title: Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion.
abstract: Carcinoma-associated fibroblasts were reported to promote colorectal cancer (CRC) invasion by secreting motility factors and extracellular matrix processing enzymes. Less is known whether fibroblasts may induce CRC cancer cell motility by contact-dependent mechanisms. To address this question we characterized the interaction between fibroblasts and SW620 and HT29 colorectal cancer cells in 2D and 3D co-culture models in vitro. Here we show that fibroblasts induce contact-dependent cancer cell elongation, motility and invasiveness independently of deposited matrix or secreted factors. These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2. Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects. FGFRs activate SRC in cancer cells and inhibition or silencing of SRC in cancer cells, but not in fibroblasts, prevents fibroblasts-mediated effects. Using an RGD-based integrin antagonist and function-blocking antibodies we demonstrate that cancer cell adhesion to fibroblasts requires integrin αvβ5. Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvβ5 integrin-dependent cancer cell adhesion to fibroblasts. The FGF-2-FGFRs-SRC-αvβ5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion.
authors.affiliation: Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, CH-1700, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Knuchel
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, CH-1000, Switzerland.
authors.forename: Pascale
authors.initials: P
authors.lastname: Anderle
authors.affiliation: Department of Oncology, University Medical Center (CHUV), University of Lausanne (UNIL), Lausanne, CH-1011, Switzerland.|Swiss National Centre of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, Lausanne, CH-1015, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Werfelli
authors.affiliation: Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Diamantis
authors.affiliation: Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, CH-1700, Switzerland.|Swiss National Centre of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, Lausanne, CH-1015, Switzerland.
authors.forename: Curzio
authors.initials: C
authors.lastname: Rüegg
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D057809:HEK293 Cells; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009361:Neoplasm Invasiveness; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D016222:Fibroblast Growth Factor 2; D019061:src-Family Kinases
keywords: FGF-2; SRC; colorectal cancer; fibroblast; integrin