Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization.
Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization.
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肿瘤细胞激活的 CARD9 信号传导有助于转移相关的巨噬细胞极化。
DOI：
10.1038/cdd.2014.45
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发表时间：
2014-08
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
作者：
巨噬细胞是肿瘤微环境的关键免疫效应细胞，其促进原发性肿瘤和转移部位中肿瘤细胞的接种、外渗和持续生长。肿瘤进展和转移受巨噬细胞亚群特定表型的动态变化的影响;然而，肿瘤细胞调节巨噬细胞极化的机制仍不完全清楚。半胱天冬酶募集结构域蛋白9（CARD 9）是一种重要的天然免疫调节蛋白。我们报道CARD 9表达增加主要位于浸润的巨噬细胞中，并与晚期组织病理学阶段和转移的存在显著相关。使用CARD 9缺陷（CARD 9 −/−）小鼠，我们表明骨髓来源的CARD 9促进结肠癌细胞的肝转移。机制研究表明，CARD 9通过激活核因子-κ B信号通路促进转移相关的巨噬细胞极化而促进肿瘤转移。我们进一步证明，肿瘤细胞分泌的血管内皮生长因子促进巨噬细胞中的脾酪氨酸激酶活化，这是形成CARD 9-B细胞淋巴瘤/白血病10-粘膜相关淋巴组织淋巴瘤易位蛋白1复合物所必需的。总之，我们的结果表明CARD 9是转移相关巨噬细胞的调节剂，这将导致对支持肿瘤转移的微环境演变的新见解，从而为抗癌治疗提供靶点。
Macrophages are critical immune effector cells of the tumor microenvironment that promote seeding, extravasation and persistent growth of tumor cells in primary tumors and metastatic sites. Tumor progression and metastasis are affected by dynamic changes in the specific phenotypes of macrophage subpopulations; however, the mechanisms by which tumor cells modulate macrophage polarization remain incompletely understood. Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens. We report that increased CARD9 expression is primarily localized in infiltrated macrophages and significantly associated with advanced histopathologic stage and the presence of metastasis. Using CARD9-deficient (CARD9−/−) mice, we show that bone marrow-derived CARD9 promotes liver metastasis of colon carcinoma cells. Mechanistic studies reveal that CARD9 contributes to tumor metastasis by promoting metastasis-associated macrophage polarization through activation of the nuclear factor-kappa B signaling pathway. We further demonstrate that tumor cell-secreted vascular endothelial growth factor facilitates spleen tyrosine kinase activation in macrophages, which is necessary for formation of the CARD9–B-cell lymphoma/leukemia 10–mucosa-associated lymphoid tissue lymphoma translocation protein 1 complex. Taken together, our results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis, thereby providing targets for anticancer therapies.
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影响因子：
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作者：
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DOI：
10.1161/atvbaha.110.215814
发表时间：
2011-01
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
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通讯作者：
Kratky D