Implications of Fibroblast Growth Factors (FGFs) in Cancer: From Prognostic to Therapeutic Applications.

Fibroblast growth factors (FGFs) are pleiotropic molecules exerting autocrine, intracrine and paracrine functions via activating four tyrosine kinase FGF receptors (FGFR), which further trigger a variety of cellular processes including angiogenesis, evasion from apoptosis, bone formation, embryogenesis, wound repair and homeostasis. Four major mechanisms including angiogenesis, inflammation, cell proliferation, and metastasis are active in FGF/FGFR-driven tumors. Furthermore, gain-of-function or loss-of-function in FGFRs1-4 which is due to amplification, fusions, mutations, and changes in tumor-stromal cells interactions, is associated with the development and progression of cancer. Although, the developed small molecule or antibodies targeting FGFR signaling offer immense potential for cancer therapy, emergence of drug resistance, activation of compensatory pathways and systemic toxicity of modulators are bottlenecks in clinical application of anti-FGFRs. In this review, we present FGF/FGFR structure and the mechanisms of its function, as well as cross-talks with other nodes and/or signaling pathways. We describe deregulation of FGF/FGFR-related mechanisms in human disease and tumor progression leading to the presentation of emerging therapeutic approaches, resistance to FGFR targeting, and clinical potentials of individual FGF family in several human cancers. Additionally, the underlying biological mechanisms of FGF/FGFR signaling, besides several attempts to develop predictive biomarkers and combination therapies for different cancers have been explored.