The role of tumor-associated macrophages in breast cancer progression (review)

Abstract

It is well established that the tumor microenvironment plays a major role in the aggressive behavior of malignant solid tumors. Among cell types associated with tumor microenvironment, tumor-associated macrophages (TAMs) are the most influential for tumor progression. Breast cancer is characterized by having a large population of TAMs, and experimental models have exposed multiple mechanisms by which TAMs interact with and influence the surrounding tumor cells. The process of metastasis involves tumor cells gaining access to the tissue outside the immediate tumor environment and invading the confining extracellular matrix (ECM). Supporting this process, TAMs secrete proangiogenic factors such as VEGF to build a network of vessels that provide nutrition for tumor cells, but also function as channels of transport into the ECM. Additionally, TAMs release factors to decrease the local pro-inflammatory antitumor response, suppressing it and providing a means of escape of the tumor cells. Similarly, hypoxia in the tumor microenvironment stimulates macrophages to further produce VEGF and suppress the T-cell immune responses, thus, enhancing the evasion of tumor cells and ultimately metastasis. Given the multiple roles of TAMS in breast cancer progression and metastasis, therapies targeting these cells are in development and demonstrate promising results.

Figure 1.

Schematic representation of the polarization of macrophages into M1 macrophages (classically activated macrophages). INF-γ primes macrophages causing an upregulation of toll-like receptors (TLRs) so that in the presence of pathogens (red discs) or pathogen products (e.g., lipopolysaccharide), those primed macrophages acquire an M1 phenotype releasing cytokines, particularly IL-12 and IL-23.

Figure 2.

Schematic representation of the polarization of the M2 macrophages by their respective stimuli. M2a macrophages are macrophages activated by IL-4 and IL-13. In the presence of immune complexes and TLR-ligands, macrophages are polarized into an M2b phenotype. Both M2a and M2b phenotypes have anti-inflammatory function and pro-tumorigenic properties. In the presence of glucocorticoids and IL-10, macrophages are polarized into M2c macrophages, and they have an immunosuppressive activity.