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, 2012, 429213

A Decade of FGF Receptor Research in Bladder Cancer: Past, Present, and Future Challenges

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A Decade of FGF Receptor Research in Bladder Cancer: Past, Present, and Future Challenges

Erica di Martino et al. Adv Urol.

Abstract

Fibroblast growth factors (FGFs) orchestrate a variety of cellular functions by binding to their transmembrane tyrosine-kinase receptors (FGFRs) and activating downstream signalling pathways, including RAS/MAPK, PLCγ1, PI3K, and STATs. In the last ten years, it has become clear that FGF signalling is altered in a high proportion of bladder tumours. Activating mutations and/or overexpression of FGFR3 are common in urothelial tumours with low malignant potential and low-stage and -grade urothelial carcinomas (UCs) and are associated with a lower risk of progression and better survival in some subgroups. FGFR1 is not mutated in UC, but overexpression is frequent in all grades and stages and recent data indicate a role in urothelial epithelial-mesenchymal transition. In vitro and in vivo studies have shown that FGFR inhibition has cytotoxic and/or cytostatic effects in FGFR-dependent bladder cancer cells and FGFR-targeted agents are currently being investigated in clinical studies for the treatment of UC. Urine-based tests detecting common FGFR3 mutations are also under development for surveillance of low-grade and -stage tumours and for general population screening. Overall, FGFRs hold promise as therapeutic targets, diagnostic and prognostic markers, and screening tools for early detection and clinical management of UC.

Figures

Figure 1
Figure 1
Schematic representation of human FGFR3 protein and corresponding FGFR3 coding exons. Exon numbering based on Tomlinson et al. [38]. Type and total number of reported mutations are based on data pooled from 11 studies [–, , , –42], including a total of 1898 bladder tumours. SP: signal peptide; IgI–III: immunoglobulin-like domain; AB: acid box; TM: transmembrane domain; TK; tyrosine-kinase domain.
Figure 2
Figure 2
Mechanisms of physiological (a)-(b) and pathological (c)–(f) activation of FGFR3. (a) Monomeric inactive receptor; (b) Ligand-dependent dimerization and activation; (c) Ligand-independent dimerization and activation induced by mutation of the extracellular portion; (d) Ligand-independent activation due to mutations of the tyrosine-kinase domain; (e) Upregulation of signalling due to receptor overexpression; (f) Alteration of splicing favouring isoforms with broader ligand specificity.
Figure 3
Figure 3
Potential applications of FGFRs in the early detection and clinical management of bladder tumours.

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