title: Autocrine fibroblast growth factor 18 signaling mediates Wnt-dependent stimulation of CD44-positive human colorectal adenoma cells.
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.
authors.affiliation: Medical University Vienna, Department of Medicine 1, Division of Bone Marrow Transplantation.
authors.forename: Inga
authors.initials: I
authors.lastname: Koneczny
authors.affiliation: Medical University Vienna Institute of Cancer Research.
authors.forename: Axel
authors.initials: A
authors.lastname: Schulenburg
authors.affiliation: Medical University Vienna, Department of Medicine 1, Division of Bone Marrow Transplantation.
authors.forename: Xenia
authors.initials: X
authors.lastname: Hudec
authors.affiliation: Medical University Vienna Department of Obstetrics and Gynaecology.
authors.forename: Martin
authors.initials: M
authors.lastname: Knöfler
authors.affiliation: Medical University Vienna, Department of Medicine 1, Division of Bone Marrow Transplantation.
authors.forename: Klaus
authors.initials: K
authors.lastname: Holzmann
authors.affiliation: Mitchell Cancer Institute, University of South Alabama.
authors.forename: Gary
authors.initials: G
authors.lastname: Piazza
authors.affiliation: Department of Medicinal Chemistry, Drug Discovery Division, Southern Research Institute.
authors.forename: Robert
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: Medical University Vienna Division of Hematology.
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.affiliation: Medical University Vienna, Department of Medicine 1, Division of Bone Marrow Transplantation.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Marian
mesh_terms: D000236:Adenoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D051153:Wnt Proteins; C113569:fibroblast growth factor 18; C543001:sulindac sulfide amide; D013467:Sulindac; D005346:Fibroblast Growth Factors; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: CD44; FGF; colon adenoma