The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter
The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter
复制标题
DOI：
10.1038/sj.onc.1203347
复制
发表时间：
2000-02-21
期刊：
影响因子：
8
通讯作者：
Werb, Z
中科院分区：
文献类型：
--
作者：
Sternlicht, MD;Bissell, MJ;Werb, Z
细胞外基质降解基质金属蛋白酶（MMPs）在上皮癌中总是上调，并且是血管生成、侵袭和转移的关键激动剂。然而，大多数MMPs不是由癌细胞本身分泌的，而是由肿瘤块内和周围的基质细胞分泌的。由于基质环境可以影响肿瘤形成，并且由于MMPs可以改变这种环境，因此MMPs也可能有助于癌症发展的初始阶段。最近在MMP过度表达和MMP缺陷小鼠中的几项研究支持这种可能性，但需要致癌物或预先存在的致癌突变来启动肿瘤发生。在这里，我们回顾了自发发展的癌前病变和恶性病变的转基因小鼠的乳腺表达的自激活形式的MMP 3/基质分解素-1的乳清酸性蛋白基因启动子的控制下。这些变化在非转基因同窝仔中不存在，并且通过共表达人金属蛋白酶组织抑制剂-1（TIMP-1）转基因而淬灭。因此，通过改变细胞微环境，基质溶解素-1可以作为天然肿瘤促进剂并增强癌症易感性。
Extracellular matrix-degrading matrix metalloproteinases (MMPs) ape invariably upregulated in epithelial cancers and are key agonists in angiogenesis, invasion and metastasis. Yet most MMPs are secreted not by the cancer cells themselves, but by stromal cells within and around the tumor mass. Because the stromal environment can influence tumor formation, and because MMPs can alter this environment, MMPs may also contribute to the initial stages of cancer development. Several recent studies in MMP-overexpressing and MMP-deficient mice support this possibility, but have required carcinogens or pre-existing oncogenic mutations to initiate tumorigenesis. Here we review the spontaneous development of premalignant and malignant lesions in the mammary glands of transgenic mice that express an autoactivating form of MMP3/stromelysin-1 under the control of the whey acidic protein gene promoter. These changes were absent in nontransgenic littermates and were quenched by co-expression of a human tissue inhibitor of metalloproteinases-1 (TIMP-1) transgene, Thus by altering the cellular microenvironment, stromelysin-l can act res a natural tumor promoter and enhance cancer susceptibility.