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

Shengqi Wang,Bowen Yang,Renlun Huang,Yifeng Zheng,Yi Lin,Zhiyu Wang,Neng Wang,Xiaoyan Liu,Honglin Situ

doi:10.3389/fphar.2019.01371

Shengqi Wang, Bowen Yang + Show 7 more

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https://doi.org/10.3389/fphar.2019.01371

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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.

Highlights

Breast cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths among women (Allemani et al, 2015; Bray et al, 2018)
By establishing the tumor-associated macrophages (TAMs)-breast cancer cells co-culture system in vitro and breast cancer xenografts in vivo, we systematically demonstrated that XIAOPI formula (XPS) could suppress M2 phenotype polarization as well as C-X-C motif chemokine ligand 1 (CXCL1) expression and secretion, which eventually led to the inhibitory effect of XPS on the self-renewal of breast cancer stem cells (CSCs)
The conditional medium (CM) of MDA-MB-231 cells significantly increased the F4/80+/CD163+ subpopulation in Thp1 macrophages while 4T1-conditioned medium (CM) significantly elevated the F4/80+/CD206+ population in mouse Raw264.7 macrophages. These results indicated that both human Thp1 macrophages and mouse Raw264.7 macrophages were successfully stimulated into M2 phenotype macrophages (Figure 1C)

Summary

Introduction

Breast cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths among women (Allemani et al, 2015; Bray et al, 2018). With encouraging efficacy in prolonging survival time, alleviating side effects, and improving the quality of life in cancer patients, Traditional Chinese Medicine (TCM) has been widely used for the prevention and treatment of cancer for thousands of years, mainly in China and surrounding areas (Nie et al, 2016; Liao et al, 2017). TCM has unique advantages in breast cancer treatment and could improve short-term treatment efficacy, extend 5-year survival, and reduce the incidence of adverse reactions in breast cancer patients after mastectomy (Tian et al, 2015; Wang et al, 2015). XIAOPI formula (XPS) is a new anti-mammary hyperplasia drug approved by the SFDA in Dec 28, 2018. It has been empirically used for mammary hyperplasia treatment in the clinic for several decades and its therapeutic efficacy has been confirmed by extensive clinical practices. The existing knowledge about the anti-breast cancer activities and mechanisms of XPS has been very limited

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