MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.
Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.
Shachaf
Catherine M
CM
Division of Medical Oncology, Department of Medicine, Stanford University, California 94305, USA.
Kopelman
Andrew M
AM
Arvanitis
Constadina
C
Karlsson
Asa
A
Beer
Shelly
S
Mandl
Stefanie
S
Bachmann
Michael H
MH
Borowsky
Alexander D
AD
Ruebner
Boris
B
Cardiff
Robert D
RD
Yang
Qiwei
Q
Bishop
J Michael
JM
Contag
Christopher H
CH
Felsher
Dean W
DW
D000818:Animals; D017209:Apoptosis; D001652:Bile Ducts / Q000166:cytology / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics*; D008163:Luminescent Measurements; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
D014408:Biomarkers, Tumor; D016271:Proto-Oncogene Proteins c-myc