Clinical issue
Urothelial cell carcinoma (UCC) of the bladder is the fifth most common cancer worldwide. Because bladder cancer has a tendency to recur even in the non-invasive cases, it is one of the most expensive and labor-intensive cancers to manage. Fibroblast growth factor receptor 3 (FGFR3) is a receptor tyrosine kinase that is known to mediate the effects of fibroblast growth factors (FGFs). Several studies have shown that mutations in FGFR3 are closely associated with bladder cancer of a low tumor grade and stage. However, whether and how FGFR3 mutations contribute to bladder tumorigenesis is unknown. Thus, generation of a relevant mouse model is essential not only for investigating this issue but also for testing potential therapeutic approaches.
Results
In this paper, the authors test the capacity of FGFR3 activating mutations to drive UCC by creating a mouse model in which mutated Fgfr3 is targeted to the urothelium, using Cre-loxP recombination driven by a urothelium-specific promoter. Their findings demonstrate that activating mutations in FGFR3 are unlikely to be the sole initiating factor for UCC, even in the presence of activating mutations in K-Ras or β-catenin. However, sporadic ectopic Cre recombinase expression in the skin and lung of these mice shows that an Fgfr3 activating mutation can cause papillomas (by cooperating with K-Ras) and promote lung tumorigenesis (by cooperating with β-catenin). Furthermore, somatic Fgfr3 mutations cause upregulation of the ERK-MAPK pathway, as well as upregulation of Sprouty2 (a feedback inhibitor of the pathway) in the urothelium, but do not lead to UCC formation. By contrast, the formation of papillomas in mice carrying activating mutations in both Fgfr3 and K-Ras were not associated with upregulation of Sprouty2, potentially leading to uncontrolled activation of the ERK-MAPK pathway in these mice. Therefore, the authors speculate that feedback inhibitors of the FGF signaling pathway might be one of the mechanisms by which UCC is normally prevented.
Implications and future directions
These data indicate that activating mutations in FGFR3 can cooperate with other mutations to drive tumorigenesis in a context-dependent manner. However, further studies of how the FGFR3 signaling pathway is dysregulated in UCC are required to enable patient stratification according to risk of progression and recurrence, and to aid in patient selection for single-agent or combination therapies. Moreover, identifying molecular events that cooperate with FGFR3 activating mutations to drive UCC formation will aid in the development of genetic models of UCC to test these therapies.