Recent findings suggested that premetastatic niche (PMN) is a prerequisite in mediating cancer metastasis. Previously we demonstrated that XIAOPI formula could inhibit breast cancer lung metastasis via inhibiting tumor associated macrophages (TAMs)-secreted CXCL1. Herein, we aimed to explore the effects of XIAOPI formula on preventing breast cancer PMN formation and its underlying molecular mechanisms. It was found that XIAOPI formula could inhibit the proliferation of M2 phenotype macrophages and reduce CXCL1 expression in a dose-dependent manner. TAMs/CXCL1 signaling was subsequently found to stimulate the recruitment of c-Kit+/Sca-1+ HSPCs and their differentiation into CD11b+/Gr-1+ MDSCs, which were symbolic events accounting for PMN formation. Moreover, XIAOPI formula was effective in inhibiting HSPCs activation and blocking the proliferation and metastasis of breast cancer cells 4T1 induced by HSPCs and TAMs co-culture system, implying that XIAOPI was effective in preventing PMN formation in vitro. Breast cancer xenograft experiments further demonstrated that XIAOPI formula could inhibit breast cancer growth and metastasis in vivo. More importantly, XIAOPI formula significantly delayed the time of cancer cell seeding in the lung tissues. Meanwhile, the populations of HSPCs in the bone marrow and MDSCs size in both tumor and lung tissues were all remarkably declined by XIAOPI formula treatment. However, the inhibitory effects of XIAOPI formula could be relieved by CXCL1 overexpression in the TAMs. Taken together, our study provided preclinical evidence supporting the application of XIAOPI formula in preventing breast cancer PMN formation, and highlighted TAMs/CXCL1 as a potential therapeutic strategy for PMN targeting therapy.

Citation Format: Zhiyu Wang, Yifeng Zheng, Neng Wang, Shengqi Wang, Bowen Yang, Yi Lin. XIAOPI formula inhibits breast cancer pre-metastatic niche formation via blocking TAMs/CXCL1 pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2723.