Divergent Matrix-Remodeling Strategies Distinguish Developmental from Neoplastic Mammary Epithelial Cell Invasion Programs.
Divergent Matrix-Remodeling Strategies Distinguish Developmental from Neoplastic Mammary Epithelial Cell Invasion Programs.
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DOI：
10.1016/j.devcel.2018.08.025
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发表时间：
2018-10-22
影响因子：
11.8
通讯作者：
Weiss SJ
中科院分区：
文献类型：
--
作者：
Feinberg TY;Zheng H;Liu R;Wicha MS;Yu SM;Weiss SJ
转移性乳腺癌细胞已被假设为动员组织侵入活动，通过增选蛋白水解系统采用的正常乳腺上皮细胞进行分支形态发生。然而，形态发生的关键效应子仍然没有确定，它们与乳腺癌侵袭程序的关系尚未建立。在这里，我们确定的膜锚定的基质金属蛋白酶，Mmp 14/MT 1-MMP，但不是密切相关的蛋白酶，Mmp 15/MT 2-MMP，作为主导的蛋白水解效应的分支形态发生和癌细胞在体内的侵袭。然而，出乎意料的是，上皮细胞特异性靶向的Mmp 14/MT 1-MMP在正常乳腺不能损害分支，而删除癌细胞中的蛋白酶废除入侵，保留基质结构和完全阻断转移。相比之下，在正常乳腺中，只有当Mmp 14/MT 1-MMP表达从导管周围基质中特异性缺失时，细胞外基质重塑和形态发生才被消融。总之，这些发现揭示了重叠，但不同的战略，发展与肿瘤基质重塑计划的基础。乳腺癌细胞被认为是增选蛋白水解系统在发育分支形态发生。Feinberg等人表明，这些过程确实都依赖于相同的蛋白酶MT 1-MMP，但正常的乳腺发育需要基质中的蛋白酶活性，而在癌症中，癌细胞本身驱动侵袭程序。
Metastasizing breast carcinoma cells have been hypothesized to mobilize tissue-invasive activity by co-opting the proteolytic systems employed by normal mammary epithelial cells undergoing branching morphogenesis. However, the critical effectors underlying morphogenesis remain unidentified and their relationship to breast cancer invasion programs have yet to be established. Here we identify the membrane-anchored matrix metalloproteinase, Mmp14/MT1-MMP, but not the closely related proteinase, Mmp15/MT2-MMP, as the dominant proteolytic effector of both branching morphogenesis and carcinoma cell invasion in vivo. Unexpectedly, however, epithelial cell-specific targeting of Mmp14/MT1-MMP in the normal mammary gland fails to impair branching, whereas deleting the proteinase in carcinoma cells abrogates invasion, preserves matrix architecture and completely blocks metastasis. By contrast, in the normal mammary gland, extracellular matrix remodeling and morphogenesis are ablated only when Mmp14/MT1-MMP expression is specifically deleted from the periductal stroma. Together, these findings uncover the overlapping, but divergent strategies that underlie developmental versus neoplastic matrix remodeling programs. Breast carcinoma cells are thought to co-opt proteolytic systems employed during developmental branching morphogenesis. Feinberg et al. show that these processes indeed both depend on the same protease, MT1-MMP, but that normal mammary gland development requires protease activity in the stroma, whereas in cancer, the carcinoma cells themselves drive the invasion program.
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通过IL6/STAT3和NO/Notch交叉交叉信号传导，髓样衍生的抑制细胞赋予乳腺癌细胞类似茎状的质量。
影响因子：
11.2
作者：
Peng D;Tanikawa T;Li W;Zhao L;Vatan L;Szeliga W;Wan S;Wei S;Wang Y;Liu Y;Staroslawska E;Szubstarski F;Rolinski J;Grywalska E;Stanisławek A;Polkowski W;Kurylcio A;Kleer C;Chang AE;Wicha M;Sabel M;Zou W;Kryczek I
通讯作者：
Kryczek I
影响因子：
8
作者：
Lodillinsky, C.;Infante, E.;Chavrier, P.
通讯作者：
Chavrier, P.
影响因子：
64.5
作者：
Cheung KJ;Gabrielson E;Werb Z;Ewald AJ
通讯作者：
Ewald AJ
影响因子：
11.4
作者：
Gutierrez-Fernandez, Ana;Soria-Valles, Clara;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos
影响因子：
64.8
作者：
Fischer KR;Durrans A;Lee S;Sheng J;Li F;Wong ST;Choi H;El Rayes T;Ryu S;Troeger J;Schwabe RF;Vahdat LT;Altorki NK;Mittal V;Gao D
通讯作者：
Gao D