Tumor-associated macrophage

Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes (monocyte-derived macrophages) or yolk sac progenitors (tissue-resident macrophages), but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.

Although there is some debate, most evidence suggests that TAMs have a tumor-promoting phenotype. TAMs affect most aspects of tumor cell biology and drive pathological phenomena including tumor cell proliferation, tumor angiogenesis, invasion and metastasis, immunosuppression, and drug resistance.

Tumor angiogenesis is the process by which a tumor forms new blood vessels in order to maintain a supply of nutrients and oxygen and to grow beyond a few millimeters in size. The formation of vasculature also facilitates the escape of malignant cells into blood circulation and the onset of metastasis. One of the primary tumor-promoting mechanisms of TAMs is the secretion of potent pro-angiogenic factors. The most highly expressed and well-characterized angiogenic factor produced by TAMs is vascular endothelial growth factor A (VEGF-A). TAMs accumulate in hypoxic regions of the tumor, which induces the expression of hypoxia-inducible factors (HIF-1) that regulate VEGF expression. In addition to producing VEGF-A, TAMs have been shown to modulate VEGF-A concentration through matrix metalloproteinase (MMP)-9 activity and by producing WNT7B that induces endothelial cells to produce VEGF-A.

In addition to VEGF-A, TAMs secrete the pro-angiogenic factors tumor necrosis factor α (TNFα), basic fibroblast growth factor, urokinase-type plasminogen activator, adrenomedullin, and semaphorin 4D. Moreover, cytokines produced by TAMs induce tumor cells to produce pro-angiogenic factors, thereby working cooperatively to turn on the angiogenic switch.

A class of TAMs expressing Tie2 have been shown to induce tumor angiogenesis. Tie2+ TAMs associate with blood vessels through angiopoietin-2 produced by endothelial cells and activate angiogenesis through paracrine signaling. When angiopoietin-2 is bound, these TAMs upregulate expression of more angiogenic factors, such as thymidine phosphorylase and cathepsin B. Angiopoietin-2 also causes Tie2+ TAMs to express T-cell regulating factors interleukin (IL)-10 and chemokine (C-C motif) ligand (CCL) 17; these factors limit T-cell proliferation and upregulate expansion of regulatory T cells, allowing tumor cells to evade immune responses. Moreover, tumor-produced colony stimulating factor-1 (CSF1), which regulates macrophage lineage, increases expression of Tie2 on TAMs, suggesting that CSF1 and Tie2+ TAMs may play a role in the angiogenic switch.

Tumor lymphangiogenesis is closely related to tumor angiogenesis, and there is substantial evidence that factors produced by TAMs, especially those of the VEGF family and their receptor tyrosine kinases, are responsible for this link.

This page was last edited on 9 June 2018, at 13:39 (UTC).
Reference: https://en.wikipedia.org/wiki/Tumour-associated_macrophage under CC BY-SA license.

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