XIAOPI formula inhibits the pre-metastatic niche formation in breast cancer via suppressing TAMs/CXCL1 signaling

Abstract

Background: 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.Methods: CXCL1 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 epithelialmesenchymal 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.(Continued on next page)

Research trends in pharmacological modulation of tumor‐associated macrophages

“…Circulatory or residential TAMs can release chemokines that guide the localization of cancer cells into the PMN with increased expression levels of MMPs, fibronectins, S100A8, and S100A9 75–77 . Our recent report demonstrated that TAMs‐derived CXCL1 exerted an important role in recruiting breast cancer cells into the PMN 78 . Thus, TAMs act as an indispensable factor in fostering cancer cells traveling from the primary site to metastatic lesions.…”

“…[75][76][77] Our recent report demonstrated that TAMs-derived CXCL1 exerted an important role in recruiting breast cancer cells into the PMN. 78 Thus, TAMs act as an indispensable factor in fostering cancer cells traveling from the primary site to metastatic lesions. Molecular elucidation of TAMs regulation in cancer development is thus warranted and critical for further developing cancertargeting strategies.…”

Role of Tumor-Associated Myeloid Cells in Breast Cancer

“…The XIAOPI formula is an inhibitor of CXCL1, which is released from TAMs and inhibits the formation of a premetastatic niche in breast cancer [178] and breast cancer cell proliferation and metastasis [202]. ZnPPIX, a specific inhibitor of HO-1 and heat shock protein 32 (HSP32), effectively suppresses breast cancer cell growth [107].…”

Immunotherapy Targeting Tumor-Associated Macrophages

“…Primary tumor cells are thought to initiate the formation of PMN by the secretion of proinflammatory cytokines, chemokines, and angiogenic factors that recruit BM-derived cells into future metastatic sites, and these cells induce PMN formation in reverse ( 70 ). For example, CXCL1 secreted by TAMs was reported to recruit CXCR2 + myeloid suppressor cells to promote liver PMN formation ( 71 , 72 ).…”