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

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.
PMID
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Authors

Mayor MeshTerms
Keywords

DNA damage

HCC

NAD(+)

adenomas

galectin-3

hepatic progenitor cells

hepatocytes

lineage tracking

regenerative nodules

α-ketoglutarate

Journal Title cell reports
Publication Year Start




PMID- 28423321
OWN - NLM
STAT- In-Process
DA  - 20170419
LR  - 20170419
IS  - 2211-1247 (Electronic)
VI  - 19
IP  - 3
DP  - 2017 Apr 18
TI  - Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign
      Lesions from Hepatic Progenitor Cells.
PG  - 584-600
LID - S2211-1247(17)30420-5 [pii]
LID - 10.1016/j.celrep.2017.03.059 [doi]
AB  - 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 alpha-ketoglutarate paracrine signals emanating
      from oncogene-expressing hepatocytes instruct HPCs toward HCCs.
      alpha-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.
CI  - Copyright (c) 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Tummala, Krishna S
AU  - Tummala KS
AD  - Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro
      Nacional de Investigaciones Oncologicas (CNIO), Madrid 28029, Spain.
FAU - Brandt, Marta
AU  - Brandt M
AD  - Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro
      Nacional de Investigaciones Oncologicas (CNIO), Madrid 28029, Spain.
FAU - Teijeiro, Ana
AU  - Teijeiro A
AD  - Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro
      Nacional de Investigaciones Oncologicas (CNIO), Madrid 28029, Spain.
FAU - Grana, Osvaldo
AU  - Grana O
AD  - Structural Biology and Biocomputing Programme, Bioinformatics Unit, Centro
      Nacional de Investigaciones Oncologicas (CNIO), Madrid 28029, Spain.
FAU - Schwabe, Robert F
AU  - Schwabe RF
AD  - Department of Medicine, Columbia University, New York, NY 10032, USA.
FAU - Perna, Cristian
AU  - Perna C
AD  - Department of Pathology, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid
      28034, Spain.
FAU - Djouder, Nabil
AU  - Djouder N
AD  - Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro
      Nacional de Investigaciones Oncologicas (CNIO), Madrid 28029, Spain. Electronic
      address: [email protected]
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
OTO - NOTNLM
OT  - DNA damage
OT  - HCC
OT  - NAD(+)
OT  - adenomas
OT  - galectin-3
OT  - hepatic progenitor cells
OT  - hepatocytes
OT  - lineage tracking
OT  - regenerative nodules
OT  - alpha-ketoglutarate
EDAT- 2017/04/20 06:00
MHDA- 2017/04/20 06:00
CRDT- 2017/04/20 06:00
PHST- 2015/11/11 [received]
PHST- 2017/02/08 [revised]
PHST- 2017/03/21 [accepted]
AID - S2211-1247(17)30420-5 [pii]
AID - 10.1016/j.celrep.2017.03.059 [doi]
PST - ppublish
SO  - Cell Rep. 2017 Apr 18;19(3):584-600. doi: 10.1016/j.celrep.2017.03.059.

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