Griffioen A W, Damen C A, Martinotti S, Blijham G H, Groenewegen G
Department of Internal Medicine, University Hospital Utrecht, the Netherlands.
Cancer Res. 1996 Mar 1;56(5):1111-17.
Intercellular adhesion molecule 1 (ICAM-1) is involved in the recirculation of blood leukocytes and, presumably, in the infiltration of cytolytic effector leukocytes into tumors. The present report describes a down-regulated expression of vascular ICAM-1 on tumor-infiltrating endothelial cells (EC) in renal cell carcinoma. This finding was obtained by flow cytometric analysis of tumor EC compared to EC obtained from healthy tissue. Since growth of solid tumors is dependent on the formation of new blood vessels (angiogenesis), we hypothesized that angiogenic factors are responsible for the down-regulation of ICAM-1. This hypothesis was investigated in vitro using human umbilical vein- and dermis-derived EC. Using flow cytometry, we found a biphasic regulation of ICAM-1 during stimulation of cultured EC with the angiogenic agent basic fibroblast growth factor (bFGF). Although 16-24 h after activation a marked up-regulation of ICAM-1 was observed, expression was significantly decreased after 48h. The longevity of this down-regulation was at least 7 days. Northern blot analysis revealed down-regulation of the steady-state mRNA level of the gene. ICAM-2 showed similar results of intial up- and later down-regulation. Functional relevance for the changes in ICAM-1 expression was demonstrated by a corresponding biphasic regulation of EC-leukocyte adhesion after EC activation by bFGF. The described effects are specific for bFGF since other angiogenic factors (such as vascular endothelial growth factor, transforming growth factor beta, and interleukin 8) did not affect adhesion molecule expression. Subsequent experiments showed that angiogenic factors decrease the sensitivity of EC to activation with tumor necrosis factor-alpha in regard to adhesion molecule expression. The present results reveal a tumor-derived escape mechanism from cytolytic effector leukocytes by down-regulation of vascular adhesion molecules in vivo and in vitro and decreased responsiveness to proinflammatory cytokines.
细胞间黏附分子1（ICAM-1）参与血液白细胞的再循环，并且可能参与溶细胞效应白细胞向肿瘤的浸润。本报告描述了肾细胞癌中肿瘤浸润内皮细胞（EC）上血管ICAM-1的表达下调。通过对肿瘤EC与从健康组织获得的EC进行流式细胞术分析得出这一发现。由于实体瘤的生长依赖于新血管的形成（血管生成），我们推测血管生成因子是ICAM-1下调的原因。使用人脐静脉和真皮来源的EC在体外研究了这一假设。通过流式细胞术，我们发现在用血管生成剂碱性成纤维细胞生长因子（bFGF）刺激培养的EC期间，ICAM-1呈双相调节。虽然在激活后16 - 24小时观察到ICAM-1明显上调，但在48小时后表达显著下降。这种下调的持续时间至少为7天。Northern印迹分析显示该基因的稳态mRNA水平下调。ICAM-2显示出类似的初始上调和随后下调的结果。bFGF激活EC后，EC-白细胞黏附的相应双相调节证明了ICAM-1表达变化的功能相关性。所述效应是bFGF特有的，因为其他血管生成因子（如血管内皮生长因子、转化生长因子β和白细胞介素8）不影响黏附分子表达。随后的实验表明，血管生成因子在黏附分子表达方面降低了EC对肿瘤坏死因子-α激活的敏感性。目前的结果揭示了一种肿瘤衍生的逃避机制，通过体内和体外下调血管黏附分子以及降低对促炎细胞因子的反应性来逃避溶细胞效应白细胞。
