IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization
IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization
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DOI：
10.1038/s41467-019-10676-1
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发表时间：
2019-06-21
影响因子：
16.6
通讯作者：
Ernst, Matthias
中科院分区：
文献类型：
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作者：
Eissmann, Moritz F.;Dijkstra, Christine;Ernst, Matthias
肥大细胞在实体恶性肿瘤微环境中的作用仍有争议。在这里，我们从功能上评估肿瘤邻近、粘膜下肥大细胞积聚对小鼠和人肠型胃癌的影响。我们发现肥大细胞的基因消融或治疗性失活可抑制肿瘤相关巨噬细胞的积累，减少肿瘤细胞的增殖和血管生成，并减轻肿瘤负担。肥大细胞被白细胞介素(IL)-33激活，IL -33是肿瘤上皮响应炎症细胞因子IL-11而产生的一种警报素，是小鼠胃癌生长所必需的。因此，消融同源IL-33受体St2限制肿瘤生长，减少肥大细胞依赖性巨噬细胞吸引因子Csf2、Ccl3和ll6的产生和释放。相反，基因或治疗性巨噬细胞消耗减少肿瘤负荷而不影响肥大细胞丰度。因此，肿瘤来源的IL-33维持了肥大细胞和巨噬细胞依赖的信号级联，可用于胃癌的治疗。
The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumorassociated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and ll6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.