Abstract
Liver cancer is a poor prognosis cancer with limited treatment options. To develop a new therapeutic approach, we derived HCC cells from a known model of murine hepatocellular carcinoma (HCC). We treated adiponectin (APN) knock-out mice with the carcinogen diethylnitrosamine, and the resulting tumors were 7-fold larger than wild-type controls. Tumors were disassociated from both genotypes and their growth characteristics evaluated. A52 cells from APN KO mice had the most robust growth in vitro and in vivo, and presented with pathology similar to the parental tumor. All primary tumors and cell lines exhibited activity of the mammalian target of Rapamycin (mTOR) and Src pathways. Subsequent combinatorial treatment, with the mTOR inhibitor Rapamycin and the Src inhibitor Dasatinib reduced A52 HCC growth 29-fold in vivo. Through protein and histological analyzes we observed activation of these pathways in human HCC, suggesting that targeting both mTOR and Src may be a novel approach for the treatment of HCC.
Highlights
Liver cancer, the fifth commonest in terms of cancer incidence and the second leading cause of cancer related deaths worldwide, is a poor prognosis cancer [1]
Liver to body weight ratios increased in APN KO (APN KO: 5.51 ± 0.277%, n = 21 versus WT: 4.47 ± 0.101%, n = 22; p = 0.0009, Fig 1D), and between groups there was no difference in tumor incidence (Fig 1E)
Analyses revealed in WT, 12 pre-neoplastic foci and 23 liver carcinomas, and in the APN KO, 14 pre-neoplastic lesions and 32 carcinomas
Summary
Liver cancer (hepatocellular cancer [HCC]), the fifth commonest in terms of cancer incidence and the second leading cause of cancer related deaths worldwide, is a poor prognosis cancer [1]. The major risk factors for HCC are hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and excessive alcohol intake that promote fibrosis and cirrhosis, and oncogenic transformation. In the last 3 decades, rising rates of obesity and the metabolic syndrome have led to dramatic increases in HCC related to non-alcoholic fatty liver disease (NAFLD) and its inflammatory form non alcoholic steatohepatitis (NASH). HCC arising in this context can develop in the absence of cirrhosis [2].
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