Macrophages: An Inflammatory Link Between Angiogenesis and Lymphangiogenesis

Abstract

Angiogenesis and lymphangiogenesis often occur in response to tissue injury or in the presence of pathology (e.g. cancer), and it is these types of environments in which macrophages are activated and increased in number. Moreover, the blood vascular microcirculation and the lymphatic circulation serve as the conduits for entry and exit for monocyte-derived macrophages in nearly every tissue and organ. Macrophages both affect and are affected by the vessels through which they travel. Therefore, it is not surprising that examination of macrophage behaviors in both angiogenesis and lymphangiogenesis has yielded interesting observations that suggest macrophages may be key regulators of these complex growth and remodeling processes. In this review, we will take a closer look at macrophages through the lens of angiogenesis and lymphangiogenesis, examining how their dynamic behaviors may regulate vessel sprouting and function. We present macrophages as a cellular link that spatially and temporally connects angiogenesis with lymphangiogenesis, in both physiological growth and in pathological adaptations, such as tumorigenesis. As such, attempts to therapeutically target macrophages in order to affect these processes may be particularly effective, and studying macrophages in both settings will accelerate the field’s understanding of this important cell type in health and disease.

Suppression of KSHV-induced angiopoietin-2 inhibits angiogenesis, infiltration of inflammatory cells, and tumor growth

“…The infiltrating monocytes may differentiate and polarize into tumor-associated macrophages (TAMs), which are well known to promote angiogenesis, anti-tumor innate immunity, and tumor invasion and metastasis. 46,47 Therefore, promoting migration and Anti-angiogenesis therapy alone has been proven insufficient to cure cancer in general. A combination of these inhibitors with other anti-cancer therapies might be necessary to completely block tumor growth.…”

Histological perspective on the effects of tumor-associated macrophages in the tumor microenvironment surrounding papillary thyroid carcinoma

“…Several studies have discovered that TAMs produce some immunosuppressive factors -such as prostaglandin E2 (PGE2) and interleukin 10 (IL-10) -for induction of regulatory T cells and some chemotactic factors, such as CCL17, CCL18, and CCL22, for regulatory T cells [14,26,27,28]. Additionally, it is known that TAMs (particularly M2d subtype) secrete other cytokines, such as TNF-α and TGF-β [14,16].…”

“…TGF-β is one of the molecules produced by TAMs [16], and it has antiproliferative effects. It is also an important regulator in epithelial-mesenchymal differentiation and metastasis.…”

“…Macrophages are one of the most noticeable elements of the tumor microenvironment, and they are monocytes that transform through two subtypes of macrophages, namely M1 type (classically activated) and M2-like type (M2 type, promoting tumorigenesis, alternatively activated) by the influence of chemoattractants [15,16,17]. M2-like macrophages, particularly the M2d phenotype, expressing high levels of transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), monocyte colony stimulating factor (M-CSF), vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs), and chemokines -including chemokine (C-C motif), ligand (CCL) 17, and CCL22 -have been defined as tumor-associated macrophages (TAMs) regardless of the argument about their origins (in the bone marrow, yolk sac, or via extramedullary hematopoiesis) [14,16]. Several reports about TAMs in thyroid carcinomas have revealed that M2-like types of TAMs can be identified by CD68 (also M1 type), CD163, CD206, and CD204 immunoexpression and also that higher numbers or percentages of these cells are associated with higher histological grade (anaplastic carcinoma, poorly differentiated carcinoma), lymph node metastasis, and advanced tumor stage [1,11,16,18,19].…”

“…M2-like macrophages, particularly the M2d phenotype, expressing high levels of transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), monocyte colony stimulating factor (M-CSF), vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs), and chemokines -including chemokine (C-C motif), ligand (CCL) 17, and CCL22 -have been defined as tumor-associated macrophages (TAMs) regardless of the argument about their origins (in the bone marrow, yolk sac, or via extramedullary hematopoiesis) [14,16]. Several reports about TAMs in thyroid carcinomas have revealed that M2-like types of TAMs can be identified by CD68 (also M1 type), CD163, CD206, and CD204 immunoexpression and also that higher numbers or percentages of these cells are associated with higher histological grade (anaplastic carcinoma, poorly differentiated carcinoma), lymph node metastasis, and advanced tumor stage [1,11,16,18,19]. Recent reports have shown that TAMs promote tumorigenesis by inducing neovascularization and invasion/metastasis and by suppressing antitumor immunity via cell-to-cell interactions [20,21,22].…”