Fig. 6

CCL2 produced in primary BC tumors promotes BC progression. CCL2 production by BC cells is increased  by several mechanisms that involve CoREST1, miRNA, lncRNA, Twist1, dysadherin, KLF15, β-catenin, PTEN, NOTCH and HER2, and in response to stimuli, such as TLR4 ligands, TNFα, TGFβ, and estrogen. CCL2 is also produced by stromal cells, including macrophages, fibroblasts, ECs and pericytes, after activation by products of cancer cells and stromal cells. Decreased expression of FBXW7 in Mo-MDSCs and macrophages results in increased CCL2 production. Macrophages are the major CCL2-producing cells in the TME. Produced CCL2 promotes the recruitment of additional macrophages, mesenchymal stem cells (MSCs), and endothelial precursor cells (EPCs), and angiogenesis. Additionally, CCL2 promotes BC cell migration, survival, EMT, and proliferation, leading to BC progression, especially lung and brain metastasis. CCL2 produced at the metastatic site by both cancer cells and macrophages plays an important role in the metastatic seeding of BC cells. Downregulation of lung and bone metastasis by BC cell-derived CCL2 has also been reported, but further clarification is needed