![]() The higher CAF density is generally found at the invasive front of the tumor, and several studies have shown that CAF promote CRC progression though multiple mechanisms. Experimental and clinical evidences indicate that CAF regulate a number of tumor-promoting functions, including angiogenesis, invasion and metastasis. The presence of CAF is associated with aggressive progression and poor prognosis in several cancer types. CAF are contractile cells commonly characterized by the expression of multiple activation markers, including α-smooth muscle actin (SMA), vimentin (VIM) or fibroblast-activated protein (FAP). Nevertheless, several distinct morphological properties and functions of CAF have been described and characterized. ĭespite the fact that CAF are among the most abundant and crucial cells of the tumor microenvironment, these cells remains poorly defined due to their inherent plasticity, heterogeneity and different origins, as well as the lack of single, universal specific markers and their pleiotropic functions. Dynamic reciprocal interactions between tumor cells and their microenvironment contribute to tumor cell survival, proliferation, invasion and metastasis and are therefore increasingly considered as potential targets for novel therapeutic strategies. The tumor microenvironment consists of a variety of tumor-recruited or locally activated cells, such as bone marrow-derived cells, immune cells and carcinoma-associated fibroblasts (CAF). During tumor progression cancer cells modify the surrounding normal tissue to create a microenvironment supporting tumor growth and progression. Understanding the molecular mechanisms underlying CRC cell invasion may lead to the identification of patients at high risk for disease progression and to the discovery of novel therapeutic targets and strategies. Despite advances in treatments, existing therapies are of limited effectiveness once cancer has become invasive or metastatic. The FGF-2-FGFRs-SRC-α vβ 5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion.Ĭolorectal cancer (CRC) is the third most common cancer in the world. 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 vβ 5 integrin-dependent cancer cell adhesion to fibroblasts. Using an RGD-based integrin antagonist and function-blocking antibodies we demonstrate that cancer cell adhesion to fibroblasts requires integrin α vβ 5. FGFRs activate SRC in cancer cells and inhibition or silencing of SRC in cancer cells, but not in fibroblasts, prevents fibroblasts-mediated effects. Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects. These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2. Here we show that fibroblasts induce contact-dependent cancer cell elongation, motility and invasiveness independently of deposited matrix or secreted factors. 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. Less is known whether fibroblasts may induce CRC cancer cell motility by contact-dependent mechanisms. Received: DecemAccepted: ApPublished: May 5, 2015Ĭarcinoma-associated fibroblasts were reported to promote colorectal cancer (CRC) invasion by secreting motility factors and extracellular matrix processing enzymes. ![]() Keywords: colorectal cancer, fibroblast, FGF-2, integrin, SRC Sarah Knuchel 1, Pascale Anderle 2, Patricia Werfelli 3, 4, Eva Diamantis 5, Curzio Rüegg 1, 4ġDepartment of Medicine, Faculty of Science, University of Fribourg, Fribourg, CH-1700, SwitzerlandĢSwiss Institute of Bioinformatics, Lausanne, CH-1000, SwitzerlandģDepartment of Oncology, University Medical Center (CHUV), University of Lausanne (UNIL), Lausanne, CH-1011, SwitzerlandĤSwiss 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, SwitzerlandĥDivision of Clinical Pathology, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland ![]()
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