MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer

Catherine M. Shachaf, Andrew M. Kopelman, Constadina Arvanitis, Åsa Karlsson, Shelly Beer, Stefanie Mandl, Michael H. Bachmann, Alexander D. Borowsky, Boris Ruebner, Robert D. Cardiff, Qiwei Yang, J. Michael Bishop, Christopher H. Contag and Dean W. Felsher ()
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Catherine M. Shachaf: Division of Medical Oncology, Departments of Medicine and Pathology
Andrew M. Kopelman: Division of Medical Oncology, Departments of Medicine and Pathology
Constadina Arvanitis: Division of Medical Oncology, Departments of Medicine and Pathology
Åsa Karlsson: Division of Medical Oncology, Departments of Medicine and Pathology
Shelly Beer: Division of Medical Oncology, Departments of Medicine and Pathology
Stefanie Mandl: Stanford University
Michael H. Bachmann: Stanford University
Alexander D. Borowsky: University of California Davis Medical Center
Boris Ruebner: University of California Davis Medical Center
Robert D. Cardiff: University of California Davis Medical Center
Qiwei Yang: Division of Medical Oncology, Departments of Medicine and Pathology
J. Michael Bishop: University of California
Christopher H. Contag: Stanford University
Dean W. Felsher: Division of Medical Oncology, Departments of Medicine and Pathology

Nature, 2004, vol. 431, issue 7012, 1112-1117

Abstract: Abstract 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.

Date: 2004
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DOI: 10.1038/nature03043

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