Pathological Pattern of Intrahepatic HBV in HCC is Phenocopied by PDX-Derived Mice: a Novel Model for Antiviral Treatment.

ABSTRACT

BACKGROUND: Hepatitis B virus (HBV) is one of the most prominent risk factors for hepatocellular carcinoma (HCC) development and virus-mediated cases represents more than 80% of HCC in East Asia, where it is endemic. Currently, the HBV status of pathological HCC is not fully clarified, especially by comparison to nontumorous tissues. Lack of clinicopathological animal models of HCC impedes clinical application of antiviral treatment in the field. MATERIALS AND METHODS: A cohort sample of 14 HCC and corresponding stroma tissues were analyzed for pathological patterns of HBV antigens using immunohistochemistry; 10 fresh primary tumor tissues were inoculated into NOD/SCID mice and risk factors for patient-derived xenograft (PDX) model were identified by the univariate F test. Consistency of HBV features and cellular biomarkers between patient tissues and tumor grafts were examined. RESULTS: In HCC, HBV surface antigen (HBsAg) was mainly absent. Only 9.9% of samples showed HBsAg positivity in the tumor tissue that was limited to benign hepatocytes. In contrast, HBV core antigen (HBcAg) exhibited positive staining in all HCC tissues, located mainly in the cytoplasm of tumor cells. Of 14 HCC cases, three were diagnosed as occult infection of HBV based on HBcAg expression. The successful rate for the PDX model was 20% (2/10). Tumor lesions on hepatic lobes of V and VI, severe liver dysfunction and higher CA125 showed p-values of 0.01, 0.035, and 0.01, respectively. HBsAg absence in original tumors of #6 and 8 patients were faithfully reproduced by engraftments. Mixed distribution of HBcAg in cellular compartments of original tumor cells was also observed in mice. ki67 was dramatically increased in tumor grafts. CONCLUSION: We delineated pathological HBV profiles of HCC specimens and perilesional areas, which provided evidence for virus-based therapy in the future. PDX mice may phenocopy virological and cellular features of patient tissues, which is novel in the virus-related hepatocarcinogenesis field.