PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells
PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells
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DOI：
10.1016/j.cell.2004.12.018
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发表时间：
2005-02-11
期刊：
影响因子：
64.5
通讯作者：
Kuliopulos, A
中科院分区：
文献类型：
--
作者：
Boire, A;Covic, L;Kuliopulos, A
蛋白水解酶激活受体(PARs)是一类独特的G蛋白偶联受体，在血栓形成、炎症和血管生物学中发挥重要作用。PAR1被认为参与了多种癌症的侵袭和转移过程。然而，负责激活PAR1前侵袭功能的蛋白酶仍有待鉴定。在此，我们证明了在异种移植模型中，PAR1的表达是促进乳腺癌细胞生长和侵袭所必需的，也是充分的。此外，我们还证明了基质金属蛋白酶-1作为PAR1的蛋白酶激动剂，在适当的位置裂解受体以产生依赖于PAR1的钙信号和迁移。基质金属蛋白酶-1的活性来源于成纤维细胞，在乳腺癌细胞中不存在。这些结果表明，间质-肿瘤微环境中的基质金属蛋白酶-1可以通过PAR1改变癌细胞的行为，促进细胞的迁移和侵袭。
Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors that play critical roles in thrombosis, inflammation, and vascular biology. PAR1 is proposed to be involved in the invasive and metastatic processes of various cancers. However, the protease responsible for activating the pro-invasive functions of PAR1 remains to be identified. Here, we show that expression of PAR1 is both required and sufficient to promote growth and invasion of breast carcinoma cells in a xenograft model. Further, we show that the matrix metalloprotease, MMP-1, functions as a protease agonist of PAR1 cleaving the receptor at the proper site to generate PAR1-dependent Ca2+ signals and migration. MMP-1 activity is derived from fibroblasts and is absent from the breast cancer cells. These results demonstrate that MMP-1 in the stromal-tumor microenvironment can alter the behavior of cancer cells through PAR1 to promote cell migration and invasion.