Abstract
Abstract Liver metastasis is one of the main cause of death among patients with colorectal cancer (CRC). However, accurate prediction of liver metastasis of CRC is difficult at the inception of diagnosis. Activated receptor tyrosine kinases (RTKs) are the main mediators of the signaling pathway related to cell survival, proliferation, differentiation or apoptosis. To determine if any of these RTKs are involved in liver metastasis from CRC, we performed phospho-receptor tyrosine kinase array with matched 20 colon normal mucosa, primary tumor, metastatic liver tumor, and liver normal tissue proteins using Human Phospho-RTK Array (2009 AACR, #4951). In RTK activation profiling, FGFR1 activation was increased in a high proportion of metastatic liver tumor (p < 0.05). To evaluate the functional roles of FGFR1, DLD-1 and LoVo colon cancer cells were treated with FGFR1 specific siRNA or RTK inhibitor. Inhibition of FGFR1 inhibited phosphorylation of PI3K/AKT and ERK, a downstream cellular signaling molecule of FGFR; whereas, mTOR, p70S6K, JNK and Src activities were not affected. Also, we compared the cell migration and invasion ability by wound healing assay and invasion assay. The invasion capacity and wound closing were significantly delayed by FGFR1 inhibition (p <0.05). To evaluate in vivo anti-metastatic effect of FGFR1, we used an orthotropic liver metastasis model, generated by injecting LoVo colon cancer cells into spleen of BALB/c nu/nu mice. In control group, multiple large metastatic foci were evident, whereas the extent of liver metastasis was dramatically reduced in TKI-258 (50mg/kg/d) treated group (48.9%, p<0.05). Immunoexpression of the p-FGFR1 was much more intense in control than TKI-258 treated tumor tissues. Biological effects were also confirmed that FGFR1 inhibition resulted in a significant reduction of ERK activation and Ki-67 positive cells in tumor tissues. In conclusion, FGFR1 might be a good target for liver metastasis of CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2426. doi:1538-7445.AM2012-2426
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