Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion

// Sarah Knuchel 1 , Pascale Anderle 2 , Patricia Werfelli 3, 4 , Eva Diamantis 5 , Curzio Rüegg 1, 4 1 Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, CH-1700, Switzerland 2 Swiss Institute of Bioinformatics, Lausanne, CH-1000, Switzerland 3 Department of Oncology, University Medical Center (CHUV), University of Lausanne (UNIL), Lausanne, CH-1011, Switzerland 4 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 5 Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland Correspondence to: Curzio Rüegg, e-mail: curzio.ruegg@unifr.ch Keywords: colorectal cancer, fibroblast, FGF-2, integrin, SRC Received: December 26, 2014      Accepted: April 21, 2015      Published: May 5, 2015 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 α v β 5 . 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 α v β 5 integrin-dependent cancer cell adhesion to fibroblasts. The FGF-2-FGFRs-SRC-α v β 5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion.