Hu Min, Peluffo Guillermo, Chen Haiyan, Gelman Rebecca, Schnitt Stuart, Polyak Kornelia
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3372-7. doi: 10.1073/pnas.0813306106. Epub 2009 Feb 13.
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-kappaB pathway as one of the mediators of stromal fibroblast-derived signals regulating COX-2 expression in tumor epithelial cells. Inhibition of NF-kappaB 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-kappaB and prostaglandin signaling pathways might be used for the treatment and prevention of breast cancer.
上皮-基质细胞相互作用在乳腺肿瘤进展中起重要作用，但这些作用背后的分子机制才刚刚开始被了解。我们之前通过人导管原位癌（DCIS）的异种移植模型描述了成纤维细胞促进DCIS进展为浸润性乳腺癌，而正常肌上皮细胞则抑制这一过程。在此，我们报告成纤维细胞促进肿瘤生长和进展的作用至少部分归因于其与肿瘤上皮细胞相互作用引发的肿瘤上皮细胞中COX-2表达增加。DCIS异种移植中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浸润性组织学特征。给荷瘤小鼠施用选择性COX-2抑制剂塞来昔布可降低异种移植肿瘤重量并抑制其向浸润的进展。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能力，这种变化与MMP14表达增加和MMP9蛋白酶活性增强有关。我们确定NF-κB途径是调节肿瘤上皮细胞中COX-2表达的基质成纤维细胞衍生信号的介质之一。抑制NF-κB和COX-2活性以及下调MMP9表达可减弱成纤维细胞的促侵袭作用。这些发现支持COX-2在促进DCIS进展为浸润性乳腺癌中起作用，并表明对NF-κB和前列腺素信号通路进行治疗性靶向可能用于乳腺癌的治疗和预防。
