Fibroblast growth factors and their receptors in cancer

Abstract

FGFs (fibroblast growth factors) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration and differentiation during development and adult life. Deregulation of FGFR signalling, on the other hand, has been associated with many developmental syndromes, and with human cancer. In cancer, FGFRs have been found to become overactivated by several mechanisms, including gene amplification, chromosomal translocation and mutations. FGFR alterations are detected in a variety of human cancers, such as breast, bladder, prostate, endometrial and lung cancers, as well as haematological malignancies. Accumulating evidence indicates that FGFs and FGFRs may act in an oncogenic fashion to promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting epithelial-mesenchymal transition, invasion and tumour angiogenesis. Therapeutic strategies targeting FGFs and FGFRs in human cancer are therefore currently being explored. In the present review we will give an overview of FGF signalling, the main FGFR alterations found in human cancer to date, how they may contribute to specific cancer types and strategies for therapeutic intervention.

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…Indeed, according to previous studies, multiple FGFs, including FGF1 and 2 and FGF6-9, are upregulated in this disease, whereas FGFR1 is expressed in 40% of poorly differentiated localized prostate cancers ( 46 ). The stromal expression and release of various FGFs are related to angiogenic and tumor-promoting effects.…”

“…High FGF levels may be derived from the upregulation of FGF expression in cancer or stromal cells and the enhanced release of FGFs from the extracellular matrix ( 46 ).…”

Fibroblast growth factor receptor 1 amplification is a common event in squamous cell carcinoma of the head and neck

“…Receptor tyrosine kinases commonly contribute significantly to the development of cancer. 10 When recognizing their fibroblast growth factor ligands, FGFRs undergo dimerization, leading to the phosphorylation of specific intracellular receptor domains, and ultimately leading to the activation of cytoplasmatic effector molecules. The effector pathways following FGFR activation include the Ras/MAPK and PI3/Akt pathways, which in turn transmit the activating signal into the nucleus, where cell differentiation and proliferation are regulated.…”

Vascular-targeted agents for the treatment of angiosarcoma

“…As well as directly stimulating endothelial cells, FGFs also promote angiogenesis through the up-regulation of other pro-angiogenic pathways, including increased expression of VEGF and Ang-2 [24]. As growth factors that stimulate a broad range of cellular processes, including proliferation, survival, migration and invasion, it is unsurprising that aberrant FGF signalling has been identified in a wide range of tumours [25]. Drugs to target FGF signalling are in development, including tyrosine kinase inhibitors (TKIs) such as Brivanib and BIBF1120, however these agents also inhibit VEGF and PDGF receptors [26]; newer agents under investigation including AZD4547 are more potent and selective inhibitors of FGFRs [27].…”