title: FGFR3 has tumor suppressor properties in cells with epithelial phenotype.
abstract: BACKGROUND
  Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical.
  
  
  RESULTS
  FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors.
  
  
  CONCLUSIONS
  In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.
authors.affiliation: INSERM U1035, Université Bordeaux Segalen, 146 rue Léo Saignat, Bordeaux 33076, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lafitte
authors.forename: Isabelle
authors.initials: I
authors.lastname: Moranvillier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Garcia
authors.forename: Evelyne
authors.initials: E
authors.lastname: Peuchant
authors.forename: Juan
authors.initials: J
authors.lastname: Iovanna
authors.forename: Benoit
authors.initials: B
authors.lastname: Rousseau
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Véronique
authors.initials: V
authors.lastname: Guyonnet-Dupérat
authors.forename: Geneviève
authors.initials: G
authors.lastname: Belleannée
authors.forename: Jeanne
authors.initials: J
authors.lastname: Ramos
authors.forename: Aurélie
authors.initials: A
authors.lastname: Bedel
authors.forename: Hubert
authors.initials: H
authors.lastname: de Verneuil
authors.forename: François
authors.initials: F
authors.lastname: Moreau-Gaudry
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dabernat
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D008024:Ligands; D051498:Receptor, Fibroblast Growth Factor, Type 3
references.citation: Int J Cancer. 1994 Dec 1;59(5):667-75
references.pmid: 7960240
references.citation: J Biol Chem. 1998 Aug 14;273(33):21137-44
references.pmid: 9694869
references.citation: Oncogene. 2001 Feb 8;20(6):686-91
references.pmid: 11314002
references.citation: Mol Cancer. 2012 Oct 22;11:81
references.pmid: 23088623
references.citation: Biochem Biophys Res Commun. 2007 Aug 17;360(1):109-14
references.pmid: 17585878
references.citation: Br J Cancer. 2009 Dec 15;101(12):2030-7
references.pmid: 19888223
references.citation: Oncogene. 2001 Jun 14;20(27):3553-62
references.pmid: 11429702
references.citation: Blood. 2001 Apr 15;97(8):2413-9
references.pmid: 11290605
references.citation: Nat Genet. 1999 Sep;23(1):18-20
references.pmid: 10471491
references.citation: Carcinogenesis. 2006 Apr;27(4):740-7
references.pmid: 16338952
references.citation: Nat Genet. 1996 Apr;12(4):390-7
references.pmid: 8630492
references.citation: Nat Rev Cancer. 2010 Feb;10(2):116-29
references.pmid: 20094046
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3576-80
references.pmid: 7724601
references.citation: Cell Cycle. 2010 Aug 1;9(15):3085-99
references.pmid: 20699642
references.citation: J Clin Oncol. 2006 Aug 1;24(22):3664-71
references.pmid: 16877735
references.citation: Hum Mol Genet. 1999 Jan;8(1):35-44
references.pmid: 9887329
references.citation: Anal Cell Pathol. 2001;23(2):45-9
references.pmid: 11904459
references.citation: J Cell Sci. 2010 Apr 15;123(Pt 8):1295-305
references.pmid: 20332115
references.citation: Exp Cell Res. 2005 Apr 1;304(2):417-31
references.pmid: 15748888
references.citation: Eur J Surg Oncol. 2006 Mar;32(2):231-7
references.pmid: 16412606
references.citation: J Natl Cancer Inst. 2002 Jan 16;94(2):129-42
references.pmid: 11792751
references.citation: Cancer Res. 2005 Oct 1;65(19):8836-45
references.pmid: 16204054
references.citation: Bone. 2010 Jul;47(1):102-10
references.pmid: 20362703
references.citation: J Biol Chem. 1996 Jun 21;271(25):15292-7
references.pmid: 8663044
references.citation: Clin Cancer Res. 2005 Apr 1;11(7):2702-12
references.pmid: 15814652
references.citation: J Cell Physiol. 2008 Jul;216(1):261-8
references.pmid: 18286540
references.citation: J Invest Dermatol. 2007 Jul;127(7):1664-6
references.pmid: 17255960
references.citation: Nat Genet. 1997 Jul;16(3):260-4
references.pmid: 9207791
references.citation: Cancer Res. 2000 Aug 1;60(15):4049-52
references.pmid: 10945607
references.citation: World J Urol. 2007 Dec;25(6):581-93
references.pmid: 17912529
references.citation: Genes Dev. 2010 Nov 15;24(22):2463-79
references.pmid: 21078816
references.citation: Br J Cancer. 2010 Mar 30;102(7):1145-56
references.pmid: 20234367
references.citation: Diabetes. 2007 Jan;56(1):96-106
references.pmid: 17192470
references.citation: Int J Cancer. 2009 Nov 1;125(9):2095-103
references.pmid: 19637316