Shachaf, CM, Kopelman, AM, Arvanitis, C, Karlsson, A, Beer, S, Mandl, S et al.. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431: 1112-1117

Division of Medical Oncology, Department of Medicine, Stanford University, California 94305, USA.
Nature (Impact Factor: 41.46). 11/2004; 431(7012):1112-7. DOI: 10.1038/nature03043
Source: PubMed


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.

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Available from: Stefanie Mandl, Oct 05, 2015
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    • "They have a variety of actions including: anti-inflammatory and immunomodulatory effects, inhibiting downstream production of mediators of cell growth88 and promoting programmed cell death.89 Studies have shown that inactivation of Myc can induce remission of HCC and atorvastatin blocks Myc activation resulting in suppression of tumour growth.90 91 "
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    • "To dissect the molecular events responsible for promoting dedifferentiation in the thyroid tumors of Thrb PV/PV Kras G12D mice, we screened for altered expression in regulators known to be involved in the dedifferentiation process. We considered MYC because abnormal MYC expression is associated with dedifferentiation [20] [21] and MYC is commonly elevated in anaplastic thyroid cancer [22] [23]. Indeed, we found a consistent inverse correlation of MYC with PAX8 and TTF1 at the protein level in the thyroid tumors of Thrb PV/PV Kras G12D mice. "
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    • "et al. 2009; Conacci-Sorrell et al. 2014). Sustained MYC activation in mice creates a state of oncogene addiction, while MYC withdrawal in established tumors, including liver carcinomas, leads to tumor involution (Shachaf et al. 2004; Soucek et al. 2008). Additionally, owing to its role in mediating oncogenic signals, MYC is required for the maintenance of some tumors in which it is not amplified, including murine lung adenomas driven by KRAS and leukemia driven by MLL-AF9 (Zuber et al. 2011b; Soucek et al. 2013). "
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