Abstract

BackgroundRecent 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.MethodsCXCL1 expression of TAMs was detected by qPCR and Western blotting assay. The influences of XIAOPI formula on the proliferation of TAMs and 4 T1 in the co-culture system were tested by CCK8 or EdU staining. Transwell experiment was applied to determine the effects of XIAOPI formula on the invasion ability of HSPCs and 4 T1. Breast cancer xenografts were built by inoculating 4 T1 cells into the mammary pads of Balb/c mice and lung metastasis was monitored by luciferase imaging. Immune fluorescence assay was used to test the epithelial-mesenchymal transition process and PMN formation in the lung tissues. The effects of XIAOPI formula on TAMs phenotype, hematopoietic stem/progenitor cells (HSPCs) and myeloid-derived suppressor cells (MDSCs) were determined by flow cytometry.ResultsIt was found that XIAOPI formula could inhibit the proliferation and polarization of M2 phenotype macrophages, and reduce CXCL1 expression in a dose-dependent manner. However, M1 phenotype macrophages were not significantly affected by XIAOPI formula. 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 suppressing the proliferation and metastasis of breast cancer cells 4 T1 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 PMN formation and subsequent lung metastasis in vivo. The populations of HSPCs in the bone marrow and MDSCs in the 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.ConclusionsTaken 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.4rAD-F1p2pRhmA-5xKKeeVVideo Graphical abstract

Highlights

  • Recent findings suggested that premetastatic niche (PMN) is a prerequisite in mediating cancer metastasis

  • tumor associated macrophages (TAMs)/CXCL1 signaling was subsequently found to stimulate the recruitment of c-Kit+/Sca-1+ hematopoietic stem/progenitor cells (HSPCs) and their differentiation into CD11b+/Gr-1+ myeloid suppressor cells (MDSCs), which were symbolic events accounting for PMN formation

  • XIAOPI formula was effective in inhibiting HSPCs activation and suppressing the proliferation and metastasis of breast cancer cells 4 T1 induced by HSPCs and TAMs co-culture system, implying that XIAOPI was effective in preventing PMN formation in vitro

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Summary

Introduction

Recent findings suggested that premetastatic niche (PMN) is a prerequisite in mediating cancer metastasis. We demonstrated that XIAOPI formula could inhibit breast cancer lung metastasis via inhibiting tumor associated macrophages (TAMs)-secreted CXCL1. We aimed to explore the effects of XIAOPI formula on preventing breast cancer PMN formation and its underlying molecular mechanisms. In 2005, a groundbreaking research done by Kaplan et al proved that factors secreted by primary tumor cells shaped the premetastatic niche (PMN) by recruiting bone marrow-derived VEGFR1+ progenitor cells [3]. Tumor associated macrophages (TAMs)-secreted CXCL1 was demonstrated to recruit CXCR2+ myeloid suppressor cells (MDSCs) to promote liver PMN formation in a colorectal cancer xenograft [11]. PMN theory has shifted our attention from cancer cell killing strategy to niche component regulation in the perspective of metastasis prevention

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