Journal
CELL
Volume 155, Issue 2, Pages 384-396Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.09.031
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Funding
- Superfund Basic Research Program [P42ES010337]
- NIH [CA118165, CA155120]
- Wellcome Trust [WT086755]
- American Diabetes Association [7-08-MN-29]
- Center for Translational Science [UL1RR031980, UL1TR000100]
- National Center for Research Resources IMAT program [N12R1CA155615]
- Damon Runyon Cancer Research Foundation
- American Liver Foundation
- Daiichi Sankyo Foundation of Life Science
- California Institute for Regenerative Medicine Stem Cell Training Grant II [TG2-01154]
- Kanzawa Medical Research Foundation
- German Research Foundation (DFG) [SH721/1-1]
- National Childhood Cancer Foundation
- Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases
- Grants-in-Aid for Scientific Research [25460981] Funding Source: KAKEN
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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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