Primary breast myopithelial cells exert an invasion-suppressor effect on breast cancer cells via paracrine down-regulation of MMP expresssion in fibroblasts and tumour cells
Primary breast myopithelial cells exert an invasion-suppressor effect on breast cancer cells via paracrine down-regulation of MMP expresssion in fibroblasts and tumour cells
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DOI：
10.1002/path.1483
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发表时间：
2003-12-01
影响因子：
7.3
通讯作者：
Walker, RA
中科院分区：
文献类型：
--
作者：
Jones, JL;Shaw, JA;Walker, RA
在正常乳腺和导管原位癌中，肌上皮细胞形成不完整的层，将上皮隔室与基质环境分开。肌上皮-基底膜（BM）界面的渗透标志着向浸润性疾病的转变。参与肿瘤侵袭的一种机制是基质金属蛋白酶（MMP）对细胞外基质的破坏。据推测，肌上皮细胞可能通过控制MMP基因表达来调节肿瘤侵袭，在肿瘤细胞和导管周围成纤维细胞中。为了研究这一点，从正常乳腺的肌上皮细胞进行纯化和表征，并评估其对肿瘤细胞侵袭潜力的影响。单独培养或与原代正常乳腺成纤维细胞组合培养的乳腺癌细胞对MMP基因表达的影响也使用具有ELISA定量的RTPCR进行分析，使用酶谱分析来测量酶活性。当正常乳腺肌上皮细胞单独培养或在成纤维细胞群存在下培养时，它们显著降低了乳腺癌细胞系MCF-7、T47 D、MDA-MB 231和MDA-MB 468的侵袭。侵袭性降低与MMP基因表达的变化相关。在那些表达MMP的肿瘤细胞中，MMP-2（MDA-MB 468，p < 0.001）、MMP-9（MDA-MB 231，p = 0.05; MDA-MB 468，p < 0.001）和MT 1-MMP（MDA-MB 231和MDA-MB 468均p < 0.001）显著下调。肌上皮细胞也引起MMP基因表达的显着下降，在共培养的成纤维细胞。此外，这与通过酶谱法鉴定的明胶分解活性降低有关。这项研究首次证明，来自正常乳腺的原代肌上皮细胞减少了乳腺癌细胞的侵袭，这是通过调节肿瘤细胞和成纤维细胞功能介导的。这强调了肌上皮细胞在控制乳腺微环境中的重要性，并关注了随着疾病进展该群体损失的潜在意义。版权所有（C）2003约翰威利父子有限公司。
In normal breast and ductal carcinoma in situ, myoepithelial cells form an incomplete layer separating the epithelial compartment from the stromal environment. Transition to invasive disease is marked by penetration of the myoepithelial-basement membrane (BM) interface. One mechanism involved in tumour invasion is breakdown of extracellular matrices by matrix metalloproteinases (MMPs). It was hypothesized that myoepithelial cells may modulate tumour invasion by controlling MMP gene expression, both in tumour cells and in peri-ductal fibroblasts. To investigate this, myoepithelial cells from normal breast were purified and characterized and their effect on tumour cell invasive potential was assessed. The effect on MMP gene expression of breast cancer cells cultured alone or in combination with primary normal breast fibroblasts was also analysed using RTPCR with ELISA quantitation, with zymographic analysis to measure enzyme activity. Normal breast myoepithelial cells significantly reduced invasion by the breast cancer cell lines MCF-7, T47D, MDA-MB 231, and MDA-MB 468 when they were cultured alone or in the presence of a fibroblast population. Reduced invasion was associated with changes in MMP gene expression. In those tumour cells expressing MMP, there was a significant down-regulation of MMP-2 (MDA-MB 468, p < 0.001), MMP-9 (MDA-MB 231, p = 0.05; MDA-MB 468, p < 0.001), and MT1-MMP (p < 0.001 for both MDA-MB 231 and MDA-MB 468). Myoepithelial cells also caused a significant decrease in MMP gene expression in cocultured fibroblasts. Furthermore, this was associated with reduced gelatinolytic activity as identified by zymography. This study demonstrates for the first time that primary myoepithelial cells from normal breast reduce breast cancer cell invasion and that this is mediated via modulation of both tumour cell and fibroblast function. This emphasizes the importance of the myoepithelial cell in controlling the breast microenvironment and focuses on the potential significance of the loss of this population with disease progression. Copyright (C) 2003 John Wiley Sons, Ltd.