title: Des-γ-carboxyl prothrombin is associated with tumor angiogenesis in hepatocellular carcinoma.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is a hypervascular tumor, and angiogenesis plays an important role in its development. Previously, we demonstrated that des-γ-carboxyl prothrombin (DCP) promotes both cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) by inducing the autophosphorylation of kinase insert domain receptor (KDR). In the present study, DCP-associated tumor angiogenesis was assessed by comparing hypovascular and common hypervascular HCC.
  
  
  METHODS
  The solitary HCCs of 827 patients were classified into two groups according to the tumor density at the arterial phase of a dynamic computed tomography scan; the initial clinical data of patients with the hyper- and hypovascular types were compared. The HCC tissues from 95 tumors were analyzed by immunohistochemical staining for DCP and phosphorylated KDR, and intratumoral microvessel density (MVD) was analyzed to evaluate microvessel angiogenesis.
  
  
  RESULTS
  The serum DCP levels (320 ± 3532 mAU/mL) and tumor size (18.4 ± 9.0 mm) of patients with hypervascular HCC were significantly greater than those with hypovascular HCC (38.7 ± 80 mAU/mL and 14.6 ± 5.2 mm, P < 0.001). Immunohistochemical analysis revealed that the expressions of DCP and phospho-KDR were significantly greater in hypervascular HCC (71.4% and 31.0%, respectively) than in hypovascular HCC (7.6% and 5.7%, respectively). Intratumoral MVD was significantly correlated with DCP (r = 0.48, P < 0.0001).
  
  
  CONCLUSIONS
  des-γ-carboxyl prothrombin production is associated with tumor angiogenesis in HCC.
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Matsubara
authors.forename: Hidenori
authors.initials: H
authors.lastname: Shiraha
authors.forename: Jyunro
authors.initials: J
authors.lastname: Kataoka
authors.forename: Masaya
authors.initials: M
authors.lastname: Iwamuro
authors.forename: Shigeru
authors.initials: S
authors.lastname: Horiguchi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Nishina
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takaoka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Uemura
authors.forename: Akinobu
authors.initials: A
authors.lastname: Takaki
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakamura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nouso
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism*; D019735:Carbon-Carbon Ligases / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000097:blood / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D011498:Protein Precursors / Q000097:blood / Q000378:metabolism*; D011516:Prothrombin / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D017077:Culture Media, Conditioned; D011498:Protein Precursors; C008208:acarboxyprothrombin; D011516:Prothrombin; D040301:Vascular Endothelial Growth Factor Receptor-2; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase