Abstract
Certain immune cells and inflammatory cytokines are essential components in the tumor microenvironment to promote breast cancer progression. To identify key immune players in the tumor microenvironment, we applied highly invasive MDA-MB-231 breast cancer cell lines to co-culture with human monocyte THP-1 cells and identified CXCL7 by cytokine array as one of the increasingly secreted cytokines by THP-1 cells. Further investigations indicated that upon co-culturing, breast cancer cells secreted CSF1 to induce expression and release of CXCL7 from monocytes, which in turn acted on cancer cells to promote FAK activation, MMP13 expression, migration, and invasion. In a xenograft mouse model, administration of CXCL7 antibodies significantly reduced abundance of M2 macrophages in tumor microenvironment, as well as decreased tumor growth and distant metastasis. Clinical investigation further suggested that high CXCL7 expression is correlated with breast cancer progression and poor overall survival of patients. Overall, our study unveils an important immune cytokine, CXCL7, which is secreted by tumor infiltrating monocytes, to stimulate cancer cell migration, invasion, and metastasis, contributing to the promotion of breast cancer progression.
Highlights
Breast cancer is the most commonly occurring cancer and the leading cause of cancer-related death in women worldwide [1]
Most macrophages in the tumor microenvironment (TME) are originated from bone marrowderived monocytes that are recruited through inflammatory signals released by cancer cells [24]
CSF1 is crucial for the differentiation and survival of macrophages [25], and elevated expression of CSF1 correlates with high grade and poor prognosis in breast cancer [26]
Summary
Breast cancer is the most commonly occurring cancer and the leading cause of cancer-related death in women worldwide [1]. The TAMs in breast cancer are largely derived from bone marrow monocytes that are recruited to the TME through inflammatory cytokines released by cancer cells [6]. In TME, TAMs promote cancer progression by participating in the tumor growth, angiogenesis, cell invasion, cell survival, and immune suppression [4]. Medium with 10% FBS in lower chamber was considered protein enhanced chemotaxis of monocytes and promoted migration and invasion of breast cancer cells through FAK- and MMP13-mediated pathways. On the interplay of invasive breast cancer cells and tumor infiltrating monocytes in the TME to promote breast cancer cell growth and metastasis, and CXCL7 may serve as a potential therapeutic target for breast cancer immunotherapy. All the recombinant chemokines and antibodies used in this study were listed in Supplemental Table S2
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