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Cell Rep. 2017 Apr 18;19(3):584-600. doi: 10.1016/j.celrep.2017.03.059.

Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells.

Author information

1
Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain.
2
Structural Biology and Biocomputing Programme, Bioinformatics Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain.
3
Department of Medicine, Columbia University, New York, NY 10032, USA.
4
Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid 28034, Spain.
5
Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain. Electronic address: ndjouder@cnio.es.

Abstract

Hepatocellular carcinoma (HCC) is an aggressive primary liver cancer. However, its origin remains a debated question. Using human data and various hepatocarcinogenesis mouse models, we show that, in early stages, transformed hepatocytes, independent of their proliferation status, activate hepatic progenitor cell (HPC) expansion. Genetic lineage tracing of HPCs and hepatocytes reveals that, in all models, HCC originates from hepatocytes. However, whereas in various models tumors do not emanate from HPCs, tracking of progenitors in a model mimicking human hepatocarcinogenesis indicates that HPCs can generate benign lesions (regenerative nodules and adenomas) and aggressive HCCs. Mechanistically, galectin-3 and α-ketoglutarate paracrine signals emanating from oncogene-expressing hepatocytes instruct HPCs toward HCCs. α-Ketoglutarate preserves an HPC undifferentiated state, and galectin-3 maintains HPC stemness, expansion, and aggressiveness. Pharmacological or genetic blockage of galectin-3 reduces HCC, and its expression in human HCC correlates with poor survival. Our findings may have clinical implications for liver regeneration and HCC therapy.

KEYWORDS:

DNA damage; HCC; NAD(+); adenomas; galectin-3; hepatic progenitor cells; hepatocytes; lineage tracking; regenerative nodules; α-ketoglutarate

PMID:
28423321
PMCID:
PMC5409928
DOI:
10.1016/j.celrep.2017.03.059
[Indexed for MEDLINE]
Free PMC Article

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