Hepatocellular carcinoma is generally refractory to clinical treatment1. 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 α-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.
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We thank H. Bujard for providing us with the LAP-tTA mice; Y. Kim for assistance with the array CGH analysis; L. Germain for the CK-19 antibody; I. Weissman, P. Khavari and J. Sage for critical reading of the manuscript; and N. Bradon, S. Youssef and members of the Felsher laboratory for their suggestions. This work was supported, in part, by the National Cancer Institute (D.W.F. and C.H.C.), the ASCO Young Investigator Award, a Pilot Feasibility Grant from the UCSF Liver Center, a Pilot Award from the Stanford University Digestive Disease Center (D.W.F), Weiland Family Fellowship (C.M.S.), Howard Hughes Medical Institute Medical Student Fellowship (A.M.K.) and a PHS NRSA training grant (A.K., S.B.).
The authors declare that they have no competing financial interests.
Immunohistochemical analysis of MYC induced liver cancer. (JPG 84 kb)
MYC inactivation uncovers pluripotent differentiative properties in hepatocellular cancer. (JPG 85 kb)
Tumours that are restored after MYC reactivation remained dependent on MYC expression. (JPG 47 kb)
Bioluminescence imaging can be used as a sensitive and accurate strategy to measure tumour growth and regression. (JPG 57 kb)
Normal liver cells do not engraft in SCID hosts. (JPG 81 kb)
Relapsed tumour after MYC inactivation. (JPG 16 kb)
Model for consequence of oncogene inactivation in hepatocellular cancer. (JPG 80 kb)
Immunohistochemistry techniques used. (DOC 20 kb)
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Shachaf, C., Kopelman, A., Arvanitis, C. et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431, 1112–1117 (2004). https://doi.org/10.1038/nature03043
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