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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.

SUBMITTER: Tummala KS

PROVIDER: S-EPMC5409928 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Tummala Krishna S KS Brandt Marta M Teijeiro Ana A Graña Osvaldo O Schwabe Robert F RF Perna Cristian C Djouder Nabil N

Cell reports 20170401 3

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 fr ...[more]

PMID: 28423321

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Project description:BackgroundWilson's disease (WD) is a genetic disorder that impairs the excretion of copper in hepatocytes and results in excessive copper deposition in multiple organs. The replacement of disordered hepatocytes with functional hepatocytes can serve as a lifelong therapeutic strategy for the treatment of WD. The aim of this study was to determine the hepatocyte repopulation effects of fibroblast-derived hepatic progenitor cells in the treatment of WD.MethodsInduced hepatic progenitor cells (iHPCs) were generated through direct reprogramming of adult mouse fibroblasts infected with lentivirus carrying both the Foxa3 and Hnf4α genes. These iHPCs were subsequently identified and transplanted into copper-overload WD mice with the Atp7b (H1071Q) mutation via caudal vein injection.ResultsAfter lentivirus infection, the fibroblasts transformed into Foxa3- and Hnf4α-overexpressing cobblestone-like cells with reduced expression of fibroblast markers and increased expression of epithelial cell and hepatic progenitor cell markers, i.e., iHPCs. Sixteen weeks after transplantation into WD mice, approximately 2% of hepatocytes were derived from iHPCs, and these iHPC-derived hepatocytes expressed a tight junction-associated protein of the bile canal, tight junction protein 1 (Zo1). There was a decrease in the serum copper concentration and relative activity of serum ceruloplasmin at weeks 4 and 8 after iHPCs transplantation compared with those of WD fed mice administered saline or fibroblasts. Furthermore, iHPC transplantation markedly reduced the proportion of CD8+ T lymphocytes and natural killer cells compared with those in fibroblast-transplanted WD mice and downregulated the transcription of the inflammatory cytokines, including tumor necrosis factor α (Tnfα), interleukin 1β (IL-1β), and IL-6, compared with those in WD mice and in fibroblast-transplanted WD mice.ConclusioniHPCs reprogrammed from adult fibroblasts can repopulate hepatocytes and exert therapeutic effects in WD mice, representing a potential replacement therapy for clinical application.

Project description:Considerable progress has been made in developing antifibrotic agents and other strategies to treat liver fibrosis; however, significant long-term restoration of functional liver mass has not yet been achieved. Therefore, we investigated whether transplanted hepatic stem/progenitor cells can effectively repopulate the liver with advanced fibrosis/cirrhosis. Stem/progenitor cells derived from fetal livers or mature hepatocytes from DPPIV(+) F344 rats were transplanted into DPPIV(-) rats with thioacetamide (TAA)-induced fibrosis/cirrhosis; rats were sacrificed 1, 2, or 4 months later. Liver tissues were analyzed by histochemistry, hydroxyproline determination, reverse-transcription polymerase chain reaction (RT-PCR), and immunohistochemistry. After chronic TAA administration, DPPIV(-) F344 rats exhibited progressive fibrosis, cirrhosis, and severe hepatocyte damage. Besides stellate cell activation, increased numbers of stem/progenitor cells (Dlk-1(+), AFP(+), CD133(+), Sox-9(+), FoxJ1(+)) were observed. In conjunction with partial hepatectomy (PH), transplanted stem/progenitor cells engrafted, proliferated competitively compared to host hepatocytes, differentiated into hepatocytic and biliary epithelial cells, and generated new liver mass with extensive long-term liver repopulation (40.8 ± 10.3%). Remarkably, more than 20% liver repopulation was achieved in the absence of PH, associated with reduced fibrogenic activity (e.g., expression of alpha smooth muscle actin, platelet-derived growth factor receptor ?, desmin, vimentin, tissue inhibitor of metalloproteinase-1) and fibrosis (reduced collagen). Furthermore, hepatocytes can also replace liver mass with advanced fibrosis/cirrhosis, but to a lesser extent than fetal liver stem/progenitor cells.This study is a proof of principle demonstration that transplanted epithelial stem/progenitor cells can restore injured parenchyma in a liver environment with advanced fibrosis/cirrhosis and exhibit antifibrotic effects.

Project description:BackgroundSquamous cell carcinoma is the most common genital, ocular and gastric tumour in horses. Equus caballus papillomavirus type 2 (EcPV2) DNA has been detected in several studies in equine penile squamous cell carcinomas (SCCs) and precursor lesions providing evidence of a causal role of EcPV2 in equine genital SCCs. Recently, EcPV2 E6/E7 nucleic acids were also detected in equine gastric SCCs, but further studies are required to determine the role of EcPV2 infection in the pathogenesis of gastric SCC. EcPV2 nucleic acids have been rarely described in ocular SCCs and precursor lesions.ObjectivesTo investigate the presence of EcPV2 nucleic acids with polymerase chain reaction (PCR) and in situ hybridisation (ISH) in penile hyperplasias, papillomas and SCCs in horses and to determine whether EcPV2 nucleic acids can be detected in SCCs affecting other locations, including the stomach, ocular tissues and larynx.MethodsTwenty-one archival formalin-fixed paraffin embedded (FFPE) tissue samples, including 12 genital lesions comprising penile hyperplasias, papillomas and SCCs, 6 ocular SCCs, 2 gastric SCCs and 1 laryngeal SCC, were screened by PCR and ISH for EcPV2 E6/E7 DNA and mRNA. Archival FFPE tissue samples (eyelid and penile mucosa and preputium) from six horses without a diagnosis or history of neoplastic or papillomavirus-associated disease were included as controls.ResultsEcPV2 nucleic acids were detected by PCR and ISH in all genital lesions (12/12) and gastric SCCs (2/2), in two ocular SCCs (2/6) and in one laryngeal SCC (1/1). In control horses, one eyelid sample was positive in PCR but not in ISH. The remaining control samples were negative for EcPV2 E6/E7 nucleic acids in PCR and ISH.ConclusionsThese results further support the role of EcPV2 infection in the development of equine genital SCCs and suggest that EcPV2 infection may also act as a predisposing factor for other SCCs in horses, including gastric, ocular and laryngeal SCCs.

Dataset Information

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

Publications

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

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