FGFR4 role in epithelial-mesenchymal transition and its therapeutic value in colorectal cancer

• Published in: PloS one Vol. 8; no. 5; p. e63695
• Main Authors: Peláez-García, Alberto, Barderas, Rodrigo, Torres, Sofía, Hernández-Varas, Pablo, Teixidó, Joaquín, Bonilla, Félix, de Herreros, Antonio Garcia, Casal, J Ignacio
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.05.2013; Public Library of Science (PLoS)
• Subjects: AKT protein; Angiogenesis; Animal tissues; Animals; Antibodies; Apoptosi; Apoptosis; Apoptosis - genetics; Apoptosis - physiology; Biology; Biotechnology; Bladder; Blotting, Western; Cancer; Cell adhesion & migration; Cell Adhesion - genetics; Cell Adhesion - physiology; Cell Line, Tumor; Cell migration; Cell Proliferation; Cell survival; Chemokines; Colon; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cèl·lules; E-cadherin; Epithelial-Mesenchymal Transition - genetics; Epithelial-Mesenchymal Transition - physiology; Extracellular signal-regulated kinase; Fibroblast growth factor receptor 4; Fibroblast growth factors; Fibroblasts; Gene amplification; Gene expression; Growth factors; Health aspects; Humans; Invasiveness; Kinases; Laboratories; Ligands; Medical prognosis; Medicine; Mesenchyme; Metastasis; Mice; Mice, Nude; Multiple myeloma; Mutation; Polyclonal antibodies; Polymorphism, Single Nucleotide - genetics; Proliferació; Prostate cancer; Proteins; Real-Time Polymerase Chain Reaction; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Receptor, Fibroblast Growth Factor, Type 4 - metabolism; Reversion; Rodents; Signal transduction; Signaling; Solid tumors; Stem cells; Survival; Transforming growth factors; Tumor cell lines; Tumorigenesis; Tumors; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0063695

Fibroblast growth factor receptor 4 (FGFR4) is vital in early development and tissue repair. FGFR4 expression levels are very restricted in adult tissues, except in several solid tumors including colorectal cancer, which showed overexpression of FGFR4. Here, FGFR4 mutation analysis discarded the presence of activating mutations, other than Arg(388), in different colorectal cancer cell lines and tumoral samples. Stable shRNA FGFR4-silencing in SW480 and SW48 cell lines resulted in a significant decrease in cell proliferation, adhesion, cell migration and invasion. This decrease in the tumorigenic and invasive capabilities of colorectal cancer cells was accompanied by a decrease of Snail, Twist and TGFβ gene expression levels and an increase of E-cadherin, causing a reversion to a more epithelial phenotype, in three different cell lines. In addition, FGFR4-signaling activated the oncogenic SRC, ERK1/2 and AKT pathways in colon cancer cells and promoted an increase in cell survival. The relevance of FGFR4 in tumor growth was supported by two different strategies. Kinase inhibitors abrogated FGFR4-related cell growth and signaling pathways at the same extent than FGFR4-silenced cells. Specific FGFR4-targeting using antibodies provoked a similar reduction in cell growth. Moreover, FGFR4 knock-down cells displayed a reduced capacity for in vivo tumor formation and angiogenesis in nude mice. Collectively, our data support a crucial role for FGFR4 in tumorigenesis, invasion and survival in colorectal cancer. In addition, FGFR4 targeting demonstrated its applicability for colorectal cancer therapy.