Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth.
Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth.
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DOI：
10.1016/j.celrep.2016.12.079
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发表时间：
2017-01-31
期刊：
影响因子：
8.8
通讯作者：
Kleer CG
中科院分区：
文献类型：
--
作者：
Gonzalez ME;Martin EE;Anwar T;Arellano-Garcia C;Medhora N;Lama A;Chen YC;Tanager KS;Yoon E;Kidwell KM;Ge C;Franceschi RT;Kleer CG
乳腺癌(BC)相关间充质干细胞/多能基质细胞(MSC)增加胶原沉积促进转移，但其机制尚不清楚。在这里，我们报告了胶原受体Discoidin结构域受体2(DDR2)是基质-BC通讯所必需的。在人的BC转移中，DDR2在转移性癌和多潜能间充质基质细胞中一致上调。在从人BC转移中分离的MSCs中，DDR2维持成纤维细胞的表型，并伴有胶原沉积，并诱导BC细胞中DDR2信号的病理性激活。骨髓间充质干细胞中DDR2的缺失会损害其促进BC细胞中DDR2磷酸化的能力，从而影响BC细胞的排列、迁移和转移。Slie突变纯合子的雌性DDR2缺陷小鼠表现出低效的自发性BC转移。这些结果证明了间充质干细胞DDR2在转移中的作用，并建议了一种治疗转移性BC的方法。
Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor Discoidin Domain Receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results document a role for mesenchymal stem cell DDR2 in metastasis, and suggest a therapeutic approach for metastatic BC.