Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model
Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model
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DOI：
10.1073/pnas.97.8.3884
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发表时间：
2000-04-11
影响因子：
11.1
通讯作者：
Moses, MA
中科院分区：
文献类型：
--
作者：
Fang, JM;Shing, Y;Moses, MA
肿瘤发生过程中最早和最重要的阶段是血管生成过程的激活，这一事件被称为“向血管生成表型的转变”。“我们已经开发出一种体内系统，可以可靠地概括肿瘤发展中代表这种转变的阶段。使用这个模型，我们已经收获和研究肿瘤结节，可以区分彼此的基础上，他们的血管化程度。血管生成性肿瘤结节的特点是存在毛细血管的因子VIII免疫组化，血管生成和蛋白水解活性在体外。与此相反，血管生成前结节缺乏微血管，并在体外表现出很少的血管生成或蛋白水解活性。添加特定的金属蛋白酶抑制剂导致在废除的血管生成和蛋白水解活性的血管生成结节在体外。比较底物凝胶电泳检测到一个突出的基质金属蛋白酶（MMP-2）的存在下，在血管生成的结节相比，血管生成前的。MMP-2活性的抑制反义寡核苷酸在血管结节中导致在体外和体内的鸡胚绒毛尿囊膜测定中的血管生成潜力的损失。此外，这种抑制MMP-2活性的血管生成结节抑制肿瘤生长在体内约70%。这些结果强烈暗示MMP-2的活性是转换为血管生成表型的必要条件，并验证了该模型作为一种可靠的和可重复的工具，通过该模型可以研究血管生成表型获得中涉及的其他细胞和生化因子。
Among the earliest and most important stages during tumorigenesis is the activation of the angiogenic process, an event that is termed the "switch to the angiogenic phenotype." We have developed an in vivo system that can reliably recapitulate the stages in tumor development that represent this transition. Using this model, we have harvested and studied tumor nodules that can be distinguished from each other on the basis of their degree of vascularization. Angiogenic tumor nodules were characterized by the presence of capillary vessels as determined by factor VIII immunohistochemistry, and both angiogenic and proteolytic activities in vitro. In contrast, preangiogenic nodules were devoid of microvessels and showed little angiogenic or proteolytic activity in vitro. Addition of a specific metalloproteinase inhibitor resulted in the abrogation of both angiogenic and proteolytic activities of the angiogenic nodules in vitro. Comparative substrate gel electrophoresis detected the presence of a prominent matrix metalloproteinase (MMP-2) in the angiogenic nodules when compared with the preangiogenic ones. Suppression of MMP-2 activity by antisense oligonucleotides in the vascular nodules resulted in the loss of angiogenic potential both in vitro and in vivo in the chick chorioallantoic membrane assay. Moreover, this suppression of MMP-2 activity in angiogenic nodules inhibited tumor growth in vivo by approximately 70%. These results strongly implicate the activity of MMP-2 as a requirement for the switch to the angiogenic phenotype and validate this model as a reliable and reproducible tool by which to study other cellular and biochemical factors involved in the acquisition of the angiogenic phenotype.