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Clinical significance of macrophage heterogeneity in human malignant tumors.

Komohara Y, Jinushi M, Takeya M - Cancer Sci. (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

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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.
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fig02: 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.

Mentions: As shown in Figure1, TAMs and tumor cells often directly contact each other, indicating that intimate cell–cell interactions exist between them. During the initial stages of tumor progression, monocyte migration factors produced by tumor cells induce infiltration of monocytes/macrophages, as described above. The macrophages that have infiltrated the tumor are activated by tumor cell-derived molecules, including IL-6, M-CSF, PGE2, and heat shock protein-27, and differentiate into protumoral/M2 macrophages.6,20 Protumoral/M2 TAMs produce a variety of angiogenic and immunosuppressive factors, as described above, and create a microenvironment conducive to tumor progression. Signal transducer and activator of transcription 3 (Stat3) has received recent attention as an important transcription factor that mediates the interaction between TAMs and tumor cells.12 Many angiogenic and immunosuppressive factors are transcriptionally regulated by Stat3. Therefore, activation of Stat3 not only plays an important role in the differentiation of macrophages into protumoral/M2 macrophages, it is also involved in tumor cell growth, metastasis, epithelial–mesenchymal transition, and the acquisition of resistance to anticancer drugs and radiation therapies.12,41 Direct coculture of tumor cells and macrophages shows that Stat3 in macrophages is activated and that various factors secreted by activated macrophages, including EGF, IL-6, and IL-10, activate Stat3 in tumor cells.18,42 Activation of the M-CSF receptor (CD115) and sphingosine-1-phosphate receptor 1 (S1PR1) on the cell surface is believed to contribute to the cell–cell interaction mediated by Stat3.42,43 Membrane-type M-CSF on the surface of tumor cells serves as a ligand for CD115, and sphingosine-1-phosphate derived from tumor cells serves as a ligand for S1PR1. Stimulation of these receptors activates a variety of signal transduction pathways, including that of Stat3, causing TAMs to differentiate into the protumoral/M2 phenotype.44 The activation of Stat3 through cell–cell interactions between tumor cells and macrophages contributes to the formation of the microenvironment necessary for development of primary and metastatic lesions (Fig.2).


Clinical significance of macrophage heterogeneity in human malignant tumors.

Komohara Y, Jinushi M, Takeya M - Cancer Sci. (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4317877&req=5

fig02: 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.
Mentions: As shown in Figure1, TAMs and tumor cells often directly contact each other, indicating that intimate cell–cell interactions exist between them. During the initial stages of tumor progression, monocyte migration factors produced by tumor cells induce infiltration of monocytes/macrophages, as described above. The macrophages that have infiltrated the tumor are activated by tumor cell-derived molecules, including IL-6, M-CSF, PGE2, and heat shock protein-27, and differentiate into protumoral/M2 macrophages.6,20 Protumoral/M2 TAMs produce a variety of angiogenic and immunosuppressive factors, as described above, and create a microenvironment conducive to tumor progression. Signal transducer and activator of transcription 3 (Stat3) has received recent attention as an important transcription factor that mediates the interaction between TAMs and tumor cells.12 Many angiogenic and immunosuppressive factors are transcriptionally regulated by Stat3. Therefore, activation of Stat3 not only plays an important role in the differentiation of macrophages into protumoral/M2 macrophages, it is also involved in tumor cell growth, metastasis, epithelial–mesenchymal transition, and the acquisition of resistance to anticancer drugs and radiation therapies.12,41 Direct coculture of tumor cells and macrophages shows that Stat3 in macrophages is activated and that various factors secreted by activated macrophages, including EGF, IL-6, and IL-10, activate Stat3 in tumor cells.18,42 Activation of the M-CSF receptor (CD115) and sphingosine-1-phosphate receptor 1 (S1PR1) on the cell surface is believed to contribute to the cell–cell interaction mediated by Stat3.42,43 Membrane-type M-CSF on the surface of tumor cells serves as a ligand for CD115, and sphingosine-1-phosphate derived from tumor cells serves as a ligand for S1PR1. Stimulation of these receptors activates a variety of signal transduction pathways, including that of Stat3, causing TAMs to differentiate into the protumoral/M2 phenotype.44 The activation of Stat3 through cell–cell interactions between tumor cells and macrophages contributes to the formation of the microenvironment necessary for development of primary and metastatic lesions (Fig.2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Show MeSH
Related in: MedlinePlus