title: Alteration of cell-cell and cell-matrix adhesion in urothelial cells: an oncogenic mechanism for mutant FGFR3.
abstract: Activating mutations of FGFR3 are a common and early event in bladder cancer. Ectopic expression of mutant FGFR3 in normal urothelial cells has both pro-proliferative and antiapoptotic effects at confluence, suggesting that mutant cells are insensitive to cell-cell contact inhibition. Herein, detailed analysis revealed that these cells have reduced cell-cell adhesion, with large intercellular spaces observable at confluence, and diminished cell-substrate adhesion to collagen IV, collagen I, and fibronectin. These phenotypic alterations are accompanied by changes in the expression of genes involved in cell adhesion and extracellular matrix remodeling. Silencing of endogenous mutant FGFR3 in bladder cancer cells induced converse changes in transcript levels of CDH16, PLAU, MMP10, EPCAM, TNC, and HAS3, confirming them as downstream gene targets of mutant FGFR3. Overexpression of EPCAM, HAS3, and MMP10 transcripts was found in a large fraction of primary bladder tumors analyzed, supporting their key role in bladder tumorigenesis in vivo. However, no correlation was found between their protein and/or mRNA expression and FGFR3 mutation status in tumor specimens, indicating that these genes may be targeted by several converging oncogenic pathways. Overall, these results indicate that mutant FGFR3 favors the development and progression of premalignant bladder lesions by altering key genes regulating the cell-cell and cell-matrix adhesive properties of urothelial cells.
  
  
  CONCLUSIONS
  The ability of mutant FGFR3 to drive transcriptional expression profiles involved in tumor cell adhesion suggests a mechanism for expansion of premalignant urothelial lesions.
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St. James's University Hospital, Leeds, United Kingdom.
authors.forename: Erica
authors.initials: E
authors.lastname: di Martino
authors.affiliation: Bioinformatics and Biostatistics Service, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelly
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, St. James's University Hospital, Leeds, United Kingdom.
authors.forename: Jo-An
authors.initials: JA
authors.lastname: Roulson
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St. James's University Hospital, Leeds, United Kingdom. m.a.knowles@leeds.ac.uk.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Knowles
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009367:Neoplasm Staging; D010766:Phosphorylation; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3