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 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1112-1117 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 431 |
| Issue number | 7012 |
| DOIs | |
| State | Published - Oct 28 2004 |
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MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. / Shachaf, Catherine M.; Kopelman, Andrew M.; Arvanitis, Constadlna; Karlsson, Åsa; Beer, Shelly; Mandl, Stefanie; Bachmann, Michael H.; Borowsky, Alexander D; Ruebner, Boris; Cardiff, Robert; Yang, Qiwei; Bishop, J. Michael; Contag, Christopher H.; Felsher, Dean W.
In: Nature, Vol. 431, No. 7012, 28.10.2004, p. 1112-1117.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer
AU - Shachaf, Catherine M.
AU - Kopelman, Andrew M.
AU - Arvanitis, Constadlna
AU - Karlsson, Åsa
AU - Beer, Shelly
AU - Mandl, Stefanie
AU - Bachmann, Michael H.
AU - Borowsky, Alexander D
AU - Ruebner, Boris
AU - Cardiff, Robert
AU - Yang, Qiwei
AU - Bishop, J. Michael
AU - Contag, Christopher H.
AU - Felsher, Dean W.
PY - 2004/10/28
Y1 - 2004/10/28
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=7744220635&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=7744220635&partnerID=8YFLogxK
U2 - 10.1038/nature03043
DO - 10.1038/nature03043
M3 - Article
C2 - 15475948
AN - SCOPUS:7744220635
VL - 431
SP - 1112
EP - 1117
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7012
ER -