A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors.
A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors.
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DOI：
10.18632/oncotarget.1376
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Mañes S
中科院分区：
文献类型：
--
作者：
Mira E;Carmona-Rodríguez L;Tardáguila M;Azcoitia I;González-Martín A;Almonacid L;Casas J;Fabriás G;Mañes S
除了抑制胆固醇生物合成的能力外，他汀类药物还具有多效作用，包括抗炎和免疫调节活性。他汀类药物单独或与其他化疗药物联合治疗癌症具有临床实用性。然而，他汀类药物抗肿瘤活性的机制还不清楚。没有研究分析它们如何改变肿瘤相关的白细胞浸润，这是影响肿瘤基质和癌症演变的核心因素。本研究采用HER 2/neu转基因小鼠（Tg-neu），观察洛伐他汀（Lov）对自发性乳腺肿瘤炎症反应的影响。Lov治疗荷瘤Tg-neu小鼠没有改变已建立肿瘤的生长，但显着减少了这些小鼠中新的致癌病变的数量。此外，Lov抑制免疫活性小鼠新植入的Tg-neu肿瘤的生长，但在免疫缺陷小鼠中则不然。我们发现Lov增强了效应T细胞的肿瘤浸润，并减少了免疫抑制和促血管生成M2样肿瘤相关巨噬细胞（TAM）的数量。同时，该药物改善了肿瘤血管系统的结构和功能，测量为增强的肿瘤氧合和细胞毒性药物的渗透。微阵列分析确定了Tg-neu肿瘤中的Love诱导的遗传程序，这可能解释了这些效应;我们观察到Love诱导的胎盘生长因子下调，这引发了异常的血管生成和M2样TAM极化。我们的研究结果确定了洛伐他汀在肿瘤炎症浸润的形成和再教育中的作用，在血管生成和抗肿瘤免疫中具有功能性后果。
Beyond their ability to inhibit cholesterol biosynthesis, the statins have pleiotropic effects that include anti-inflammatory and immunomodulatory activities. Statins could have clinical utility, alone or in combination with other chemotherapeutics, in the treatment of cancer. The mechanisms that underlie the anti-tumor activity of the statins are nonetheless poorly defined. No studies have analyzed how they alter the tumor-associated leukocyte infiltrate, a central factor that influences tumor stroma and cancer evolution. Here we used HER2/neu transgenic (Tg-neu) mice to analyze the effect of lovastatin (Lov) on the inflammatory reaction of spontaneous mammary tumors. Lov treatment of tumor-bearing Tg-neu mice did not alter growth of established tumors, but significantly reduced the number of new oncogenic lesions in these mice. Moreover, Lov inhibited the growth of newly implanted Tg-neu tumors in immunocompetent but not in immunodeficient mice. We found that Lov enhanced tumor infiltration by effector T cells, and reduced the number of immunosuppressive and pro-angiogenic M2-like tumor-associated macrophages (TAM). Concomitantly, the drug improved the structure and function of the tumor vasculature, measured as enhanced tumor oxygenation and penetration of cytotoxic drugs. Microarray analysis identified a Lov-elicited genetic program in Tg-neu tumors that might explain these effects; we observed Lov-induced downregulation of placental growth factor, which triggers aberrant angiogenesis and M2-like TAM polarization. Our results identify a role for lovastatin in the shaping and re-education of the inflammatory infiltrate in tumors, with functional consequences in angiogenesis and antitumor immunity.
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影响因子：
64.5
作者：
Fischer, Christian;Jonckx, Bart;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
5.2
作者：
Chen, Yeshan;Zhang, Sheng;Wu, Gang
通讯作者：
Wu, Gang
影响因子：
6
作者：
Fujita, Emiko;Shimizu, Akira;Fukuda, Yuh
通讯作者：
Fukuda, Yuh
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
8.8
作者：
Brewer, T. M.;Masuda, H.;Ueno, N. T.
通讯作者：
Ueno, N. T.