XIAOPI Formula Inhibits Breast Cancer Stem Cells via Suppressing Tumor-Associated Macrophages/C-X-C Motif Chemokine Ligand 1 Pathway
XIAOPI Formula Inhibits Breast Cancer Stem Cells via Suppressing Tumor-Associated Macrophages/C-X-C Motif Chemokine Ligand 1 Pathway
复制标题
小皮方通过抑制肿瘤相关巨噬细胞/C-X-C基序趋化因子配体1途径抑制乳腺癌干细胞
DOI：
10.3389/fphar.2019.01371
复制
发表时间：
2019
影响因子：
5.6
通讯作者：
Wang Zhiyu
中科院分区：
文献类型：
--
作者：
Wang Shengqi;Liu Xiaoyan;Huang Renlun;Zheng Yifeng;Wang Neng;Yang Bowen;Situ Honglin;Lin Yi;Wang Zhiyu
巨噬细胞是包括乳腺癌在内的多种恶性肿瘤中与宿主免疫系统相关的最丰富的基质细胞。消癖方（XPS）临床疗效确切，无明显不良反应，于2018年获得国家食品药品监督管理局（SFDA）批准用于乳腺增生治疗。关于XPS的抗乳腺癌活性和机制的现有知识非常有限。本研究旨在研究XPS是否可以通过调节肿瘤微环境中的肿瘤相关巨噬细胞（TAMs）发挥抗乳腺癌作用。在此，使用transwell共培养系统共培养乳腺癌细胞和TAM以模拟它们的共存。XPS可显著抑制共培养体系中人和小鼠乳腺癌细胞的增殖、集落形成、乳腺癌干细胞亚群、乳腺球形成能力以及干细胞相关基因的表达。此外，XPS可以抑制M2表型极化以及C-X-C基序趋化因子配体1（CXCL 1）的表达和TAM的分泌。值得注意的是，进一步的机制探索验证了TAM/CXCL 1是XPS在共培养系统中抑制乳腺CSC自我更新的关键靶标，因为外源性CXCL 1施用可以消除XPS对乳腺CSC自我更新的抑制作用。更重要的是，XPS在体内显著抑制小鼠4 T1-Luc异种移植物中的乳腺肿瘤生长、乳腺CSC亚群和TAM/CXCL 1活性，而没有任何可检测的副作用。综上所述，本研究不仅揭示了XPS治疗乳腺癌的免疫调节机制，还为TAMs/CXCL 1作为乳腺CSC清除的潜在分子靶点提供了新的见解。
Macrophages are the most abundant stromal cells associated with the host immune system in multiple malignancies including breast cancer. With proven clinical efficacy and no noticeable adverse effects, XIAOPI formula (XPS) has been approved for breast hyperplasia treatment by the State Food and Drug Administration of China (SFDA) in 2018. The existing knowledge about the anti-breast cancer activities and mechanisms of XPS has been very limited. The present study aimed to investigate whether XPS could exert an anti-breast cancer effect by regulating tumor-associated macrophages (TAMs) in tumor microenvironment. Herein, breast cancer cells and TAMs were co-cultured using the transwell co-culture system to simulate the coexistence of them. XPS could significantly inhibit the proliferation, colony formation, breast cancer stem cells (CSCs) subpopulation, mammosphere formation abilities as well as stemness-related genes expression in both human and mouse breast cancer cells in the co-culture system. Additionally, XPS could suppress M2 phenotype polarization as well as C-X-C motif chemokine ligand 1 (CXCL1) expression and secretion of TAMs. Notably, further mechanistic explorations verified TAMs/CXCL1 as the critical target of XPS in inhibiting breast CSCs self-renewal in the co-culture system as the exogenous CXCL1 administration could abrogate the inhibitory effect of XPS on breast CSCs self-renewal. More importantly, XPS significantly inhibited mammary tumor growth, breast CSCs subpopulation, and TAMs/CXCL1 activity in mouse 4T1-Luc xenografts in vivo without any detectable side effects. Taken together, this study not only uncovers the immunomodulatory mechanism of XPS in treating breast cancer but also sheds novel insights into TAMs/CXCL1 as a potential molecular target for breast CSCs elimination.