Slit2 Inhibits Breast Cancer Metastasis by Activating M1-Like Phagocytic and Antifibrotic Macrophages.
Slit2 Inhibits Breast Cancer Metastasis by Activating M1-Like Phagocytic and Antifibrotic Macrophages.
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DOI：
10.1158/0008-5472.can-20-3909
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发表时间：
2021-10-15
期刊：
影响因子：
11.2
通讯作者：
Ganju RK
中科院分区：
文献类型：
--
作者：
Ahirwar DK;Charan M;Mishra S;Verma AK;Shilo K;Ramaswamy B;Ganju RK
肿瘤相关巨噬细胞（TAM）本质上是异质的，并且包括抗肿瘤M1样（M1-TAM）或促肿瘤M2样（M2-TAM）TAM。M2-TAM是乳腺肿瘤基质的主要成分，通过降低其吞噬能力和增加肿瘤纤维化来增强转移。然而，调节TAM表型可塑性的分子机制尚不清楚。在这里，我们报告了一种新的肿瘤抑制因子Slit 2在乳腺癌中通过调节肿瘤微环境中的TAM。Slit 2抑制自发性和同基因乳腺肿瘤和异种移植乳腺肿瘤模型的体内生长和转移。Slit 2增加了M1-TAM向肿瘤的募集，并增强了M1-TAM在体外和体内吞噬肿瘤细胞的能力。这种Slit 2介导的M1-TAM吞噬作用的增加通过抑制IL 6而发生。Slit 2还显示通过增加M1-TAM中基质金属蛋白酶13的表达来减少乳腺癌小鼠模型中的纤维化。患者样本的分析显示，Slit 2高表达与更好的患者存活率强烈相关，并与CD 163 + TAM的丰度呈负相关。总体而言，这些研究确定了Slit 2通过激活M1-TAM和消除肿瘤纤维化来抑制转移的作用。此外，这些研究结果表明Slit 2可以成为一种有前途的免疫治疗剂，可以将TAMs重新定向为侵袭性和转移性乳腺癌的肿瘤杀手。此外，Slit 2表达沿着CD 163 + TAM可用作乳腺癌患者中改善的预后生物标志物。
Tumor-associated macrophages (TAM) are heterogeneous in nature and comprise anti-tumor M1-like (M1-TAMs) or pro-tumor M2-like (M2-TAMs) TAMs. M2-TAMs are a major component of stroma in breast tumors and enhance metastasis by reducing their phagocytic ability and increasing tumor fibrosis. However, the molecular mechanisms that regulate phenotypic plasticity of TAMs are not well known. Here we report that a novel tumor suppressor Slit2 in breast cancer by regulating TAMs in the tumor microenvironment. Slit2 reduced the in vivo growth and metastasis of spontaneous and syngeneic mammary tumor and xenograft breast tumor models. Slit2 increased recruitment of M1-TAMs to the tumor and enhanced the ability of M1-TAMs to phagocytose tumor cells in vitro and in vivo. This Slit2-mediated increase in M1-TAM phagocytosis occurred via suppression of IL6. Slit2 was also shown to diminish fibrosis in breast cancer mouse models by increasing the expression of matrix metalloproteinase 13 in M1-TAMs. Analysis of patient samples showed high Slit2 expression strongly associated with better patient survival and inversely correlated with the abundance of CD163+ TAMs. Overall, these studies define the role of Slit2 in inhibiting metastasis by activating M1-TAMs and depleting tumor fibrosis. Furthermore, these findings suggest that Slit2 can be a promising immunotherapeutic agent to redirect TAMs to serve as tumor killers for aggressive and metastatic breast cancers. In addition, Slit2 expression along with CD163+ TAMs could be used as an improved prognostic biomarker in breast cancer patients.