MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.

Division of Medical Oncology, Department of Medicine, Stanford University, California 94305, USA.
Nature (Impact Factor: 42.35). 11/2004; 431(7012):1112-7. DOI: 10.1038/nature03043
Source: PubMed

ABSTRACT 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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    ABSTRACT: Hepatocellular carcinoma (HCC) is currently one of the top lethal cancers with an increasing trend. Deregulation of MYC in HCC is frequently detected and always correlated with poor prognosis. As the zebrafish genome contains two differentially expressed zebrafish myc orthologs, myca and mycb, it remains unclear about the oncogenicity of the two zebrafish myc genes. In the present study, we developed two transgenic zebrafish lines to over-express myca and mycb respectively in the liver using a mifepristone-inducible system and found that both myc genes were oncogenic. Moreover, the transgenic expression of myca in hepatocytes caused robust liver tumors with several distinct phenotypes of variable severity. ~5% of myca transgenic fish developing multinodular HCC with cirrhosis after 8 months of induced myca expression. Apoptosis was also observed with myca expression; introduction of homozygous tp53-/- mutation into the myca transgenic fish reduced apoptosis and accelerated tumor progression. The malignant status of hepatocytes was dependent on continued expression of myca; withdrawal of the mifepristone inducer resulted in a rapid regression of liver tumors, and the tumor regression occurred even in the tp53-/- mutation background. Thus, our data demonstrated the robust oncogenicity of zebrafish myca and the requirement of sustained Myc overexpression for maintenance of the liver tumor phenotype in this transgenic model. Furthermore, tumor regression is independent of the function of Tp53.
    PLoS ONE 01/2015; 10(1):e0117249. DOI:10.1371/journal.pone.0117249 · 3.53 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is a rapidly fatal disease with short life expectancy from the time of diagnosis. Therapies with pharmacological agents do not improve the prognosis of patients with unresectable HCC. This emphasizes the need to identify prognostic markers and targets for early diagnosis, chemoprevention, and treatment of the disease. Available evidence indicates that clinical outcome of HCC could reflect genetic predisposition to cancer development and progression. Numerous loci controlling HCC progression have been identified in rodents. In this review, we describe the results of preclinical studies on effector mechanisms of susceptibility/resistance genes, responsible for HCC progression, aimed at identifying new prognostic markers and therapeutic targets of this tumor. Highest c-Myc amplification, cell cycle deregulation, alterations of iNOS/IKK/NF-kB and Ras/ERK signaling, and deregulation of FoxM1 and Mybl2 occur in rapidly progressing dysplastic nodules and HCC, induced in genetic susceptible rat strains, compared to slowly progressing lesions of resistant rats. Notably, alterations of these molecular mechanisms in human HCC subtypes with poorer and better prognosis, are similar to those present in genetically susceptible and resistant rats, respectively, and may function as prognostic markers and putative therapeutic targets. Attempts to cure advanced HCC by molecular therapy with cell signaling inhibitors directed against specific targets have given contradictory results, limited therapeutic effects, and major adverse effects in some instances. To overcome these difficulties it is necessary to direct gene therapy to different molecular targets essential for the survival of tumor cells, according to HCC subtype and status. Thus, efforts are necessary to identify and test, in pre-clinical and clinical studies, new therapeutic targets for combined molecular treatments of HCC. This approach may lead to identification of numerous new prognostic markers, representing promising candidates for the identification of high risk patients who may benefit from new anticancer drugs against key components of signaling pathways.
    01/2011; DOI:10.5455/
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    ABSTRACT: Cancer stem cells (CSCs) are tumor cells that have the principal properties of self-renewal, clonal tumor initiation capacity, and clonal long-term repopulation potential. CSCs reside in niches, which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, protect them from the immune system, and facilitate their metastatic potential. In this perspective, we focus on the CSC niche and discuss its contribution to tumor initiation and progression. Since CSCs survive many commonly employed cancer therapies, we examine the prospects of targeting the niche components as preferable therapeutic targets. Copyright © 2015 Elsevier Inc. All rights reserved.

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