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Fibroblast growth factor receptor 3 activation plays a causative role in urothelial cancer pathogenesis in cooperation with Pten loss in mice
Author(s) -
Foth Mona,
Ahmad Imran,
van Rhijn Bas WG,
van der Kwast Theodorus,
Bergman Andre M,
King Louise,
Ridgway Rachel,
Leung Hing Y,
Fraser Sioban,
Sansom Owen J,
Iwata Tomoko
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4334
Subject(s) - pten , cancer research , biology , urothelial cell , urothelium , receptor tyrosine kinase , pi3k/akt/mtor pathway , pathogenesis , growth factor receptor , signal transduction , microbiology and biotechnology , immunology , endocrinology , urinary system
Although somatic mutations and overexpression of the tyrosine kinase fibroblast growth factor receptor 3 ( FGFR3 ) are strongly associated with bladder cancer, evidence for their functional involvement in the pathogenesis remains elusive. Previously we showed that activation of Fgfr3 alone is not sufficient to initiate urothelial tumourigenesis in mice. Here we hypothesize that cooperating mutations are required for Fgfr3‐dependent tumourigenesis in the urothelium and analyse a mouse model in which an inhibitor of Pi3k–Akt signalling, Pten , is deleted in concert with Fgfr3 activation ( UroIICreFgfr3 +/ K644E Pten flox /flox ). Two main phenotypical characteristics were observed in the urothelium: increased urothelial thickness and abnormal cellular histopathology, including vacuolization, condensed cellular appearance, enlargement of cells and nuclei, and loss of polarity. These changes were not observed when either mutation was present individually. Expression patterns of known urothelial proteins indicated the abnormal cellular differentiation. Furthermore, quantitative analysis showed that Fgfr3 and Pten mutations cooperatively caused cellular enlargement, while Pten contributed to increased cell proliferation. Finally, FGFR3 overexpression was analysed along the level of phosphorylated mTOR in 66 T1 urothelial tumours in tissue microarray, which supported the occurrence of functional association of these two signalling pathways in urothelial pathogenesis. Taken together, this study provides evidence supporting a functional role of FGFR3 in the process of pathogenesis in urothelial neoplasms. Given the wide availability of inhibitors specific to FGF signalling pathways, our model may open the avenue for FGFR3 ‐targeted translation in urothelial disease. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.