title: Expression of vascular endothelial growth factor receptors is closely related to the histological grade of hepatocellular carcinoma.
abstract: Angiogenesis is important for tumor growth, and is regulated by angiogenetic factors such as vascular endothelial growth factor (VEGF). In the present study, we investigated whether or not expression of VEGF receptors (VEGFRs) is related to the proliferation of tumor cells in hepatocellular carcinoma (HCC). We simultaneously stained proliferation marker Ki-67 antigen and either VEGFR1 (Flt-1) or VEGFR2 (Flk-1) on paraffin-embedded tissue sections from 50 cases of surgically resected human HCC. Based on the staining pattern of VEGFRs, we classified the cases into 4 categories; receptor double-negative, Flt-1 single-positive, Flk-1 single-positive, receptor double-positive. Interestingly, the Ki-67 index was significantly lower in receptor double-negative cases in comparison to that in either Flt-1 single-positive or Flk-1 single-positive cases (P = 0.0491, P = 0.0196, respectively). Moreover, the index was also significantly lower in receptor double-positive cases in comparison to either Flt-1 single-positive or Flk-1 single-positive cases (P = 0.0026, P < 0.0001, respectively). We further investigated 35 cases showing a Ki67 index > 10% to determine the expression of VEGFRs on Ki-67 antigen-positive proliferating cells. Surprisingly, the histological grade of HCC and the expression pattern of VEGFRs showed a characteristic relation; the well-differentiated HCC cases were all distributed in the Flk-1-positive group (7/7), moderately differentiated HCC cases were distributed in either the Flt-1 or Flk-1 single-positive group (20/21), and poorly differentiated HCC cases were predominantly distributed in either the receptor double-negative or double-positive group (6/7). These findings suggest that the expression pattern of VEGFRs influences the histological differentiation of HCC.
authors.affiliation: Department of Oncologic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. nmhty-ama@nifty.com
authors.forename: Nozomi
authors.initials: N
authors.lastname: Amaoka
authors.forename: Masanao
authors.initials: M
authors.lastname: Saio
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nonaka
authors.forename: Hisashi
authors.initials: H
authors.lastname: Imai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomita
authors.forename: Fumio
authors.initials: F
authors.lastname: Sakashita
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takami
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Adachi
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002454:Cell Differentiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis*
chemical_list: D019394:Ki-67 Antigen; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2