Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells.
Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells.
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DOI：
10.1158/0008-5472.can-08-0643
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Roberts DD
中科院分区：
文献类型：
--
作者：
Martin-Manso G;Galli S;Ridnour LA;Tsokos M;Wink DA;Roberts DD
血小板反应蛋白-1（TSP 1）对肿瘤生长的抑制通常归因于其抗血管生成活性，但也应考虑对肿瘤免疫的影响。我们发现，在黑色素瘤细胞中过度表达TSP 1增加了巨噬细胞向裸鼠或米色/裸鼠中生长的异种移植瘤中的募集。在体外，TSP 1急性诱导单核细胞表达纤溶酶原激活物抑制剂-1（派-1），表明TSP 1诱导的巨噬细胞募集至少部分由派-1介导。肿瘤相关巨噬细胞可以促进或限制肿瘤进展。在表达TSP 1的肿瘤中，表达诱导型一氧化氮合酶的M1极化巨噬细胞的百分比增加。此外，可溶性TSP 1通过释放活性氧刺激干扰素-γ分化的U937细胞体外杀伤乳腺癌和黑素瘤细胞。TSP 1通过其N-末端区域与α6β1整联蛋白相互作用，导致分化的单核细胞中佛波酯介导的超氧化物生成显著增加。血小板反应蛋白-2的N-末端结构域也刺激单核细胞产生超氧化物。细胞外钙是TSP 1诱导的巨噬细胞呼吸爆发所必需的。因此，TSP 1可能通过增强M1肿瘤相关巨噬细胞的募集和激活在抗肿瘤免疫中发挥重要作用，这为肿瘤进展期间TSP 1和血小板反应蛋白-2表达的丧失提供了额外的选择性压力。
Inhibition of tumor growth by thrombospondin-1 (TSP1) is generally attributed to its anti-angiogenic activity, but effects on tumor immunity should also be considered. We show that over-expression of TSP1 in melanoma cells increases macrophage recruitment into xenograft tumors grown in nude or beige/nude mice. In vitro, TSP1 acutely induces expression of plasminogen activator inhibitor-1 (PAI-1) by monocytic cells, suggesting that TSP1-induced macrophage recruitment is at least partially mediated by PAI-1. Tumor-associated macrophages can either promote or limit tumor progression. The percentage of M1 polarized macrophages expressing inducible nitric oxide synthase is increased in TSP1-expressing tumors. Furthermore, soluble TSP1 stimulates killing of breast carcinoma and melanoma cells by interferon-γ-differentiated U937 cells in vitro via release of reactive oxygen species. TSP1 causes a significant increase in phorbol ester-mediated superoxide generation from differentiated monocytes by interaction with α6β1 integrin through its N-terminal region. The N-terminal domain of thrombospondin-2 also stimulates monocyte superoxide production. Extracellular calcium is required for the TSP1-induced macrophage respiratory burst. Thus, TSP1 may play an important role in anti-tumor immunity by enhancing recruitment and activation of M1 tumor-associated macrophages, which provides an additional selective pressure for loss of TSP1 and thrombospondin-2 expression during tumor progression.