2024-03-29T15:56:33Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/72312023-09-21T10:39:04Zcom_20.500.12105_2174com_20.500.12105_2051com_20.500.12105_2173col_20.500.12105_2175
00925njm 22002777a 4500
dc
Tummala, Krishna S
author
Brandt, Marta
author
Teijeiro, Ana
author
Graña Castro, Osvaldo
author
Schwabe, Robert F
author
Perna, Cristian
author
Djouder, Nabil
author
2017-04-19
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.
Cell Rep. 2017;19(3):584-600.
22111247
http://hdl.handle.net/20.500.12105/7231
28423321
10.1016/j.celrep.2017.03.059
2211-1247
Cell reports
DNA damage
HCC
NAD(+)
Adenomas
Galectin-3
Hepatic progenitor cells
Hepatocytes
Lineage tracking
Regenerative nodules
α-ketoglutarate
Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells