Abstract

Fibroblast growth factor (FGF) signaling regulates cell proliferation, differentiation, survival, angiogenesis, and wound healing. Compelling evidence for deregulated FGF signaling in tumorigenesis continues to emerge, and a growing body of research suggests that FGF may also play an integral role in the resistance to anti-VEGF therapy. Although agents targeting FGF signaling are early in development, the potential to target both the VEGF and FGF pathways may translate into improvements in the clinical care of cancer patients.

Figure 1. Changes in FGF and FGFR in the microenvironment and epithelium in normal tissue and cancer

Compared to normal tissue, alternative splicing of the FGFR gene can switch expression of FGFR from the IIIb isoform to the ligand promiscuous IIIc isoforms. Furthermore, release of FGF from the tumor and stroma may initiate tumor angiogenesis. FGF-BP mediated reduction of the affinity of FGF-2 to heparin can induce its release from the ECM.

Figure 2

VEGFR2 blockade transiently stops tumor growth and decreases vascularity, followed by tumor progression, reinduction of angiogenesis, and reestablishment of the tumor vasculature (adapted from reference 82) Quantification of overall tumor burden plotted as average and standard deviation per animal at the time of initiation of treatment (t = 0; black bar) and after treatment for 10 days (gray bars) and for 4 weeks of age (white bars) for the different treatment arms. Averages from cohorts of eight to ten mice per group are plotted with their respective standard deviation bars.