XIAOPI Formula Inhibits Breast Cancer Stem Cells via Suppressing Tumor-Associated Macrophages/C-X-C Motif Chemokine Ligand 1 Pathway

Abstract

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.

Aiduqing formula inhibits breast cancer metastasis by suppressing TAM/CXCL1-induced Treg differentiation and infiltration

“…Our previous studies have found that CXCL1 is one of the most abundant chemokines secreted by TAMs [ 16 , 17 ]. TAM/CXCL1 inhibition represents a promising treatment strategy for preventing breast cancer immune escape and lung metastasis [ 17 , 18 ]. For example, CXCL1 derived from TAMs could recruit hematopoietic stem and progenitor cells (HSPCs) and induce their differentiation into MDSCs to shape the immunosuppressive TME and favor breast cancer metastasis [ 19 ].…”

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

“…In particular, GM-CSF and IL-6 could not only promote the myeloid-biased differentiation, but also induce the differentiation of myeloid precursors into functional MDSCs [40]. However, our previous findings demonstrated that CXCL1 acts as the highest chemokine secreted by TAMs isolated from breast cancer [16,41]. Moreover, CXCL1 silencing in TAMs was found to inhibit breast cancer growth and lung metastasis via inhibiting NF-κB/SOX4 signaling in both murine and human models [42].…”

“…However, our study demonstrated that XIAOPI formula could inhibit CXCL1 mRNA and protein expression. More importantly, our previous studies indicated that XIAOPI formula suppressed the promoter activity of CXCL1 gene in TAMs [41]. Meanwhile, XIAOPI formula contains thousands of phytochemicals and molecular targets, which shows a natural advantage than CXCL1 mono-targeting strategy.…”

The Tumor Microenvironment as a Driving Force of Breast Cancer Stem Cell Plasticity

“…C-X-C motif chemokine ligand 1 (CXCL1) is a chemokine secreted by macrophages whose expression in the tumor stroma is associated with poor prognosis and BC metastasis [ 55 , 56 ]. Interestingly, pharmacological inhibition of TAM-derived CXCL1 suppresses BCSCs [ 57 ]. Two complementary studies indicate that other cytokines such as interleukin-1beta (IL-1β) may be involved in the cross-talk between macrophages and BCSCs.…”