title: The effect of hepatic progenitor cells on experimental hepatocellular carcinoma in the regenerating liver.
abstract: OBJECTIVE
  Liver regeneration following hepatectomy can stimulate the growth of hepatocellular carcinoma (HCC), and major hepatectomy can be associated with activation of hepatic progenitor cells (HPCs). The aim of this study was to evaluate how HPCs influence the malignant potential of tumor cells in vitro and HCC tumor growth after surgery in a rodent model.
  
  
  METHODS
  Hepatoma cells (JM1) were cultured with conditioned medium (CM) from syngeneic HPCs (WB-F344). Growth rate, resistance to Adriamycin, and expression patterns for invasiveness and stemness were compared with naïve JM1. Microscopic HCC tumors from naïve JM1 or JM1 cultured with CM were inoculated in Fischer 344 rats undergoing 70% hepatectomy with or without simultaneous infusion of WB-F344. Tumor growth and invasiveness-related factors were compared. Buffalo rats were induced with Morris hepatoma cells. Liver tissue from both in vivo models was examined with regard to activation of cells with progenitor-like phenotype.
  
  
  RESULTS
  Co-culture with CM resulted in an increased resistance to Adriamycin and enhanced expressions of α-FP, MMP9, ABCG2, CD133, and SOX2, as well as the activation of ERK, AKT, WNT, and TGF-β1 pathways. Tumor size and metastases were significantly higher in groups with co-cultured cells or HPCs infusion. After 70% hepatectomy and tumor implantation, cells positive for α-FP, CK19, and CD133 were found, thus suggesting a progenitor-like phenotype in the setting of epithelial-mesenchymal transition.
  
  
  CONCLUSIONS
  HPCs have a marked effect on HCC cells in vitro and appear to stimulate the growth and malignant potential of experimental HCC tumors.
authors.affiliation: Department of Transplantation Medicine, Oslo University Hospital , Oslo , Norway.
authors.forename: Ji-Hua
authors.initials: JH
authors.lastname: Shi
authors.forename: Hanne
authors.initials: H
authors.lastname: Scholz
authors.forename: Henrik S
authors.initials: HS
authors.lastname: Huitfeldt
authors.forename: Pål-Dag
authors.initials: PD
authors.lastname: Line
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D006498:Hepatectomy; D006801:Humans; D008099:Liver / Q000502:physiology / Q000601:surgery; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011915:Rats, Inbred BUF; D011916:Rats, Inbred F344; D055748:SOXB1 Transcription Factors / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D047368:Tumor Burden; D060449:Wnt Signaling Pathway; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000903:Antibiotics, Antineoplastic; D053648:Cytokine Receptor Common beta Subunit; D012333:RNA, Messenger; D055748:SOXB1 Transcription Factors; C527784:Sox2 protein, rat; D053773:Transforming Growth Factor beta1; D000509:alpha-Fetoproteins; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9