The role of tumor-associated macrophage in breast cancer biology.

Breast cancer is the most commonly diagnosed malignant tumor in women worldwide and contributes significantly as the primary cause of female cancer related mortality. Hence, research is focused on discovering new and effective treatment targets. The breast tumor microenvironment (TME) comprising of recruited host stromal cells and tumor cells, has recently emerged as an important player in tumor progression, with the potential for future treatment. The TME comprises immune system elements (such as macrophages and lymphocytes), cells composing blood vessel, fibroblast, myofibroblast, mesenchymal stem cells, adipocytes and extracellular matrix (ECM). Among these cells, tumor-associated macrophages (TAM) are the prominent components of TME in breast cancers. Macrophages exhibit a high plasticity in response to various external signals and participate in innate and adoptive immune responses to control numerous factors of TME. Depending on the microenvironmental signal present, macrophages are polarized into two distinct phenotypes, the classically activated (M1) or the alternative activated (M2) macrophages. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. In human breast carcinomas, high TAM density correlates with poor prognosis. Over the years, studies into the role of TAMs in breast cancer progression have identified TAMs to be capable of inducing angiogenesis, remodelling the tumor extracellular matrix to aid invasion, modelling breast cancer cells to evade host immune system and recruiting immunosuppressive leukocytes to the tumor microenvironment. Along with these functions, the potential role for TAMs in activation of breast cancer stem cells (CSC) has also emerged. Thus, TAMs in breast cancer can enhance cancer cell invasion by degrading the ECM, stimulate tumor vascularization and angiogenesis and suppress the anti-tumor functions of cytotoxic T cells resulting in poor prognosis for patients. These observations make TAMs an attractive target for therapeutic intervention by targeting various aspects of their function. This review discusses the mechanisms responsible for TAM recruitment and highlights the roles of TAMs in regulating tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, the potential for TAM-targeted therapy as a promising novel strategy is also discussed.