title: Transformation of primary human hepatocytes in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Currently, there is limited knowledge of neoplastic transformation of hepatocytes in HCC. In clinical practice, the high rate of HCC local recurrence suggests the presence of different hepatocyte populations within the liver and particularly in the tumor proximity. The present study investigated primary human hepatocyte cultures obtained from liver specimens of patients affected by cirrhosis and HCC, their proliferation and transformation. Liver samples were obtained from seven HCC cirrhotic patients and from three patients with normal liver (NL). Immediately after surgery, cell outgrowth and primary cultures were obtained from the HCC lesion, the cirrhotic tissue proximal (CP, 1-3 cm) and distal (CD, >5 cm) to the margin of the neoplastic lesion, or from NL. Cells were kept in culture for 16 weeks. Morphologic analyses were performed and proliferation rate of the different cell populations compared over time. Glypican-3, Heppar1, Arginase1 and CD-44 positivity were tested. The degree of invasiveness of cells acquiring neoplastic characteristics was studied with a transwell migration assay. We observed that HCC cells maintained their morphology and unmodified neoplastic characteristics when cultured. Cells isolated from CP, showed a progressive morphologic transformation in HCC-like cells accompanied by modification of markers expression with signs of invasiveness. Absence of HCC contamination in the CP isolates was confirmed. In CD samples some of these characteristics were present and at significantly lower levels. With the present study, we are the first to have identified and describe the existence of human hepatocytes near the cancerous lesion that can transform in HCC in vitro.
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Montalbano
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Rastellini
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Xiaofu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Corsello
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Eltorky
authors.affiliation: Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Polyclinic, University of Palermo, Palermo, Italy.
authors.forename: Renza
authors.initials: R
authors.lastname: Vento
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Cicalese
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D001119:Arginase / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D005434:Flow Cytometry; D053673:Glypicans / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000503:physiopathology; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness
chemical_list: D000951:Antigens, Neoplasm; D053673:Glypicans; C000600022:HepPar-1 protein, human; D018960:Hyaluronan Receptors; D001119:Arginase