Macrophage Colony-stimulating Factor Mediates the Recruitment of Macrophages in Triple negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) is characterized by aggressive malignant tumor, poor prognosis and lack of targeted treatment. Several studies have established that macrophages are closely associated with the progression of TNBC. Through immunohistochemical analysis, we found that the infiltration of macrophage in TNBC tissue was more than that in non-triple negative breast cancer (nTNBC) tissue. Furthermore, the conditioned medium (CM) of MDA-MB-231 and HCC1937, the TNBC cell lines, had significant migration-promoted effect on macrophages. However, the macrophages migration-promoted ability of nTNBC cell line MCF-7 was weaker than that of MDA-MB-231 and HCC1937 cells. Mechanistically, MDA-MB-231 and HCC1937 cells secreted more macrophage colony-stimulating factor (M-CSF) than MCF-7, which is the main inducer of macrophage migration, and the secreted M-CSF promoted the increase in actin and the elongation of pseudopodia. When M-CSF was neutralized by antibody, the elongation of macrophage pseudopodia was disappeared and the migration was inhibited. In vivo, there were more macrophages in tumors induced by MDA-MB-231 than MCF-7 did. Therefore, M-CSF specially secreted by TNBC was the important cause of macrophages aggregation in TNBC, which further promoted the aggressiveness of TNBC.

Systemic Immune Dysregulation in Early Breast Cancer Is Associated With Decreased Plasma Levels of Both Soluble Co-Inhibitory and Co-Stimulatory Immune Checkpoint Molecules

“…Re-emergence of expression of M-CSF and its receptor in breast tissue also occurs during breast tumorigenesis, a scenario that is associated with immunosuppression and aggressive disease. Malignancies of the breast that fall into this category include primary breast cancer with nodal involvement ( 21 – 24 ), post-menopausal breast cancer ( 25 ), and triple-negative breast cancer ( 26 ).…”

Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

“…Metastasis-and inflammation-associated microenvironmental factor S100A4 activates the basal-like subtype of breast cancer cells to trigger monocyte-to-macrophage (M2) differentiation and polarization, and elevates secretion of pro-inflammatory cytokines such as IL-8, IL-6, CXCL10, CCL2 and CCL5 [67]. Further, macrophage colony-stimulating factor (M-CSF), the main stimulator of macrophage migration, caused aggregation of M2 macrophages through an increased elongation of pseudopodia [68]. Inhibitors of differentiation (ID) 4 significantly associates with M2 macrophage marker CD68 protein expression in a series of TNBC tissues.…”

Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis

“…Of these growth factors, TNF-α, IL-8, TGF-β, M-CSF, and VEGF can have a direct effect on OC differentiation but not on OC activity (Wang et al, 2020). Of note, MDA-MB-231 cells that in our study showed the greatest effect are known to secrete very high levels of M-CSF, also higher than MCF7 cells (Lu et al, 2019). We also found that among the carcinoma cell lines examined, Caki-1 cells can directly and strongly promote OC activity, whereas MCF7 showed a very low, although significant effect, and MDA-MB-231 cells were not able to directly induce OC-mediated collagen type I degradation.…”