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

Publication date: 18 April 2017
Source:Cell Reports, Volume 19, Issue 3
Author(s): Krishna S. Tummala, Marta Brandt, Ana Teijeiro, Osvaldo Graña, Robert F. Schwabe, Cristian Perna, Nabil Djouder
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.

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Teaser

Tummala et al. demonstrate that hepatocytes and hepatic progenitor cells participate in liver tumor heterogeneity. Malignant hepatocytes crosstalk and activate the neighboring progenitor cells through releases of galectin-3 and α-ketoglutarate. Blocking galectin-3 reduces hepatocarcinogenesis and may have important clinical implications.


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