SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment
SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment
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SCF介导的肥大细胞浸润和激活加剧肿瘤微环境中的炎症和免疫抑制
DOI：
10.1182/blood-2008-03-147033
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发表时间：
2008-08-15
期刊：
影响因子：
20.3
通讯作者：
Feng, Zuo-Hua
中科院分区：
文献类型：
--
作者：
Huang, Bo;Lei, Zhang;Feng, Zuo-Hua
尽管有证据表明炎症在癌症发生、促进和进展中的作用，但肿瘤内炎症由炎性细胞协调的确切机制仍有待确定。在这里，我们报告，肿瘤浸润肥大细胞重塑肿瘤微环境，促进肿瘤生长。肿瘤中肥大细胞的浸润和活化主要由肿瘤源性干细胞因子（SCF）及其受体c-Kit介导。低浓度SCF可有效诱导肥大细胞的趋化性迁移。高浓度SCF激活的肿瘤浸润性肥大细胞表达多种促炎因子，并增加肿瘤中IL-17的表达。肿瘤细胞NF-κ B B和AP-1的活性在肥大细胞重塑的炎症微环境中增强。SCF激活的肥大细胞还通过释放腺苷和增加T调节细胞而加剧肿瘤免疫抑制，这增强了肿瘤中T细胞和自然杀伤细胞的抑制。这些发现强调了肿瘤微环境的重塑实际上可以由肿瘤细胞释放的SCF启动，并表明肥大细胞不仅是肿瘤微环境中的炎症和免疫抑制的重要调节因子，而且是肿瘤微环境中的炎症和免疫抑制的重要调节因子。
Despite the evidence for the role of inflammation in cancer initiation, promotion, and progression, the precise mechanism by which the inflammation within tumor is orchestrated by inflammatory cells remains to be determined. Here, we report that tumor-infiltrating mast cells remodel tumor microenvironment and promote tumor growth. Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. Low concentrations of SCF efficiently induced the chemotactic migration of mast cells. Tumor-infiltrating mast cells, activated by higher concentrations of SCF, expressed multiple proinflammatory factors and increased IL-17 expression in tumors. The activity of NF-kappa B and AP-1 in tumor cells was intensified in the mast cell-remodeled inflammatory microenvironment. SCF-activated mast cells also exacerbated tumor immunosuppression by releasing adenosine and increasing T regulatory cells, which augmented the suppression of T cells and natural killer cells in tumors. These findings emphasize that the remodeling of the tumor microenvironment can actually be initiated by tumor cell-ireleased SCF and suggest that mast cells are not only a participator but also a critical regulator of inflammation and immunosuppression in the tumor microenvironment.