Macrophages promote matrix protrusive and invasive function of breast cancer cells via MIP-1β dependent upregulation of MYO3A gene in breast cancer cells
Macrophages promote matrix protrusive and invasive function of breast cancer cells via MIP-1β dependent upregulation of MYO3A gene in breast cancer cells
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DOI：
10.1080/2162402x.2016.1196299
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Bhadauria, Smrati
中科院分区：
文献类型：
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作者：
Baghel, Khemraj Singh;Tewari, Brij Nath;Bhadauria, Smrati
肿瘤细胞转移的潜力在很大程度上取决于其微环境，或与局部成分的“生态位”相互作用。肿瘤相关巨噬细胞（TAM）是肿瘤基质中最丰富的亚群，是肿瘤微环境的关键组成部分。癌细胞与邻近TAM的动态相互作用通过需要更好阐明的细胞间信号传导网络积极驱动癌症进展和转移转化。因此，目前的研究计划辨别旁分泌通信网络之间的TAM，乳腺癌细胞之间的操作，特别是癌细胞的侵袭和传播到遥远的网站。在这里，我们报告了MIP-1 β在增强转移性乳腺癌MDA-MB-231和MDA-MB-468细胞侵袭潜力中的作用。此外，转移性差的MCF-7细胞也被MIP-1 β侵袭。MIP-1 β驱动的癌细胞侵袭依赖于MYO 3A基因表达水平的上调，MYO 3A基因编码一种非常规的肌球蛋白超家族蛋白，含有激酶结构域。采用鸡胚模型和体内Syngenic 4 T1/BALB/c小鼠模型的体外研究进一步证实了上述体外发现，从而证实了其生理相关性。一致地，人乳腺癌标本显示MIP-1 β和MYO 3A的mRNA表达水平之间存在显著相关性。MIP-1 β和MYO 3A均与MMP 9（癌细胞侵袭的既定分子决定因素）呈正相关。这些基因的高表达与乳腺癌患者的生存率低相关。总的来说，这些结果指向迄今为止未公开的MIP-1 β/MYO 3A轴在转移期间起作用，其中巨噬细胞衍生的MIP-1 β通过上调癌细胞内的MYO 3A基因而增强癌细胞侵袭和转移。我们的研究揭示了为乳腺癌的有效临床管理设计潜在的抗转移策略的机会。
The potential of a tumor cell to metastasize profoundly depends on its microenvironment, or "niche" interactions with local components. Tumor-associated-macrophages (TAMs) are the most abundant subpopulation of tumor stroma and represent a key component of tumor microenvironment. The dynamic interaction of cancer cells with neighboring TAMs actively drive cancer progression and metastatic transformation through intercellular signaling networks that need better elucidation. Thus, current study was planned for discerning paracrine communication networks operational between TAMs, and breast cancer cells with special reference to cancer cell invasion and dissemination to distant sites. Here, we report role of MIP-1 beta in enhancing invasive potential of metastatic breast cancer MDA-MB-231 and MDA-MB-468 cells. In addition, the poorly metastatic MCF-7 cells were also rendered invasive by MIP-1 beta. The MIP-1 beta-driven cancer cell invasion was dependent on upregulated expression levels of MYO3A gene, which encodes an unconventional myosin super-family protein harboring a kinase domain. Ex ovo study employing Chick-embryo-model and in vivo Syngenic 4T1/BALB/c mice-model further corroborated aforementioned in vitro findings, thereby substantiating their physiological relevance. Concordantly, human breast cancer specimen exhibited significant association between mRNA expression levels of MIP-1 beta and MYO3A. Both, MIP-1 beta and MYO3A exhibited positive correlation with MMP9, an established molecular determinant of cancer cell invasion. Higher expression of these genes correlated with poor survival of breast cancer patients. Collectively, these results point toward so far undisclosed MIP-1 beta/ MYO3A axis being operational during metastasis, wherein macrophage-derived MIP-1 beta potentiated cancer cell invasion and metastasis via up regulation of MYO3A gene within cancer cells. Our study exposes opportunities for devising potential anti-metastatic strategies for efficient clinical management of breast cancer.