Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis
Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis
复制标题
DOI：
10.1158/0008-5472.can-05-2560
复制
发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Pause, A
中科院分区：
文献类型：
--
作者：
Kurban, G;Hudon, V;Pause, A
von Hippel-Lindau（VHL）肿瘤抑制基因的失活导致高度血管化的肿瘤，使VHL肿瘤综合征成为研究血管生成机制的理想系统。VHL沿着沿着两条途径发挥作用，第一条途径涉及缺氧诱导因子-α降解及其促血管生成靶基因血管内皮生长因子和血小板衍生生长因子-β的下调，第二条途径促进细胞外基质（ECM）组装。促血管生成因子的分泌被证明是血管生成的主要诱导物。在这里，我们表明，ECM组装的损失与VHL疾病中的肿瘤血管生成相关。在VHL-ECM组装途径失活后，我们观察到高度血管化的肿瘤，具有破坏的ECM，并显示增加的基质金属蛋白酶-2活性。VHL途径的缺失导致缺氧诱导因子-α降解，导致肿瘤中血管内皮生长因子水平增加，但微血管密度低，ECM组装紧密，侵袭能力低。我们的结论是，ECM完整性的丧失可以通过为血管浸润肿瘤提供途径来促进和维持肿瘤血管生成。
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene results in highly vascularized tumors, making the VHL tumor syndrome an ideal system to study the mechanisms of angiogenesis. VHL operates along two pathways with the first involving hypoxia-inducible factor-alpha degradation and down-regulation of its proangiogenic target genes vascular endothelial growth factor and platelet-derived growth factor-beta, and the second pathway promoting extracellular matrix (ECM) assembly. Secretion of proangiogenic factors was shown to be a primary inducer of angiogenesis. Here, we show that loss of ECM assembly correlates with tumor angiogenesis in VHL disease. Upon inactivation of the VHL-ECM assembly pathway, we observe tumors that are highly vascularized, have a disrupted ECM, and show increased matrix metalloproteinase-2 activity. Loss of the VHL pathway leading to hypoxia-inducible factor-alpha degradation results in tumors with increased vascular endothelial growth factor levels but with surprisingly low microvessel density, a tightly assembled ECM and low invasive ability. We conclude that loss of ECM integrity could promote and maintain tumor angiogenesis by providing a route for blood vessels to infiltrate tumors.