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Abstract
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 Arg388, 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.
Highlights
The fibroblast growth factors (FGFs) have been implicated in multiple biological processes during embryo development, wound healing, haematopoiesis and angiogenesis [1]
We investigated Fibroblast growth factor receptor 4 (FGFR4) mutations in colorectal cancer cell lines and cancer samples that could contribute to antibody recognition by overexpression or activation
FGFR4 Knockdown Reduced Adhesion, Migration and Invasion of Colorectal Cancer Cells To study the role of FGFR4 overexpression in tumorigenesis and metastasis, we studied the effect of FGFR4 expression in SW48, SW480 and SW620 colorectal cancer cell lines, which did not contain the Arg388 polymorphism
Summary
The fibroblast growth factors (FGFs) have been implicated in multiple biological processes during embryo development, wound healing, haematopoiesis and angiogenesis [1]. They bind to four FGF receptors (FGFR) designated FGFR1-4 [2]. The FGFRs structure includes a ligand-binding domain that contains three different immunoglobulin-like domains (called Ig I, Ig II and Ig III). FGFR4 is expressed in muscle myofibroblasts during regeneration following injury, but not in mature skeletal muscle [5]. FGF receptors dysregulation has been shown to play an important role in cancer development and progression. These alterations have been proposed to occur through overexpression, gene amplification or mutation [6]
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