Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells

Abstract

BackgroundMetastatic progression of breast cancer involves phenotypic plasticity of the carcinoma cells moving between epithelial and mesenchymal behaviors. During metastatic seeding and dormancy, even highly aggressive carcinoma cells take on an E-cadherin-positive epithelial phenotype that is absent from the emergent, lethal metastatic outgrowths. These phenotypes are linked to the metastatic microenvironment, though the specific cells and induction signals are still to be deciphered. Recent evidence suggests that macrophages impact tumor progression, and may alter the balance between cancer cell EMT and MErT in the metastatic microenvironment.MethodsHere we explore the role of M1/M2 macrophages in epithelial-mesenchymal plasticity of breast cancer cells by coculturing epithelial and mesenchymal cells lines with macrophages.ResultsWe found that after polarizing the THP-1 human monocyte cell line, the M1 and M2-types were stable and maintained when co-cultured with breast cancer cells. Surprisingly, M2 macrophages may conferred a growth advantage to the epithelial MCF-7 cells, with these cells being driven to a partial mesenchymal phenotypic as indicated by spindle morphology. Notably, E-cadherin protein expression is significantly decreased in MCF-7 cells co-cultured with M2 macrophages. M0 and M1 macrophages had no effect on the MCF-7 epithelial phenotype. However, the M1 macrophages impacted the highly aggressive mesenchymal-like MDA-MB-231 breast cancer cells to take on a quiescent, epithelial phenotype with re-expression of E-cadherin. The M2 macrophages if anything exacerbated the mesenchymal phenotype of the MDA-MB-231 cells.ConclusionOur findings demonstrate M2 macrophages might impart outgrowth and M1 macrophages may contribute to dormancy behaviors in metastatic breast cancer cells. Thus EMT and MErT are regulated by selected macrophage phenotype in the liver metastatic microenvironment. These results indicate macrophage could be a potential therapeutic target for limiting death due to malignant metastases in breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2411-1) contains supplementary material, which is available to authorized users.

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

“…Further, EGF and IGF-1 enhances expression of transcription factors associated with pluripotency, proliferation, and EMT (Castano et al, 2013). Macrophage phenotypic subtypes completely regulate epithelial-to-mesenchymal plasticity in breast cancer cells (Yang et al, 2016). Co-culturing of epithelial and mesenchymal cell lines with macrophages revealed that M2 macrophages might impart outgrowth and M1 macrophages may contribute to dormancy behaviors in metastatic breast cancer cells.…”

The potential role of leptin in tumor invasion and metastasis

“…It is noteworthy that macrophages can be classified into two major categories – classically activated M1 macrophages are linked with tumoricidal functions, and alternatively activated M2 macrophages are involved in tumor promotion [145]. Fascinatingly, TAMs have been considered as M2 macrophages, which could promote the EMT [145–147]. A recent study has shown that leptin may promote breast cancer progression by stimulating M2 macrophages [148].…”

IL‐1β from M2 macrophages promotes migration and invasion of ESCC cells enhancing epithelial‐mesenchymal transition and activating NF‐κB signaling pathway

“…6 Prior studies have revealed that M2 macrophages could induce the epithelial-mesenchymal transition (EMT) process and promote tumor metastasis. 7,8 However, the molecular mechanism by which M2 macrophages play in the invasion and metastasis of ESCC remains largely unknown.…”