Clinical significance of macrophage heterogeneity in human malignant tumors

Abstract

The fact that various immune cells, including macrophages, can be found in tumor tissue has long been known. With the recent introduction of the novel concept of macrophage differentiation into a classically activated phenotype (M1) and an alternatively activated phenotype (M2), the role of tumor-associated macrophages (TAMs) is gradually beginning to be elucidated. Specifically, in human malignant tumors, TAMs that have differentiated into M2 macrophages act as "protumoral macrophages" and contribute to the progression of disease. Based on recent basic and preclinical research, TAMs that have differentiated into protumoral or M2 macrophages are believed to be intimately involved in the angiogenesis, immunosuppression, and activation of tumor cells. In this paper, we specifically discuss both the role of TAMs in human malignant tumors and the cell-cell interactions between TAMs and tumor cells.

Keywords: CD163; Cancer; M2; TAM; macrophage.

Figure 1

Tumor microenvironment. (a) Tumor tissue contains not only tumor cells, but also large numbers of normal cells, including tumor-associated macrophages, lymphocytes, blood vessels, and fibroblasts, that affect tumor development in various ways. The photographs show an example of a clinical case of human breast cancer (invasive ductal carcinoma). The relative distributions of the above-mentioned cell types differ by organ and tissue type as well as individual case. CK, cytokeratin. (b) Metastatic tumors contain a larger number of tumor-associated macrophages. The photographs show an example of a clinical case of human kidney cancer (clear cell renal cell carcinoma). The primary tumor tissues and the metastatic (lung) tumors are shown.

Figure 2

Schema of the functional role of tumor-associated macrophages (TAMs). Tumor-associated macrophages are activated by macrophage colony-stimulating factor (M-CSF), interleukin (IL)-6, and other compounds secreted by tumor cells both to induce angiogenesis by producing angiogenic factors such as VEGF and platelet-derived growth factor, and to create immunosuppressive conditions by producing immunosuppressive factors such as IL-10 and prostaglandin E2 (PGE₂). At the same time, growth factors that are secreted by TAMs, such as epidermal growth factor (EGF), directly promote cancer cell growth, whereas MMP and other compounds responsible for stroma remodeling promote tumor cell infiltration and metastasis. Activation of tumor cells and TAMs induced by direct cell–cell interactions may represent an extremely important event in relation to the development of malignant tumors. bFGF, basic fibroblast growth factor; CCL, chemokine (C-C motif) ligand; MDSC, myeloid-derived suppressor cell; PDGF, platelet-derived growth factor; Stat3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor-β; TP, thymidine phosphorylase; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.