Role of COX-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast
Role of COX-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast
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DOI：
10.1073/pnas.0813306106
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发表时间：
2009-03-03
影响因子：
11.1
通讯作者：
Polyak, Kornelia
中科院分区：
文献类型：
--
作者：
Hua, Min;Peluffo, Guillermo;Polyak, Kornelia
上皮-基质细胞相互作用在乳腺肿瘤进展中发挥重要作用，但这些作用背后的分子机制才刚刚开始被了解。我们之前通过使用人类 DCIS 异种移植模型描述了成纤维细胞促进导管原位癌 (DCIS) 进展为浸润性乳腺癌，而正常肌上皮细胞则抑制。在这里，我们报告说，成纤维细胞的肿瘤生长和进展促进作用至少部分归因于肿瘤上皮细胞与成纤维细胞相互作用引起的COX-2表达增加。 DCIS 异种移植物中 COX-2 的上调导致 VEGF 和 MMP14 表达增加，这可能导致表达 COX-2 的肿瘤重量更大且具有侵袭性组织学特征。给荷瘤小鼠施用塞来昔布（一种选择性 COX-2 抑制剂）可降低异种移植肿瘤重量并抑制侵袭进展。成纤维细胞与 DCIS 上皮细胞共培养增强了它们的运动性和侵袭性，这种变化与 MMP14 表达和 MMP9 蛋白酶活性增加有关。我们确定 NF-kappa B 通路是基质成纤维细胞衍生信号调节肿瘤上皮细胞中 COX-2 表达的介质之一。抑制 NF-κ B 和 COX-2 活性以及下调 MMP9 表达可减弱成纤维细胞的侵袭促进作用。这些发现支持 COX-2 在促进 DCIS 进展为浸润性乳腺癌中的作用，并表明 NF-κ B 和前列腺素信号通路的治疗靶向可用于治疗和预防乳腺癌。
Epithelial-stromal cell interactions have an important role in breast tumor progression, but the molecular mechanisms underlying these effects are just beginning to be understood. We previously described that fibroblasts promote, whereas normal myoepithelial cells inhibit, the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinomas by using a xenograft model of human DCIS. Here, we report that the tumor growth and progression-promoting effects of fibroblasts are at least in part due to increased COX-2 expression in tumor epithelial cells provoked by their interaction with fibroblasts. Up-regulation of COX-2 in DCIS xenografts resulted in increased VEGF and MMP14 expression, which may contribute to the larger weight and invasive histology of COX-2-expressing tumors. Administration of celecoxib, a selective COX-2 inhibitor, to tumor-bearing mice decreased xenograft tumor weight and inhibited progression to invasion. Coculture of fibroblasts with DCIS epithelial cells enhanced their motility and invasion, and this change was associated with increased MMP14 expression and MMP9 protease activity. We identified the NF-kappa B pathway as one of the mediators of stromal fibroblast-derived signals regulating COX-2 expression in tumor epithelial cells. Inhibition of NF-kappa B and COX-2 activity and down-regulation of MMP9 expression attenuated the invasion-promoting effects of fibroblasts. These findings support a role for COX-2 in promoting the progression of DCIS to invasive breast carcinomas, and suggest that therapeutic targeting of the NF-kappa B and prostaglandin signaling pathways might be used for the treatment and prevention of breast cancer.