Generation and analysis of genetically defined liver carcinomas derived from bipotential liver progenitors.
Hepatocellular carcinoma is a chemoresistant cancer and a leading cause of cancer mortality; however, the molecular mechanisms responsible for the aggressive nature of this disease are poorly understood. In this study, we developed a new liver cancer mouse model that is based on the ex vivo genetic manipulation of embryonic liver progenitor cells (hepatoblasts). After retroviral gene transfer of oncogenes or short hairpin RNAs targeting tumor suppressor genes, genetically altered liver progenitor cells are seeded into the liver of otherwise normal recipient mice. We show that histopathology of the engineered liver 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 that are characteristic for human hepatocellular carcinoma. This model provides a powerful platform for applications like cancer gene discovery or high-throughput preclinical drug testing.
Zender
L
L
Cold Spring Harbor Laboratory, New York 11724, USA.
Xue
W
W
Cordón-Cardo
C
C
Hannon
G J
GJ
Lucito
R
R
Powers
S
S
Flemming
P
P
Spector
M S
MS
Lowe
S W
SW
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D049452:Green Fluorescent Proteins / Q000235:genetics; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D034622:RNA Interference; D011994:Recombinant Proteins / Q000235:genetics; D014161:Transduction, Genetic
D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins