Amaoka Nozomi, Saio Masanao, Nonaka Kenichi, Imai Hisashi, Tomita Hiroyuki, Sakashita Fumio, Takahashi Takao, Sugiyama Yasuyuki, Takami Tsuyoshi, Adachi Yosuke
Department of Oncologic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Oncol Rep. 2006 Jul;16(1):3-10.
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.
血管生成对肿瘤生长至关重要，并受血管内皮生长因子（VEGF）等血管生成因子的调节。在本研究中，我们调查了VEGF受体（VEGFRs）的表达是否与肝细胞癌（HCC）中肿瘤细胞的增殖有关。我们对50例手术切除的人类HCC石蜡包埋组织切片同时进行增殖标志物Ki-67抗原和VEGFR1（Flt-1）或VEGFR2（Flk-1）的染色。根据VEGFRs的染色模式，我们将病例分为4类：受体双阴性、Flt-1单阳性、Flk-1单阳性、受体双阳性。有趣的是，与Flt-1单阳性或Flk-1单阳性病例相比，受体双阴性病例中的Ki-67指数显著更低（分别为P = 0.0491，P = 0.0196）。此外，与Flt-1单阳性或Flk-1单阳性病例相比，受体双阳性病例中的指数也显著更低（分别为P = 0.0026，P < 0.0001）。我们进一步研究了35例Ki67指数> 10%的病例，以确定Ki-67抗原阳性增殖细胞上VEGFRs的表达。令人惊讶的是，HCC的组织学分级与VEGFRs的表达模式呈现出特征性的关系；高分化HCC病例均分布在Flk-1阳性组（7/7），中分化HCC病例分布在Flt-1或Flk-1单阳性组（20/21），低分化HCC病例主要分布在受体双阴性或双阳性组（6/7）。这些发现表明，VEGFRs的表达模式影响HCC的组织学分化。
