INHIBITION OF ANGIOGENESIS IN HUMAN GLIOBLASTOMAS BY CHROMOSOME-10 INDUCTION OF THROMBOSPONDIN-1

Glioblastoma multiforme is distinguished from its less malignant astro cytoma precursors by intense angiogenesis and frequent loss of tumor s uppressor genes on chromosome 10, Here we link these traits by showing that when a did-type chromosome 10 was returned to any of three human glioblastoma cell lines U251, U87, or LG11, they lost their ability t o form tumors in nude mice and switched to an antiangiogenic phenotype , as measured by the inhibition of capillary endothelial cell migratio n and of corneal neovascularization, This change in angiogenesis was d irectly due to the increased secretion of a potent inhibitor of angiog enesis, thrombospondin-l, because: (a) neutralizing thrombospondin com pletely relieved the inhibition; (b) the inhibitory activity of thromb ospondin 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 growt h factor and had an ED,, of 10 mu g/ml in media conditioned by parenta l cells and 9-13 mu g/ml in media conditioned by chromosome 10 reverta nts, Normal human astrocytes were also antiangiogenic due to secreted thrombospondin, The effect of chromosome 10 on thrombospondin producti on in vitro was reflected in patient material. Normal brain and lower grade astrocytomas known to retain chromosome 10 stained strongly for thrombospondin, but IZ of 13 glioblastomas, the majority of which lose chromosome 10, did not, These data indicate that the loss of tumor su ppressors on chromosome 10 contributes to the aggressive malignancy of glioblastomas in part by releasing constraints on angiogenesis that a re maintained by thrombospondin in lower grade tumors.