Abstract
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.
Highlights
Cancer metastasis, consisting of dissemination and secondary colonization of cancer cells, is the major cause of cancer-related death
Because more metastasis occurs in unexposed lungs after tumortargeted irradiation, one possibility we speculated is that irradiation may have altered the pulmonary microenvironment remotely so that the lungs become more accommodative to the circulating tumor cells
Considering that CCL5–CCR5 axis is critical for the recruitment of T cells and macrophages, we examined the immunocytes by flow cytometry and found that irradiated control mesenchymal stromal cells (MSCs), but not irradiated sicGAS or siSTING MSCs, could significantly increase the accumulation of macrophages in the lung (Fig. 4f, g)
Summary
Cancer metastasis, consisting of dissemination and secondary colonization of cancer cells, is the major cause of cancer-related death. Radiation therapy is widely used for the management of cancer[1]. Almost half of the cancer patients receive radiotherapy[1]. Radiation therapy was shown to promote tumor metastasis in some mouse models[2]. There is increasing evidence showing that radioresistance is attributed to tumor cells themselves, and to the complex biological interactions between the tumor and its microenvironment. Radiation can results in remodeling in normal tissues, which may facilitate the initiation, invasion and metastasis of cancer cells[3].
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