Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells
Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells
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DOI：
10.1158/0008-5472.can-05-2082
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Covic, L
中科院分区：
文献类型：
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作者：
Nguyen, N;Kuliopulos, A;Covic, L
基质金属蛋白酶（MMPs）在重塑肿瘤间质微环境中发挥核心作用。我们最近确定基质来源的MMP-1也作为一种信号分子，通过切割蛋白酶激活受体1（PAR 1）引起乳腺癌细胞迁移和侵袭。在这里，我们表明，异位PAR 1表达诱导表达的血管生成因子Cyr 61（CCN 1）在乳腺癌细胞。肿瘤来源的Cyr 61作为一种侵袭性信号分子，诱导MMP-1在相邻基质成纤维细胞中的表达。乳腺癌细胞中Cyr 61的基因沉默抑制基质成纤维细胞中MMP-1的诱导，导致癌细胞向成纤维细胞迁移的主要损失。Cyr 61依赖性迁移损失由外源性MMP-1补充，并且需要乳腺癌细胞上存在功能性PAR 1受体。这些结果表明，通过靶向Cyr 61来中断肿瘤-基质细胞通信。可以为浸润性乳腺癌的治疗提供一种替代的治疗方法。
Matrix metalloproteinases (MMPs) play a central role in remodeling the tumor-stromal microenvironment. We recently determined that stromal-derived MMP-1 also acts as a signaling molecule by cleaving protease-activated receptor 1 (PAR1) to cause breast cancer cell migration and invasion. Here, we show that ectopic PAR1 expression induces expression of the angiogenic factor Cyr61(CCN1) in breast cancer cells. The tumor-derived Cyr61 acts as an invasogenic signaling molecule that induces MMP-1 expression in adjacent stromal fibroblasts. Gene silencing of Cyr61 in breast cancer cells suppresses MMP-1 induction in stromal fibroblasts resulting in a major loss in migration of the cancer cells toward the fibroblasts. Cyr61-dependent loss of migration was complemented by exogenous MMP-1 and required the presence of the functional PAR1 receptor on the breast cancer cells. These results suggest that interrupting tumor-stromal cell communication by targeting Cyr61. may provide an alternative therapeutic approach for the treatment of invasive breast cancer.