Preclinical trial for prevention of metastasis of hepatocellular carcinoma by targeting c-Met –dependent and –independent signaling using LZ8

• Main Authors: Pei-Ling Ma, 馬珮羚
• Other Authors: Wen-Sheng Wu
• Format: Others
• Language: zh-TW
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/r83j6d

碩士 === 慈濟大學 === 醫學檢驗生物技術學系醫學生物技術碩士班 === 102 === Hepatocellular carcinoma (HCC) is one of the most common causes of death from cancer worldwide. Surgery of small HCC may result in marked increase in 5-year survival rate from 20% to 50%. However, the poor prognosis and recurrence of HCC are very high, due to intrahepatic and extrahepatic metastasis. Hepatocyte growth factor (HGF) is well known to be a metastatic factors secreted in tumor microenvironment. Elevated expression of c-Met, the receptor tyrosine kinase of HGF, was frequently observed in recurrent HCC. Mounting studies highlighted the provital role of HGF/c-MET axis in driving the tumor progression of HCC. Therefore, c-Met represents a potential therapeutic target for hepatocellular carcinoma. However, there are still problems about the resistance and side effects of c-Met targeting approaches in terms of personalized therapy. In regard with the resistance, one of the major concern is that HGF/c-Met signaling may not be activated in all HCC tissue. For those HCC with negative c-Met signaling, c-Met targeting approach will not be adequate. On the other hand, side effects of c-Met targeting may occur due to the broad expression HGF and Met in adult tissues, required for essential physiological processes. Therefore, to prepare for a personalized treatment for HGF/c-Met targeting approach, whether HGF/c-Met signaling is active within individual HCC should be addressed first. On the other hand, the therapeutic efficiency (including targeting capability and toxicity) of c-Met antagonists should be evaluated. Currently, JNJ-38877605, PF04217903, and ARQ197 are small molecules known to acquire high specificity in suppressing c-Met activity. However, the therapeutic efficiency of these c-Met inhibitors has not been assessed for HCC thus far. Currently, we have screened a lot of HCC patients for the feasibility of HGF/c-Met targeting approach. Using IHC (immunohistochemistry) staining, we found phosphorylated c-Met in tumor part on tissue section was positive in about 48.15% of 27 of HCC cases. On the other hand, western blot of phosphorylated c-Met coupled with downstream signal molecules including p-ERK, p-JNK in the tumor lysate were carried for validation of the positive results obtained by IHC. In summary, we confirmed about 40% HCC cases were positive with active HGF/c-Met signaling. Moreover, HCC cell lines derived from HCC with positive c-Met signaling were established for examination of the efficiency of potential c-Met antagonists for suppressing the tumor progression of the HCC both in vitro and in vivo. Based on our study, preclinical and clinical trials for personalized treatment of HCC aiming at HGF/c-Met pathway will be established in the future.