Preclinical study of c-Met inhibitor as an adjuvant treatment for hepatocellular carcinoma with macroscopic portal vein invasion.

Abstract

301 Background: Patients with advanced hepatocellular carcinoma (HCC) demonstrating a macroscopic portal vein tumor thrombus (PVTT) have been reported to have an extremely poor prognosis. Palliative sorafenib is the only recommended treatment option. Methods: We statistically compared the patient characteristics and surgical outcomes in HCC patients with PVTT. Among 1,611 hepatic resections, 105 cases of PVTT were identified. Microarray analysis was performed in three patients to identify gene expression changes in PVTT compared with those in the principal tumor, and the changes were validated in 20 human HCC tissues with PVTT. The human HCC cell lines HuH-7 and SKHep-1 were used for this experimental study. A subcutaneously transplanted xenograft model was employed for the in vivo study. The c-Met inhibitor SU11274 was used in both in vitro and in vivoanalyses. Results: The median survival time in patients with PVTT was 2.01 years, while that in patients without PVTT was 6.43 years; the median time to recurrence was 0.31 and 1.61 years, respectively. Microarray analysis revealed 36 genes related to PVTT. Immunohistochemistry analysis revealed that compared with the principal tumor, E-cadherin (a key regulator of cancer metastatic potential) significantly decreased in PVTT in all 20 patients. The c-Met inhibitor elevated the E-cadherin expression level in HCC cells both in vitro and in vivo. This inhibitor induced sheet formation and attenuated the migration of HCC cells. Conclusions: Although liver resection provides acceptable overall survival for patients with PVTT, the recurrence rate remains high. The c-Met inhibitor exhibits an anti-metastatic effect in vitro and in vivo and may be useful as an adjuvant treatment for PVTT.