title: Colorectal cancer cells activate adjacent fibroblasts resulting in FGF1/FGFR3 signaling and increased invasion.
abstract: Cancer-associated fibroblasts expressing fibroblast activation protein (FAP) have been implicated in the invasive behavior of colorectal cancer. In this study, we use FAP expression as a marker of fibroblast activation and analyze the effect of activated fibroblasts on colorectal cancer migration and invasion in experimental cell studies. We also investigated the expression pattern of FAP in cancer-associated fibroblasts during transformation from benign to malignant colorectal tumors. In immunohistochemical analyses, FAP was expressed in fibroblasts in all colorectal cancer samples examined, whereas all normal colon, hyperplastic polyps, or adenoma samples were negative. In in vitro studies, conditioned medium from colon cancer cells, but not adenoma cells, activated fibroblasts by inducing FAP expression. These activated fibroblasts increased the migration and invasion of colon cancer cells in Boyden chamber experiments and in a three-dimensional cell culture model. We identify fibroblast growth factor 1/fibroblast growth factor receptor 3 (FGF1/FGFR-3) signaling as mediators leading to the increased migration and invasion. Activated fibroblasts increase their expression of FGF1, and by adding a fibroblast growth factor receptor inhibitor, as well as an FGF1-neutralizing antibody, we reduced the migration of colon cancer cells. Our findings provide evidence of a possible molecular mechanism involved in the cross talk between cancer cells and fibroblasts leading to cancer cell invasion.
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden. maria.henriksson@medbio.umu.se
authors.forename: Maria L
authors.initials: ML
authors.lastname: Henriksson
authors.forename: Sofia
authors.initials: S
authors.lastname: Edin
authors.forename: Anna M
authors.initials: AM
authors.lastname: Dahlin
authors.forename: Per-Arne
authors.initials: PA
authors.lastname: Oldenborg
authors.forename: Åke
authors.initials: Å
authors.lastname: Öberg
authors.forename: Bethany
authors.initials: B
authors.lastname: Van Guelpen
authors.forename: Jörgen
authors.initials: J
authors.lastname: Rutegård
authors.forename: Roger
authors.initials: R
authors.lastname: Stenling
authors.forename: Richard
authors.initials: R
authors.lastname: Palmqvist
mesh_terms: D000199:Actins / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D010450:Endopeptidases; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000199:Actins; D017077:Culture Media, Conditioned; D010450:Endopeptidases; D016220:Fibroblast Growth Factor 1; D018093:Gelatinases; D008565:Membrane Proteins; D051498:Receptor, Fibroblast Growth Factor, Type 3; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C496365:FGFR3 protein, human