title: Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation.
abstract: Aberrant expression and polymorphism of fibroblast growth factor receptor 4 (FGFR4) has been linked to tumor progression and anticancer drug resistance. We describe here a novel mechanism of tumor progression by matrix degradation involving epithelial-to-mesenchymal transition in response to membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14) induction at the edge of tumors expressing the FGFR4-R388 risk variant. Both FGFR4 and MT1-MMP were upregulated in tissue biopsies from several human cancer types including breast adenocarcinomas, where they were partially coexpressed at the tumor/stroma border and tumor invasion front. The strongest overall coexpression was found in prostate carcinoma. Studies with cultured prostate carcinoma cell lines showed that the FGFR4-R388 variant, which has previously been associated with poor cancer prognosis, increased MT1-MMP-dependent collagen invasion. In this experimental model, knockdown of FGFR4-R388 or MT1-MMP by RNA interference blocked tumor cell invasion and growth in collagen. This was coupled with impaired phosphorylation of FGFR substrate 2 and Src, upregulation of E-cadherin, and suppression of cadherin-11 and N-cadherin. These in vitro results were substantiated by reduced MT1-MMP content and in vivo growth of prostate carcinoma cells after the FGFR4-R388 gene silencing. In contrast, knockdown of the alternative FGFR4-G388 allele enhanced MT1-MMP and invasive tumor cell growth in vivo and within three-dimensional collagen. These results will help to explain the reported association of the FGFR4-R388 variant with the progression and poor prognosis of certain types of tumors.
authors.affiliation: Molecular Cancer Biology Research Program, Departments of Pathology and Virology, Haartman Institute, Helsinki, Finland.
authors.forename: Nami
authors.initials: N
authors.lastname: Sugiyama
authors.forename: Markku
authors.initials: M
authors.lastname: Varjosalo
authors.forename: Pipsa
authors.initials: P
authors.lastname: Meller
authors.forename: Jouko
authors.initials: J
authors.lastname: Lohi
authors.forename: Marko
authors.initials: M
authors.lastname: Hyytiäinen
authors.forename: Sami
authors.initials: S
authors.lastname: Kilpinen
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Signe
authors.initials: S
authors.lastname: Ingvarsen
authors.forename: Lars H
authors.initials: LH
authors.lastname: Engelholm
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Jorma
authors.initials: J
authors.lastname: Keski-Oja
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehti
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002455:Cell Division / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005109:Extracellular Matrix / Q000473:pathology*; D005260:Female; D005346:Fibroblast Growth Factors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006706:Homeostasis; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000235:genetics; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D018076:DNA, Complementary; D034741:RNA, Small Interfering; D005346:Fibroblast Growth Factors; C496371:FGFR4 protein, human; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4