The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, China.
Cell Death Dis. 2020 May 7;11(5):326. doi: 10.1038/s41419-020-2546-5.
Emerging evidence indicates that mesenchymal stromal cells (MSCs) have an important role in cancer metastasis. Although tumor microenvironment, which includes MSCs and immune cells, can be altered by ionizing radiation (IR), whether irradiation can promote metastasis through MSCs remains unclear. Using the lung colonization model of transplanted 4T1 breast cancer cells, we found an increased lung metastasis in mice exposed to ionizing radiation, even when the thorax was shielded during whole-body irradiation. This radiation-induced lung metastasis can be replicated using irradiated MSCs. cGAS-STING signaling pathway was found to be activated in MSCs, accompanied by upregulation of type I interferon-related genes, including chemokine CCL5. Disruption of cGAS-STING signaling in MSCs abolished their pro-metastatic effect. Deletion of CCL5 in MSCs also abrogated the pro-metastatic effect endowed by IR. Furthermore, we showed that the lung pro-metastatic effect of irradiated MSCs required the presence of macrophages. Our results indicate that radiation-induced alterations in distant mesenchymal stromal cells facilitate cancer metastasis.
新出现的证据表明，间充质基质细胞（MSCs）在癌症转移中具有重要作用。尽管肿瘤微环境（包括 MSCs 和免疫细胞）可以被电离辐射（IR）改变，但辐照是否可以通过 MSCs 促进转移尚不清楚。我们使用移植的 4T1 乳腺癌细胞的肺定植模型发现，即使在全身照射时用胸部屏蔽，接受电离辐射的小鼠肺部转移增加。用辐照的 MSC 可以复制这种辐射诱导的肺转移。在 MSC 中发现 cGAS-STING 信号通路被激活，同时上调 I 型干扰素相关基因，包括趋化因子 CCL5。在 MSC 中破坏 cGAS-STING 信号通路可消除其促转移作用。CCL5 在 MSC 中的缺失也消除了 IR 赋予的促转移作用。此外，我们表明，辐照 MSC 的肺部促转移作用需要巨噬细胞的存在。我们的研究结果表明，辐射诱导的远处间充质基质细胞的改变促进了癌症转移。
