S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β.
S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β.
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DOI：
10.1084/jem.20160392
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发表时间：
2017-09-04
期刊：
影响因子：
--
通讯作者：
Brüne B
中科院分区：
文献类型：
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作者：
Weichand B;Popp R;Dziumbla S;Mora J;Strack E;Elwakeel E;Frank AC;Scholich K;Pierre S;Syed SN;Olesch C;Ringleb J;Ören B;Döring C;Savai R;Jung M;von Knethen A;Levkau B;Fleming I;Weigert A;Brüne B
转移是癌症死亡的主要原因。WeicHand等人的研究。描述一种解释肿瘤相关巨噬细胞如何促进转移扩散的新机制，包括通过S1P受体1和NLRP3炎症体促进肿瘤淋巴管生成。转移是癌症死亡的主要原因。炎性肿瘤微环境有助于转移，例如，通过招募血管和淋巴管。在肿瘤浸润性免疫细胞中，肿瘤相关巨噬细胞(TAMs)在促进肿瘤血管生成和转移方面起着中心作用。我们发现，仅CD11bhi CD206+TAMs中S1P受体1(S1PR1)的基因缺失就可以阻止肺转移和肿瘤淋巴管的生成。在非亲缘关系的甲基胆蒽诱导的纤维肉瘤模型中也观察到淋巴管生成减少。对这两个实体分离的TAM的转录组分析显示，在S1PR1缺陷的TAM中，炎症体成分Nlrp3的表达减少。巨噬细胞依赖的淋巴管生成是在炎性小体激活后触发的，需要S1PR1信号和IL-1β的产生。最后，肿瘤浸润性巨噬细胞中NLRP3的表达与乳腺癌患者的生存、淋巴结侵犯和转移有关。从概念上讲，我们的研究表明，NLRP3炎症小体通过S1PR1信号下游的淋巴管促进巨噬细胞转移的作用尚未被认识。
Metastasis is the primary cause of cancer death. Weichand et al. describe a new mechanism explaining how tumor-associated macrophages contribute to metastatic spread, which involves promoting tumor lymphangiogenesis via S1P receptor 1 and the NLRP3 inflammasome. Metastasis is the primary cause of cancer death. The inflammatory tumor microenvironment contributes to metastasis, for instance, by recruiting blood and lymph vessels. Among tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) take a center stage in promoting both tumor angiogenesis and metastatic spread. We found that genetic deletion of the S1P receptor 1 (S1pr1) alone in CD11bhi CD206+ TAMs infiltrating mouse breast tumors prevents pulmonary metastasis and tumor lymphangiogenesis. Reduced lymphangiogenesis was also observed in the nonrelated methylcholanthrene-induced fibrosarcoma model. Transcriptome analysis of isolated TAMs from both entities revealed reduced expression of the inflammasome component Nlrp3 in S1PR1-deficient TAMs. Macrophage-dependent lymphangiogenesis in vitro was triggered upon inflammasome activation and required both S1PR1 signaling and IL-1β production. Finally, NLRP3 expression in tumor-infiltrating macrophages correlated with survival, lymph node invasion, and metastasis of mammary carcinoma patients. Conceptually, our study indicates an unappreciated role of the NLRP3 inflammasome in promoting metastasis via the lymphatics downstream of S1PR1 signaling in macrophages.
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影响因子：
3.8
作者：
Kelm, JM;Timmins, NE;Nielsen, LK
通讯作者：
Nielsen, LK
影响因子：
4.8
作者：
Brecht, Kerstin;Weigert, Andreas;Bruene, Bernhard
通讯作者：
Bruene, Bernhard
影响因子：
4
作者：
Fleming, I;Fisslthaler, B;Busse, R
通讯作者：
Busse, R
影响因子：
21.1
作者：
Kolb, Ryan;Liu, Guang-Hui;Janowski, Ann M.;Sutterwala, Fayyaz S.;Zhang, Weizhou
通讯作者：
Zhang, Weizhou
影响因子：
64.8
作者：
通讯作者：
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