Generation and Analysis of Genetically Defined Liver Carcinomas Derived from Bipotential Liver Progenitors

Abstract

Hepatocellular carcinoma is a chemoresistant cancer and a leading cause of cancer mortality; however, the molecular mechanismsresponsible for the aggressive nature of this disease are poorly understood. In this study, we developed a new livercancer mouse model that is based on the ex vivo genetic manipulation of embryonic liver progenitor cells (hepatoblasts). Afterretroviral gene transfer of oncogenes or short hairpin RNAs targeting tumor suppressor genes, genetically altered liverprogenitor cells are seeded into the liver of otherwise normal recipient mice. We show that histopathology of the engineeredliver carcinomas reveals features of the human disease. Furthermore, representational oligonucleotide microarray analysis(ROMA) of murine liver tumors initiated by two defined genetic hits revealed spontaneously acquired genetic alterations thatare characteristic for human hepatocellular carcinoma. This model provides a powerful platform for applications like cancergene discovery or high-throughput preclinical drug testing.