Forskning ved Københavns Universitet - Københavns Universitet


Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Nami Sugiyama
  • Markku Varjosalo
  • Pipsa Meller
  • Jouko Lohi
  • Marko Hyytiäinen
  • Sami Kilpinen
  • Olli Kallioniemi
  • Signe Ingvarsen
  • Engelholm, Lars Henning
  • Jussi Taipale
  • Kari Alitalo
  • Jorma Keski-Oja
  • Kaisa Lehti
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.
TidsskriftAccomplishments in Cancer Research
Udgave nummer20
Sider (fra-til)7851-61
Antal sider11
StatusUdgivet - 15 okt. 2010
Eksternt udgivetJa

ID: 34178191