Hsu S C, Volpert O V, Steck P A, Mikkelsen T, Polverini P J, Rao S, Chou P, Bouck N P
Department of Microbiology-Immunology, R.H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Cancer Res. 1996 Dec 15;56(24):5684-91.
Glioblastoma multiforme is distinguished from its less malignant astrocytoma precursors by intense angiogenesis and frequent loss of tumor suppressor genes on chromosome 10. Here we link these traits by showing that when a wild-type chromosome 10 was returned to any of three human glioblastoma cell lines U251, U87, or LG11, they lost their ability to form tumors in nude mice and switched to an antiangiogenic phenotype, as measured by the inhibition of capillary endothelial cell migration and of corneal neovascularization. This change in angiogenesis was directly due to the increased secretion of a potent inhibitor of angiogenesis, thrombospondin-1, because: (a) neutralizing thrombospondin completely relieved the inhibition; (b) the inhibitory activity of thrombospondin was not dependent on transforming growth factor beta; and (c) chromosome 10 introduction did not alter secreted inducing activity. The inducing activity was dependent on vascular endothelial cell growth factor and had an ED50 of 10 microg/ml in media conditioned by parental cells and 9-13 microg/ml in media conditioned by chromosome 10 revertants. Normal human astrocytes were also antiangiogenic due to secreted thrombospondin. The effect of chromosome 10 on thrombospondin production in vitro was reflected in patient material. Normal brain and lower grade astrocytomas known to retain chromosome 10 stained strongly for thrombospondin, but 12 of 13 glioblastomas, the majority of which lose chromosome 10, did not. These data indicate that the loss of tumor suppressors on chromosome 10 contributes to the aggressive malignancy of glioblastomas in part by releasing constraints on angiogenesis that are maintained by thrombospondin in lower grade tumors.
多形性胶质母细胞瘤与恶性程度较低的星形细胞瘤前体的区别在于其强烈的血管生成以及10号染色体上肿瘤抑制基因的频繁缺失。在此，我们通过以下研究将这些特征联系起来：当将野生型10号染色体导入三种人类胶质母细胞瘤细胞系U251、U87或LG11中的任何一种时，这些细胞系在裸鼠中失去了形成肿瘤的能力，并转变为抗血管生成表型，这通过抑制毛细血管内皮细胞迁移和角膜新生血管形成来衡量。血管生成的这种变化直接归因于血管生成强效抑制剂血小板反应蛋白-1分泌的增加，原因如下：(a) 中和血小板反应蛋白可完全解除抑制作用；(b) 血小板反应蛋白的抑制活性不依赖于转化生长因子β；(c) 导入10号染色体并未改变分泌的诱导活性。诱导活性依赖于血管内皮细胞生长因子，在亲本细胞条件培养基中的ED50为10μg/ml，在10号染色体回复细胞条件培养基中的ED50为9 - 13μg/ml。正常人类星形胶质细胞也因分泌血小板反应蛋白而具有抗血管生成作用。10号染色体对体外血小板反应蛋白产生的影响在患者材料中也有体现。已知保留10号染色体的正常脑和低级别星形细胞瘤对血小板反应蛋白染色强烈，但13例胶质母细胞瘤中有12例未染色，其中大多数失去了10号染色体。这些数据表明，10号染色体上肿瘤抑制因子的缺失部分地通过解除血小板反应蛋白在低级别肿瘤中对血管生成的限制，从而导致胶质母细胞瘤的侵袭性恶性发展。
