Autocrine fibroblast growth factor 18 signaling mediates Wnt-dependent stimulation of CD44-positive human colorectal adenoma cells

Academic Article

Abstract

  • Expansion of a stem-like subpopulation with increased growth and survival potential is thought to drive colorectal tumor growth and progression. We investigated a CD44-positive (CD44(+)) subpopulation with extended growth and survival capacity in the human colon adenoma cell line LT97. This subpopulation expressed elevated levels of fibroblast growth factor 18 (FGF18) and fibroblast growth factor receptor FGFR3-IIIc. Expression levels of the FGFR3-IIIb, which does not bind FGF18, were similar in CD44(+) and CD44(-). Addition of FGF18 to the medium or its overexpression from an adenoviral vector increased the colony formation capacity of CD44(+) threefold, and stimulated phosphorylation of ERK and GSK3β in both total LT97 populations and CD44(+) cells. FGFR3 signaling blockade by expression of a dominant-negative FGFR3-IIIc mutant led to inhibition of both colony formation and down-stream signaling in the CD44(+) cells. CD44(-) cells did not respond. Blockade of the wnt-pathway by a dominant-negative Tcf4-mutant inhibited FGFR3 activation in LT97 cells as well as in HT29 colorectal cancer cells. The chemical wnt-inhibitor sulindac sulfide amide inhibited expression of FGF18 and FGFR3-IIIc and led to inhibition of receptor activation to less than 30% of control treated cells, both in LT97 and HT29 cultures. Our results demonstrate that an FGF18/FGFR3-IIIc autocrine growth and survival loop is up-regulated in a wnt-dependent manner and drives tumor cell growth in a subpopulation of colon adenoma cells. This subpopulation can be regarded as a precursor of colon cancer development and can be targeted for CRC-prevention by blocking either wnt- or FGFR3-signaling.
  • Published In

    Digital Object Identifier (doi)

    Pubmed Id

  • 21783490
  • Author List

  • Koneczny I; Schulenburg A; Hudec X; Knöfler M; Holzmann K; Piazza G; Reynolds R; Valent P; Marian B
  • Start Page

  • 789
  • End Page

  • 799
  • Volume

  • 54
  • Issue

  • 9