title: The role of multipotent cancer associated fibroblasts in hepatocarcinogenesis.
abstract: BACKGROUND
  The presence of tumor supporting cells in various cancer, including in hepatocellular carcinoma (HCC), has become an important target in the study of carcinogenesis. The cancer-associated fibroblast (CAF), one of the most important cellular components in the cancer stroma, might contribute to the progression of the disease due to its plasticity, a behavior of the stem cells. In this study, we investigate the significance of the CAF and its role in the HCC progression and metastasis.
  
  
  METHODS
  Primary CAF and non-tumoral fibroblast (NTF) from nine paired HCC and distant non-tumoral liver tissues were isolated and cultured. The cells were characterized by flow cytometry, RT-PCR, anchorage-independent assay and in vitro cells directed trans-differentiation. Co-culture study was performed in Transwell system and xenograft assay was performed in immunodeficient mice.
  
  
  RESULTS
  CAF and NTF were positive for CD90, CD44, αSMA, and vimentin and negative for CD34, CD45, CD117, and CD133. When stimulated, they showed the potential to differentiate into adipocytes, osteoblasts, and pancreatic cells. When co-cultured with human HCC cell lines, CAF up-regulated gene expressions of TGFB1 and FAP of HuH-7 and JHH-6 while NTF did not induced either of the genes. Xenograft assay showed that the CAF had the capacity to enter into circulation as confirmed by RT-PCR and DNA sequencing.
  
  
  CONCLUSIONS
  Our data provides evidence of the plasticity of the CAF and the NTF as stem cells in the process of hepatocarcinogenesis and metastasis. These cells mutually interacts with HCC cells. Their trans-differentiation flexibility may induce a switch from normal to cancerous microenvironment.
authors: Department of Medicine Surgery and Health Sciences, University of Trieste, 34100, Trieste, Italy. caecilia.sukowati@csf.units.it.|Fondazione Italiana Fegato - Italian Liver Foundation, AREA Science Park Basovizza, 34149, Trieste, Italy. caecilia.sukowati@csf.units.it.
authors: Caecilia Hapsari Ceriapuri
authors: CH
authors: Sukowati
authors: Fondazione Italiana Fegato - Italian Liver Foundation, AREA Science Park Basovizza, 34149, Trieste, Italy. b.anfuso@csf.units.it.
authors: Beatrice
authors: B
authors: Anfuso
authors: Department of Medicine Surgery and Health Sciences, University of Trieste, 34100, Trieste, Italy. lcroce@units.it.|Fondazione Italiana Fegato - Italian Liver Foundation, AREA Science Park Basovizza, 34149, Trieste, Italy. lcroce@units.it.
authors: Lory Saveria
authors: LS
authors: Crocé
authors: Department of Medicine Surgery and Health Sciences, University of Trieste, 34100, Trieste, Italy. ctliver@csf.units.it.|Fondazione Italiana Fegato - Italian Liver Foundation, AREA Science Park Basovizza, 34149, Trieste, Italy. ctliver@csf.units.it.
authors: Claudio
authors: C
authors: Tiribelli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D016130:Immunophenotyping; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype