TY - JOUR
T1 - XIdentification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling
AU - He, Guobin
AU - Dhar, Debanjan
AU - Nakagawa, Hayato
AU - Font-Burgada, Joan
AU - Ogata, Hisanobu
AU - Jiang, Yuhong
AU - Shalapour, Shabnam
AU - Seki, Ekihiro
AU - Yost, Shawn E.
AU - Jepsen, Kristen
AU - Frazer, Kelly A.
AU - Harismendy, Olivier
AU - Hatziapostolou, Maria
AU - Iliopoulos, Dimitrios
AU - Suetsugu, Atsushi
AU - Hoffman, Robert M.
AU - Tateishi, Ryosuke
AU - Koike, Kazuhiko
AU - Karin, Michael
N1 - Funding Information:
We acknowledge the Biogem facility at UCSD for their assistance with transcriptome analysis and A. Arian, K. Iwaisako, Y. Hiroshima, and H. Matsui for technical assistance. We thank Dr. J. Hidalgo (Universitat Autonoma de Barcelona, Spain) for the Il6 F/F mice. Research was supported by the Superfund Basic Research Program (P42ES010337), NIH (CA118165 and CA155120), Wellcome Trust (WT086755), American Diabetes Association (7-08-MN-29), the Center for Translational Science (UL1RR031980 and UL1TR000100), the National Center for Research Resources IMAT program (N12R1CA155615), and postdoctoral research fellowships from the Damon Runyon Cancer Research Foundation (G.H.), American Liver Foundation (D.D.), Daiichi Sankyo Foundation of Life Science (H.N.), California Institute for Regenerative Medicine Stem Cell Training Grant II (TG2-01154) fellowship (J.F.-B.), Kanzawa Medical Research Foundation (H.O.), the German Research Foundation (DFG, SH721/1-1 to S.S.), and a Young Investigator Award from the National Childhood Cancer Foundation, “CureSearch” (D.D.). M.K. is an ACS Research Professor and is a recipient of the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.
PY - 2013/10/10
Y1 - 2013/10/10
N2 - Hepatocellular carcinoma (HCC) is a slowly developing malignancy postulated to evolve from premalignant lesions in chronically damaged livers. However, it was never established that premalignant lesions actually contain tumor progenitors that give rise to cancer. Here, we describe isolation and characterization of HCC progenitor cells (HcPCs) from different mouse HCC models. Unlike fully malignant HCC, HcPCs give rise to cancer only when introduced into a liver undergoing chronic damage and compensatory proliferation. Although HcPCs exhibit a similar transcriptomic profile to bipotential hepatobiliary progenitors, the latter do not give rise to tumors. Cells resembling HcPCs reside within dysplastic lesions that appear several months before HCC nodules. Unlike early hepatocarcinogenesis, which depends on paracrine IL-6 production by inflammatory cells, due to upregulation of LIN28 expression, HcPCs had acquired autocrine IL-6 signaling that stimulates their in vivo growth and malignant progression. This may be a general mechanism that drives other IL-6-producing malignancies.
AB - Hepatocellular carcinoma (HCC) is a slowly developing malignancy postulated to evolve from premalignant lesions in chronically damaged livers. However, it was never established that premalignant lesions actually contain tumor progenitors that give rise to cancer. Here, we describe isolation and characterization of HCC progenitor cells (HcPCs) from different mouse HCC models. Unlike fully malignant HCC, HcPCs give rise to cancer only when introduced into a liver undergoing chronic damage and compensatory proliferation. Although HcPCs exhibit a similar transcriptomic profile to bipotential hepatobiliary progenitors, the latter do not give rise to tumors. Cells resembling HcPCs reside within dysplastic lesions that appear several months before HCC nodules. Unlike early hepatocarcinogenesis, which depends on paracrine IL-6 production by inflammatory cells, due to upregulation of LIN28 expression, HcPCs had acquired autocrine IL-6 signaling that stimulates their in vivo growth and malignant progression. This may be a general mechanism that drives other IL-6-producing malignancies.
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U2 - 10.1016/j.cell.2013.09.031
DO - 10.1016/j.cell.2013.09.031
M3 - Article
C2 - 24120137
AN - SCOPUS:84885671431
SN - 0092-8674
VL - 155
SP - 384
JO - Cell
JF - Cell
IS - 2
ER -
