The role of fibroblast growth factors in tumor growth

Abstract

Biological processes that drive cell growth are exciting targets for cancer therapy. The fibroblast growth factor (FGF) signaling network plays a ubiquitous role in normal cell growth, survival, differentiation, and angiogenesis, but has also been implicated in tumor development. Elucidation of the roles and relationships within the diverse FGF family and of their links to tumor growth and progression will be critical in designing new drug therapies to target FGF receptor (FGFR) pathways. Recent studies have shown that FGF can act synergistically with vascular endothelial growth factor (VEGF) to amplify tumor angiogenesis, highlighting that targeting of both the FGF and VEGF pathways may be more efficient in suppressing tumor growth and angiogenesis than targeting either factor alone. In addition, through inducing tumor cell survival, FGF has the potential to overcome chemotherapy resistance highlighting that chemotherapy may be more effective when used in combination with FGF inhibitor therapy. Furthermore, FGFRs have variable activity in promoting angiogenesis, with the FGFR-1 subgroup being associated with tumor progression and the FGFR-2 subgroup being associated with either early tumor development or decreased tumor progression. This review highlights the growing knowledge of FGFs in tumor cell growth and survival, including an overview of FGF intracellular signaling pathways, the role of FGFs in angiogenesis, patterns of FGF and FGFR expression in various tumor types, and the role of FGFs in tumor progression.

Fig. 1

Evolutionary relationships within the human FGF family (reproduced from reference 3).

Fig. 2

Representative view of FGF transmembrane receptors, showing additional diversity created by use of splice variants (reproduced from reference 30). The alternate C-terminus variants are designated C1 and C3. The open square in the extracellular domain represents the acid box region.

Fig. 3

Intracellular signaling pathways for the FGF/FGFR complex (adapted from reference 33).

Fig. 4

FGFR signal transduction contributes to both early and late phase tumor angiogenesis (adapted from reference 127).