Fibroblast Growth Factor Receptor 2iiic Enhances The Growth Of Colorectal Adenocarcinoma Cells

Backgrounds: Colorectal carcinoma (CRC) is one of the most common cancers throughout the world, and the prognosis remains unfavorable when the disease has progressed to an unresectable stage. New therapeutic strategies such as molecular-targeted agent are a high priority for advanced CRC. Single nucleotide polymorphisms of Fibroblast growth factor receptor 2 (FGFR2) gene are associated with breast and endometrial carcinogenesis. Therefore, FGFR2 has been noted as a novel candidate for molecular targeting of certain cancers. Alternative splicing variants of FGFR2, IIIb and IIIc, determine the binding specificity of fibroblast growth factor (FGF) members, and class switch of FGFR2IIIb to FGFR2IIIc is associated with a more malignant phenotype in prostate and bladder cancers. In CRCs, we have previously reported that overexpression of FGFR2IIIb was associated with the well-differentiated histological type, and expression of FGF7, a specific ligand for FGFR2IIIb was related to angiogenesis and adhesion to type-IV collagen. However, the expression and role of FGFR2IIIc in CRC have not been well clarified. In the present study, we examine the expression and roles of FGFR2IIIc mRNA and proteins in CRC cell lines and human CRC tissues. Methods: To determine the expression of FGFR2IIIc, we used immunohistochemical staining (IHC) and in situ hybridization analysis (ISH) in human colorectal tissues; the tissues were diagnosed as hyperplastic polyp, adenoma, adenocarcinoma and carcinoma in/with adenoma, according to the criteria of the World Health Organization. Furthermore, we constructed a FGFR2 IIIc-gene-transfected CRC cell line from DLD-1cells and FGFR2IIIc- shRNA-transfected CRC cell line from LoVo cells, and examined the effects of FGFR2 IIIc on cell behaviors. Results: In normal colorectal tissues, IHC and ISH showed the expression of FGFR2IIIc in fibroblasts, endothelium and the surface layer of normal colorectal epithelium. The expression level of FGFR2IIIc was increased in the following order; carcinoma > adenoma > hyperplastic polyp. In CRC cases, expression of FGFR2IIIc correlates with liver metastasis and poor prognosis. FGFR2IIIc-stably transfected DLD-1 cells, which overexpress FGFR2 IIIc, induced increases in colony-forming activities. In contrast, FGFR2IIIc shRNA-stably transfected LoVo cells, which express a lower level than sham transfected cells, induced decreases in colony-forming activities. Heterotopic and orthotopic implantation of FGFR2 IIIc-transfected DLD-1 cells in nude mice increased the tumor volume compared to that in mice receiving sham-transfected cells. Conclusion: These findings suggest that FGFR2IIIc plays important roles in colorectal carcinogenesis as well as tumor progression. FGFR2IIIc may thus serve as a novel candidate for molecular targeting in CRCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 285.