title: TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis.
abstract: Angiogenesis is a critical step in the development and progression of hepatocellular carcinoma (HCC). Myeloid lineage cells, such as macrophages and monocytes, have been reported to regulate angiogenesis in mouse tumor models. TIE2, a receptor of angiopoietins, conveys pro-angiogenic signals and identifies a monocyte/macrophage subset with pro-angiogenic activity. Here, we analyzed the occurrence and kinetics of TIE2-expressing monocytes/macrophages (TEMs) in HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC. We examined the frequency of TEMs, as defined as CD14+CD16+TIE2+ cells, in the peripheral blood and liver. The localization of TEMs in the liver was determined by immunofluorescence staining. Micro-vessel density in the liver was measured by counting CD34+ vascular structures. We found that the frequency of circulating TEMs was significantly higher in HCC than non-HCC patients, while being higher in the liver than in the blood. In patients who underwent local radio-ablation or resection of HCC, the frequency of TEMs dynamically changed in the blood in parallel with HCC recurrence. Most TEMs were identified in the perivascular areas of tumor tissue. A significant positive correlation was observed between micro-vessel density in HCC and frequency of TEMs in the blood or tumors, suggesting that TEMs are involved in HCC angiogenesis. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 serum levels as diagnostic marker for HCC.
  
  
  CONCLUSIONS
  TEMs increase in patients with HCC and their frequency changes with the therapeutic response or recurrence. We thus suggest that TEM frequency can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver.
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Tokuhiro
authors: T
authors: Matsubara
authors: Tatsuya
authors: T
authors: Kanto
authors: Shoko
authors: S
authors: Kuroda
authors: Sachiyo
authors: S
authors: Yoshio
authors: Koyo
authors: K
authors: Higashitani
authors: Naruyasu
authors: N
authors: Kakita
authors: Masanori
authors: M
authors: Miyazaki
authors: Mitsuru
authors: M
authors: Sakakibara
authors: Naoki
authors: N
authors: Hiramatsu
authors: Akinori
authors: A
authors: Kasahara
authors: Yoshito
authors: Y
authors: Tomimaru
authors: Akira
authors: A
authors: Tomokuni
authors: Hiroaki
authors: H
authors: Nagano
authors: Norio
authors: N
authors: Hayashi
authors: Tetsuo
authors: T
authors: Takehara
mesh_terms: D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood; D015415:Biomarkers / Q000097:blood; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000175:diagnosis* / Q000453:epidemiology; D015897:Comorbidity; D018450:Disease Progression; D005260:Female; D006526:Hepatitis C / Q000453:epidemiology; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply* / Q000175:diagnosis* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011498:Protein Precursors / Q000097:blood; D011516:Prothrombin; D042787:Receptor, TIE-2 / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: C097353:AFP protein, human; D042702:Angiopoietin-2; D015415:Biomarkers; D014408:Biomarkers, Tumor; D018950:Lipopolysaccharide Receptors; D011498:Protein Precursors; D017452:Receptors, IgG; D000509:alpha-Fetoproteins; C008208:acarboxyprothrombin; D011516:Prothrombin; D042787:Receptor, TIE-2