Neurotrophin-3 modulates breast cancer cells and the microenvironment to promote the growth of breast cancer brain metastasis.
Neurotrophin-3 modulates breast cancer cells and the microenvironment to promote the growth of breast cancer brain metastasis.
复制标题
DOI：
10.1038/onc.2012.417
复制
发表时间：
2013-08-29
期刊：
影响因子：
8
通讯作者：
Chen, El
中科院分区：
文献类型：
--
作者：
Louie, E.;Chen, X. F.;Coomes, A.;Ji, K.;Tsirka, S.;Chen, El
转移是一个高度特异性的过程，在分子和生化水平上仍未完全表征。尽管弥散性癌细胞有能力向远处组织内转移，但长期以来人们一直认为，只有有限的靶器官会发生临床上明显的转移。因此，弥散性癌细胞对外来组织微环境的后续适应决定了这些细胞的转移潜伏期和组织趋向性。因此，研究播散性癌细胞与邻近基质细胞之间的相互作用将以组织特异性的方式更好地理解是什么构成了对播散性癌细胞有利或不利的微环境。先前，我们报道了脑转移的蛋白质特征，显示脑转移性乳腺癌细胞抵抗氧化应激的能力增强。在这项研究中，我们发现另一种来自脑转移蛋白特征的蛋白质，神经营养因子-3 (NT-3)，具有调节转移性乳腺癌细胞的转移生长和减少大脑免疫反应激活的双重功能。更重要的是，转移性乳腺癌细胞中NT-3分泌的增加导致间充质样（EMT）状态向上皮样（MET）状态的逆转，反之亦然。NT-3在emt样乳腺癌细胞中的异位表达降低了其迁移能力，增加了细胞-细胞交界处HER2（人表皮生长因子受体2）和E-cadherin的表达。此外，内源性和异位表达NT-3都减少了完全激活的细胞毒性小胶质细胞的数量。总之，NT-3似乎通过促进转移性乳腺癌细胞的再上皮化和下调小胶质细胞的细胞毒性反应来促进脑转移性乳腺癌细胞的生长。最重要的是，我们的研究结果为HER2阳性乳腺癌患者中枢神经系统大转移的潜伏期和发展提供了新的见解，并为HER2阳性乳腺癌脑转移靶向HER2信号提供了机制依据。
Metastasis, which remains incompletely characterized at the molecular and biochemical levels, is a highly specific process. Despite the ability of disseminated cancer cells to intravasate into distant tissues, it has been long recognized that only a limited subset of target organs develop clinically overt metastases. Therefore, subsequent adaptation of disseminated cancer cells to foreign tissue microenvironment determines the metastatic latency and tissue tropism of these cells. As a result, studying interactions between the disseminated cancer cells and the adjacent stromal cells will provide a better understanding of what constitutes a favorable or unfavorable microenvironment for disseminated cancer cells in a tissue-specific manner. Previously, we reported a protein signature of brain metastasis showing increased ability of brain metastatic breast cancer cells to counteract oxidative stress. In this study, we showed that another protein from the brain metastatic protein signature, neurotrophin-3 (NT-3), has a dual function of regulating the metastatic growth of metastatic breast cancer cells and reducing the activation of immune response in the brain. More importantly, increased NT-3 secretion in metastatic breast cancer cells results in a reversion of mesenchymal-like (EMT) state to epithelial-like (MET) state and vice versa. Ectopic expression of NT-3 in EMT-like breast cancer cells reduces their migratory ability and increases the expression of HER2 (human epidermal growth factor receptor 2) and E-cadherin at the cell–cell junction. In addition, both endogenous and ectopic expression of NT-3 reduced the number of fully activated cytotoxic microglia. In summary, NT-3 appears to promote growth of metastatic breast cancer cells in the brain by facilitating the re-epithelialization of metastatic breast cancer cells and downmodulating the cytotoxic response of microglia. Most importantly, our results provide new insights into the latency and development of central nervous system macrometastases in patients with HER2-positive breast tumors and provide mechanistic rationale to target HER2 signaling for HER2-positive breast cancer brain metastasis.
登录
查看更多内容
DOI：
10.1186/bcr2773
发表时间：
2010
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Louie E;Nik S;Chen JS;Schmidt M;Song B;Pacson C;Chen XF;Park S;Ju J;Chen EI
通讯作者：
Chen EI
影响因子：
4
作者：
Fitzgerald, Daniel P.;Palmieri, Diane;Hua, Emily;Hargrave, Elizabeth;Herring, Jeanne M.;Qian, Yongzhen;Vega-Valle, Eleazar;Weil, Robert J.;Stark, Andreas M.;Vortmeyer, Alexander O.;Steeg, Patricia S.
通讯作者：
Steeg, Patricia S.
影响因子：
3.8
作者：
Cameron, David;Casey, Michelle;Geyer, Charles E.
通讯作者：
Geyer, Charles E.
影响因子：
11.2
作者：
Chaffer, Christine L.;Brennan, Janelle P.;Williams, Elizabeth D.
通讯作者：
Williams, Elizabeth D.
影响因子：
37.3
作者：
Chao YL;Shepard CR;Wells A
通讯作者：
Wells A