Offner F A, Schiefer J, Wirtz H C, Bigalke I, Pavelka M, Hollweg G, Ensinger C, Klosterhalfen B, Mittermayer C, Kirkpatrick C J
Department of Pathology, University of Innsbruck, Austria.
Virchows Arch. 1996 May;428(2):99-106. doi: 10.1007/BF00193937.
Damage to vascular endothelium may play an important role during metastasis. We used a three-dimensional model of tumour cell extravasation to test the hypothesis that certain types of tumour cells are able to induce vascular endothelial cell injury. Multicellular tumour spheroids (MCTS) of 14 human cancer cell lines and spheroids from two benign cell lines were transferred onto confluent monolayers of human endothelial cells (EC). MCTS from 4 of 7 melanoma cell lines induced damage of the endothelium which was closely associated with tumour cell attachment. Endothelial cell injury became evident morphologically by loss of cell membrane integrity and sensitivity to shear stress. Similar results were obtained with EC derived from human umbilical veins, umbilical arteries and saphenous veins. Addition of the oxygen radical scavenger catalase showed a dose- and time-dependent inhibition (up to 48 h) of EC damage in the case of the melanoma cell lines ST-ML-11, ST-ML-14 and SK-MEL-28. The scavenging enzyme superoxide dismutase proved to be protective (up to 12 h) in ST-ML-12 MCTS. In contrast, allopurinol, deferoxamine mesylate, ibuprofen, nor-dihydroguaretic acid, soybean trypsin inhibitor or aprotinin had no protective effect. None of the non-melanoma cancer cell lines or benign cells induced endothelial cell damage. Endothelial injury has been shown to enhance the process of metastasis. Our results suggest that free-radical-mediated endothelial cell damage may be one of the mechanisms contributing to the devastating metastatic potential of melanoma.
血管内皮损伤可能在转移过程中起重要作用。我们使用肿瘤细胞外渗的三维模型来检验某些类型的肿瘤细胞能够诱导血管内皮细胞损伤这一假说。将14种人类癌细胞系的多细胞肿瘤球体（MCTS）和两种良性细胞系的球体转移到人内皮细胞（EC）的汇合单层上。7种黑色素瘤细胞系中的4种的MCTS诱导了内皮损伤，这与肿瘤细胞附着密切相关。内皮细胞损伤在形态上表现为细胞膜完整性丧失和对剪切应力的敏感性，这一点变得明显。从人脐静脉、脐动脉和大隐静脉获得的内皮细胞也得到了类似结果。添加氧自由基清除剂过氧化氢酶显示出对黑色素瘤细胞系ST-ML-11、ST-ML-14和SK-MEL-28的内皮细胞损伤具有剂量和时间依赖性抑制作用（长达48小时）。清除酶超氧化物歧化酶在ST-ML-12 MCTS中被证明具有保护作用（长达12小时）。相比之下，别嘌呤醇、甲磺酸去铁胺、布洛芬、去甲二氢愈创木酸、大豆胰蛋白酶抑制剂或抑肽酶没有保护作用。非黑色素瘤癌细胞系或良性细胞均未诱导内皮细胞损伤。内皮损伤已被证明会增强转移过程。我们的结果表明，自由基介导的内皮细胞损伤可能是导致黑色素瘤具有毁灭性转移潜能的机制之一。
