Jiang C, Jiang W, Ip C, Ganther H, Lu J
Center for Cancer Causation and Prevention, AMC Cancer Research Center, Denver, Colorado 80214, USA.
Mol Carcinog. 1999 Dec;26(4):213-25. doi: 10.1002/(sici)1098-2744(199912)26:4<213::aid-mc1>3.0.co;2-z.
The trace element nutrient selenium (Se) has been shown to possess cancer-preventive activity in both animal models and humans, but the mechanisms by which this occurs remain to be elucidated. Because angiogenesis is obligatory for the genesis and growth of solid cancers, we investigated, in the study presented here, the hypothesis that Se may exert its cancer-preventive activity, at least in part, by inhibiting cancer-associated angiogenesis. The effects of chemopreventive levels of Se on the intra-tumoral microvessel density and the expression of vascular endothelial growth factor in 1-methyl-1-nitrosourea-induced rat mammary carcinomas and on the proliferation and survival and matrix metalloproteinase activity of human umbilical vein endothelial cells in vitro were examined. Increased Se intake as Se-enriched garlic, sodium selenite, or Se-methylselenocysteine led to a significant reduction of intra-tumoral microvessel density in mammary carcinomas, irrespective of the manner by which Se was provided: continuous exposure (7-wk feeding) with a chemoprevention protocol or acute bolus exposure (3 d) after carcinomas had established. Compared with the untreated controls, significantly lower levels of vascular endothelial growth factor expression were observed in a sizeable proportion of the Se-treated carcinomas. In contrast to the mammary carcinomas, the microvessel density of the uninvolved mammary glands was not altered by Se treatment. In cell culture, direct exposure of human umbilical vein endothelial cells to Se induced cell death predominantly through apoptosis, decreased the gelatinolytic activities of matrix metalloproteinase-2, or both. These results indicate a potential for Se metabolites to inhibit key attributes (proliferation, survival, and matrix degradation) of endothelial cells critical for angiogenic sprouting. Therefore, inhibition of angiogenesis associated with cancer may be a novel mechanism for the anticancer activity of Se in vivo, and multiple mechanisms are probably involved in mediating the anti-angiogenic activity.
微量元素营养素硒（Se）已被证明在动物模型和人类中均具有防癌活性，但其发生机制仍有待阐明。由于血管生成对于实体癌的发生和生长至关重要，因此在本文所述的研究中，我们探讨了硒可能至少部分通过抑制癌症相关血管生成来发挥其防癌活性的假说。研究了化学预防水平的硒对1-甲基-1-亚硝基脲诱导的大鼠乳腺癌瘤内微血管密度和血管内皮生长因子表达的影响，以及对体外人脐静脉内皮细胞增殖、存活和基质金属蛋白酶活性的影响。通过富含硒的大蒜、亚硒酸钠或硒甲基硒代半胱氨酸增加硒摄入量，均可导致乳腺癌瘤内微血管密度显著降低，而与硒的提供方式无关：采用化学预防方案持续暴露（7周喂养）或在癌瘤形成后急性大剂量暴露（3天）。与未处理的对照组相比，在相当比例的经硒处理的癌瘤中观察到血管内皮生长因子表达水平显著降低。与乳腺癌不同，未受累乳腺的微血管密度并未因硒处理而改变。在细胞培养中，人脐静脉内皮细胞直接暴露于硒主要通过凋亡诱导细胞死亡，降低基质金属蛋白酶-2的明胶分解活性，或两者兼而有之。这些结果表明硒代谢产物有可能抑制对血管生成芽至关重要的内皮细胞的关键特性（增殖、存活和基质降解）。因此，抑制与癌症相关的血管生成可能是硒在体内抗癌活性的一种新机制，并且可能涉及多种机制来介导其抗血管生成活性。
