Overexpression of the fibroblast growth factor receptor-1 gene correlates with liver metastasis in colorectal cancer

Abstract

Abstract. Expression of the fibroblast growth factor (FGF)-1, FGF-2, fibroblast growth factor receptor (FGFR)-1, andFGFR-2 genes has been reported in various cancers and is associated with poor outcomes in patients with solid tumors. This study examined the relations between the relative expression of the FGF genes and clinicopathological factors, especially invasion and metastasis, in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal carcinoma. The relative expression levels of FGF-1, FGF-2, FGFR-1, and FGFR-2 mRNA in cancer and in normal adjacent mucosa were measured by quantitative real-time, reverse-transcription polymerase chain reaction. The relative expression level of the FGFR-2 gene was higher in normal adjacent mucosa than in cancer, whereas the relative expression levels of the FGF-1, FGF-2, and FGFR-1 genes were similar. FGFR-1 gene expression levels were higher in the presence than in the absence of liver metastasis. An analysis of the relation between clinicopathological features and gene expression showed that overexpression of FGFR-1 correlated with liver metastasis. Our results suggested that overexpression of the FGFR-1 gene might lead to liver metastasis in colorectal cancer. Overexpression of the FGFR-1 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer. IntroductionFibroblast growth factors (FGFs) are a family of heparinbinding growth factors. FGFs promote angiogenesis by interacting with various endothelial cell-surface receptors, including tyrosine kinase receptors, heparin-sulfate proteoglycans, and integrins. The relation between angiogenesis and tumor growth is well established, and numerous inducers of angiogenesis have been identified (1). Gospodarowicz (2) discovered FGF-2 in 1974. This protein was found to strongly promote the proliferation of fibroblasts. Since then, 22 structurally-related members of the FGF family and 4 FGFhomologous factors have been identified. FGFs exert their biological activities by binding to high-affinity tyrosine kinase FGF receptors (FGFRs) on the surface of target cells. Angiogenic potential has been assessed for only a limited number of the 22 members of the FGF family in vitro and in vivo. Most experimental studies have focused on the prototypes FGF-1 and FGF-2 (3).FGFs exert their biologic activity by interacting with highaffinity FGFRs. Four members of the FGFR family (FGFR-1, FGFR-2, FGFR-3, and FGFR-4) are encoded by distinct genes, and their structural variability is increased by alternative splicing. FGFR-1 is expressed by endothelial cells in vivo and in vitro. Some cultured endothelial cells can express FGFR-2 (3,4).Expression levels of the FGF-1, FGF-2, FGFR-1, and FGFR-2 genes have been examined in various cancers, including breast cancer (5-8), brain tumors (9-12), hepatocellular carcinoma (13-15), cervical and esophageal cancers (16-20), and pancreatic cancer (21-23). Correlations between FGF...

Prognostic significance of the co-overexpression of fibroblast growth factor receptors 1, 2 and 4 in gastric cancer

“…To the best of our knowledge, the present study is the first to demonstrate that the high expression of FGFR1 is associated with poor survival in gastric cancer. The overexpression of FGFR1 was also found to be correlated with liver metastasis in colorectal cancer (29), whereas the amplification and overexpression of FGFR1 may contribute to poor outcomes in luminal-type breast cancer by driving anchorage-independent proliferation and resistance to endocrine therapy (25). The co-overexpression of FGF1 and FGFR1 has also been associated with poor outcomes in esophageal squamous cell carcinoma (30); however, we did not assess FGF expression in this study.…”

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

“…Translocation events implicating the FGFR1 gene and various fusions of FGFR1 are found in myeloproliferative syndromes (12); chromosomal translocations of FGFR1 or FGFR3 and the transforming acidic coiled-coil genes (TACC1 or TACC3) are oncogenic in glioblastoma multiforme, bladder cancer, head and neck cancer, and lung cancer (13)(14)(15)(16); oncogenic mutations of FGFR2 and FGFR3 are observed in lung squamous cell carcinoma; FGFR2 N549K is observed in 25% of endometrial cancers; FGFR3 t(4;14) alterations are reported in 15-20% of multiple myeloma (17)(18)(19); FGFR4 Y367C mutation in the transmembrane domain drives constitutive activation and enhanced tumorigenic phenotypes in a breast carcinoma cell line (20)(21)(22); and K535 and E550 mutants are reported to activate FGFR4 in rhabdomyosarcoma (23). FGFR amplification is reported in various cancers (24,25): FGFR1 is amplified in colorectal, lung, and renal cell cancers (26,27); FGFR2 is amplified in gastric cancer and colorectal cancer (28,29); FGFR3 is commonly amplified in bladder cancer and also is reported for cervical, oral, and hematological cancers (30)(31)(32); and FGFR4 is amplified in hepatocellular carcinoma, gastric cancer, pancreatic cancer, and ovarian cancer (33)(34)(35)(36)(37). FGFR also is involved in autocrine activation of STAT3 as a positive feedback in many drug-treated cancer cells which are driven by diverse oncogenes such as EGFR, ALK, MET, and KRAS (38).…”

Fibroblast Growth Factor Receptor 2 IIIc as a Therapeutic Target for Colorectal Cancer Cells

“…A high percentage of colorectal carcinomas overexpress a number of growth factors and their receptors, including fibroblast growth factor (FGF) and FGF receptor (FGFR; refs. [3][4][5][6][7].…”