title: Fibroblast growth factor receptor 3 activation plays a causative role in urothelial cancer pathogenesis in cooperation with Pten loss in mice.
abstract: 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.
authors: School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; Beatson Institute for Cancer Research, Glasgow, UK.
authors: Mona
authors: M
authors: Foth
authors: Imran
authors: I
authors: Ahmad
authors: Bas W G
authors: BW
authors: van Rhijn
authors: Theodorus
authors: T
authors: van der Kwast
authors: Andre M
authors: AM
authors: Bergman
authors: Louise
authors: L
authors: King
authors: Rachel
authors: R
authors: Ridgway
authors: Hing Y
authors: HY
authors: Leung
authors: Sioban
authors: S
authors: Fraser
authors: Owen J
authors: OJ
authors: Sansom
authors: Tomoko
authors: T
authors: Iwata
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D048429:Cell Size; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D001743:Urinary Bladder / Q000201:enzymology* / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019459:Urothelium / Q000201:enzymology* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C546843:mTOR protein, mouse; D058539:Phosphatidylinositol 3-Kinase; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: comparative pathology; fibroblast growth factors; personalized therapy; prognostic marker; transgenic mouse model; transitional cell carcinoma