The effect of normal fibroblasts and cancer associated fibroblasts on monocyte recruitment, macrophage polarization and invasion in breast cancer

In breast cancer, macrophages represent up to %50 of the tumor mass and there is a correlation between the number of tumor associated macrophages (TAM) and poor prognosis. TAMs usually resemble M2 macrophages. Unlike M1-macrophages which have pro-inflammatory and anti-cancer functions, M2-macrophages are immunosuppressive, hence favor tumor growth. Macrophages originate from blood monocytes, which differentiate into either M1 or M2 subtype macrophages depending on the environmental stimulus they receive. Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumor microenvironment. CAFs have recently been drawn attention for their function as a regulator of immune cell recruitment and function. In this study the role of normal fibroblasts, cancer associated fibroblasts and breast cancer cells on monocyte recruitment and macrophage polarization were determined in breast cancer. In this study, we found that CAFs and MDA-MB-231 cells recruited monocytes effectively. MCP-1 and SDF-1 were important chemotactic cytokines that secreted from breast cancer cells and stromal cells We showed that CAFs from invasive breast cancer differentiated monocytes to M2-like protumoral macrophages phenotypically in contrast to fibroblasts from normal breast. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages.