Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis
Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis
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DOI：
10.2353/ajpath.2006.050677
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发表时间：
2006-02-01
影响因子：
6
通讯作者：
Schedin, P
中科院分区：
文献类型：
--
作者：
McDaniel, SM;Rumer, KK;Schedin, P
哺乳后退化期间的乳腺微环境与炎症有相似之处，包括高基质金属蛋白酶活性、纤维状胶原沉积以及纤连蛋白和层粘连蛋白的生物活性片段的释放。由于炎症可以促进肿瘤发生，我们评估了退化腺体的组织微环境是否也是促进性的。细胞外基质分离自未经产大鼠或经历断奶诱导退化的乳腺大鼠的乳腺。使用这些基质作为基质，发现milliparous matrix在三维培养中促进正常乳腺上皮MCF-12 A细胞的导管组织化，并在transwell滤膜测定中抑制乳腺肿瘤MDA-MB-231细胞的侵袭。相反，退化基质不能支持正常细胞中的导管发育，并促进肿瘤细胞的侵袭性。为了评价这些基质对体内转移的影响，将与Matrigel、milliparous基质或退化基质预混的MDA-MB-231细胞注射到裸鼠的乳房脂肪垫中。在退化基质组中，肺、肝和肾的转移增加，并且与肿瘤血管内皮生长因子表达的两倍增加和血管生成增加相关。这些数据表明，乳腺微环境在退化过程中促进肿瘤细胞传播，从而提供了一个合理的机制来解释妊娠相关乳腺癌发生的高转移率。
The mammary gland microenvironment during post-lactational involution shares similarities with inflammation, including high matrix metalloproteinase activity, fibrillar collagen deposition, and release of bioactive fragments of fibronectin and laminin. Because inflammation can promote tumorigenesis, we evaluated whether the tissue microenvironment of the involuting gland is also promotional. Extracellular matrix was isolated from mammary glands of nulliparous rats or rats with mammary glands undergoing weaning-induced involution. Using these matrices as substratum, milliparous matrix was found to promote ductal organization of normal mammary epithelial MCF-12A cells in three-dimensional culture and to suppress invasion of mammary tumor MDA-MB-231 cells in transwell filter assays. Conversely, involution matrix failed to support ductal development in normal cells and promoted invasiveness in tumor cells. To evaluate the effects of these matrices on metastasis in vivo, MDA-MB-231 cells, premixed with Matrigel, milliparous matrix, or involution matrix, were injected into mammary fat pads of nude mice. Metastases to lung, liver, and kidney were increased in the involution matrix group, and correlated with a twofold increase in tumor vascular endothelial growth factor expression and increased angiogenesis. These data suggest that the mammary gland microenvironment becomes promotional for tumor cell dissemination during involution, thus providing a plausible mechanism to explain the high rate of metastases; that occur with pregnancy-associated breast cancer.