Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors
Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors
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DOI：
10.1016/s1535-6108(03)00240-x
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发表时间：
2003-10-01
期刊：
影响因子：
50.3
通讯作者：
Benezra, R
中科院分区：
文献类型：
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作者：
Ruzinova, MB;Schoer, RA;Benezra, R
Id突变小鼠的血管生成缺陷抑制肿瘤异种移植物的生长，为抗血管生成应激提供了遗传模型。我们的工作测试了这种压力对更多生理性 Pten(+/-) 肿瘤进展的影响。尽管血管生成受损，肿瘤仍会生长，但 Id 丢失导致的脉管系统破坏会导致肿瘤细胞缺氧和坏死，其程度取决于肿瘤。我们表明，骨髓源性内皮前体对一些但不是所有 Pten(+/-) 肿瘤的新血管系统有功能性贡献，部分挽救了 Id 突变表型。我们证明，肿瘤内皮细胞中 Id1 的缺失会导致多种促血管生成基因的下调，包括 α6 和 β4 整联蛋白、基质金属蛋白酶 2 和成纤维细胞生长因子受体 1。在体内血管生成测定中，抑制这些因子会导致 Id 的表型丢失。
Angiogenic defects in Id mutant mice inhibit the growth of tumor xenografts, providing a genetic model for antiangiogenic stress. Our work tests the consequences of such stress on progression of more physiological Pten(+/-) tumors. While tumor growth occurs despite impaired angiogenesis, disruption of vasculature by Id loss causes tumor cells to experience hypoxia and necrosis, the extent of which is tumor dependent. We show that bone-marrow-derived endothelial precursors contribute functionally to neovasculature of some but not all Pten(+/-) tumors, partially rescuing Id mutant phenotype. We demonstrate that loss of Id1 in tumor endothelial cells results in downregulation of several proangiogenic genes, including alpha6 and beta4 integrins, matrix metalloprotease-2, and fibroblast growth factor receptor-1. Inhibition of these factors phenocopies loss of Id in in vivo angiogenesis assays.