Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor
Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor
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DOI：
10.1073/pnas.95.18.10820
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发表时间：
1998-09-01
影响因子：
11.1
通讯作者：
Keshet, E
中科院分区：
文献类型：
--
作者：
Jain, RK;Safabakhsh, N;Keshet, E
导致肿瘤血管消退的事件顺序以及这些血管在消融治疗期间的功能特征尚不清楚。这是因为缺乏适当的动物模型和监测技术。通过使用体内显微镜和原位分子分析的雄激素依赖性盐野木癌生长在严重的联合免疫缺陷小鼠，我们表明，这些小鼠的去势导致肿瘤消退和血管内皮生长因子（VEGF）的表达伴随减少，雄激素戒断是已知的诱导凋亡盐野木肿瘤细胞。令人惊讶的是，肿瘤内皮细胞开始在肿瘤细胞之前经历凋亡，并且肿瘤血管的稀疏先于肿瘤大小的减小。退化的血管开始表现出正常的表型，即，直径较小、迂曲、血管通透性和白细胞粘附。去势后两周，血管生成和肿瘤生长的第二波开始伴随着VEGF表达的增加。由于人类肿瘤经常在肿瘤消融治疗后复发，我们的数据表明，这些患者可能受益于联合抗VEGF治疗。
The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone-ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi carcinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression, Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular permeability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone-ablation therapy, our data suggest that these patients may benefit from combined anti-VEGF therapy.