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

Date Published: July 31, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Erica di Martino, Darren C. Tomlinson, Margaret A. Knowles.

http://doi.org/10.1155/2012/429213

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.

Partial Text

Bladder cancer is a common malignancy with over 70,000 estimated new cases and 14,000 deaths per year in the USA alone [1]. In western countries, around 90% of bladder tumours are transitional cell carcinoma, with rare cases of squamous cell carcinoma and adenocarcinoma [2]. Bladder tumours are classified using the TNM classification system [3] according to their invasiveness (stage Ta: confined to the urothelium; T1: invading the lamina propria; T2: invading the muscular layer; T3: invading the submuscular layers; T4: disseminating to other organs) and their differentiation state (1973 WHO grading system: grade 1, 2, or 3 [4]; 2004 WHO grading system: PUNLMP: papillary urothelial neoplasm of low-malignant potential, low grade: well-differentiated neoplasms, high grade: poorly differentiated neoplasms [2]). At presentation, the vast majority of urothelial carcinomas (UC) (~70%) are low-grade superficial papillary tumours with a relatively benign prognosis. Their conventional treatment involves surgical resection and intravesical chemo- or immunotherapy [5]. One of the major challenges in the management of these tumours is their propensity to recur, therefore requiring frequent and often life-long surveillance with cystoscopy and urine cytology. This, coupled with a relatively long life expectancy (5-year survival rate >90%), makes superficial bladder cancer the most expensive and time-consuming malignancy to treat [6, 7]. A minority of superficial tumours (~15%) will eventually progress to become invasive. Despite treatment with radical cystectomy, radiotherapy, and adjuvant or neoadjuvant chemotherapy, newly diagnosed invasive bladder tumours and superficial tumours that have progressed to invasion often metastasize and the 5-year survival rate is poor (<40%) [8]. In humans, fibroblast growth factors are a family comprising 18 growth factors (FGFs) and 4 FGF-homologous factors (FHFs), many of which play a crucial role during both normal physiological processes, such as embryogenesis, development, and wound healing, and a range of pathological conditions [12–14]. The effects of FGFs are mediated by a family of four fibroblast growth factor receptors (FGFR1–4). FGFRs are transmembrane glycoproteins with a conserved structure comprising an extracellular portion with two to three immunoglobulin-like domains (IgI–III), a transmembrane domain, and an intracellular split tyrosine-kinase domain. IgI and IgII are separated by a short negatively charged serine-rich segment, termed the “acid box”, followed by a heparin-binding domain with high affinity for heparan sulphate proteoglycans (HSPGs) [12, 13]. IgI and the acid box are thought to have an auto-inhibitory function [15], while IgII and IgIII bind to FGFs in association with HSPGs. FGF binding to the monomeric receptor triggers its dimerization and subsequent transphosphorylation of tyrosine residues in the kinase domain. This initiates a phosphorylation cascade involving a number of docking proteins, resulting in signalling through various downstream pathways, including PLCγ1, RAS-MAPK, and PI3K and STATs [16]. These pathways regulate a variety of cellular functions, including proliferation, migration, and differentiation [16]. The potential applications of FGFRs in the early diagnosis and clinical management of bladder cancer are summarized in Figure 3. In the last decade, it has become clear that FGFRs play a key role in the development of UC and hold promise as therapeutic targets, screening tools, and diagnostic, and prognostic biomarkers. Future challenges include detailed elucidation of downstream signalling, refining FGFR-based screening and prognostic tests, identification of markers to select patients most likely to benefit from FGFR-targeted therapies and development of strategies to overcome recurrence after treatment withdrawal or development of resistance. There is great hope that in the near future the results of research on the role of FGFRs in UC will be translated into the clinical management of these tumours.   Source: http://doi.org/10.1155/2012/429213

 

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