Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis
Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis
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DOI：
10.1038/onc.2010.49
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发表时间：
2010-05-01
期刊：
影响因子：
8
通讯作者：
Lopez-Otin, C.
中科院分区：
文献类型：
--
作者：
El Hour, M.;Moncada-Pazos, A.;Lopez-Otin, C.
ADAMTS（一个具有血小板反应蛋白基元的崩解素和金属蛋白酶结构域）构成了一个与基质金属蛋白酶相关的内肽酶家族。这些蛋白酶在很大程度上与组织重塑和血管生成相关的生理和病理过程有关。为了阐明ADAMTS-12的体内功能，我们产生了一个敲除小鼠品系（Adamts12(-/-)），其中Adamts12基因被删除。突变小鼠妊娠正常，在生长、寿命和生育能力方面无明显缺陷。通过对Adamts12（-/-）小鼠进行三种不同的体内血管生成模型（恶性角化细胞移植、基质塞和主动脉环试验），我们提供了这种宿主酶对血管生成和癌症进展的保护作用的证据。在缺乏Adamts-12的情况下，血管生成反应和肿瘤对宿主组织的侵袭均增加。利用过表达人ADAMTS-12细胞的培养基获得互补结果，在主动脉环实验中，ADAMTS-12抑制血管生长。ADAMTS-12的血管抑制作用与酶活性无关，因为在主动脉环实验中，这种酶的突变失活形式在抑制内皮细胞发芽方面与野生型相似。总之，我们的研究结果表明，ADAMTS-12具有抗血管生成特性，并保护宿主免受肿瘤进展。中华肿瘤杂志（2010）29,3025-3032；doi: 10.1038 / onc.2010.49;2010年3月8日在线发布
ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) constitute a family of endopeptidases related to matrix metalloproteinases. These proteases have been largely implicated in tissue remodeling and angiogenesis associated with physiological and pathological processes. To elucidate the in vivo functions of ADAMTS-12, we have generated a knockout mouse strain (Adamts12(-/-)) in which Adamts12 gene was deleted. The mutant mice had normal gestations and no apparent defects in growth, life span and fertility. By applying three different in vivo models of angiogenesis (malignant keratinocyte transplantation, Matrigel plug and aortic ring assays) to Adamts12(-/-) mice, we provide evidence for a protective effect of this host enzyme toward angiogenesis and cancer progression. In the absence of Adamts-12, both the angiogenic response and tumor invasion into host tissue were increased. Complementing results were obtained by using medium conditioned by cells overexpressing human ADAMTS-12, which inhibited vessel outgrowth in the aortic ring assay. This angioinhibitory effect of ADAMTS-12 was independent of its enzymatic activity as a mutated inactive form of the enzyme was similarly efficient in inhibiting endothelial cell sprouting in the aortic ring assay than the wild-type form. Altogether, our results show that ADAMTS-12 displays antiangiogenic properties and protect the host toward tumor progression. Oncogene (2010) 29, 3025-3032; doi:10.1038/onc.2010.49; published online 8 March 2010