Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis

Abstract

Tumor angiogenesis is an essential process for supplying rapidly growing malignant tissues with essential nutrients and oxygen. An angiogenic switch allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic disease. Monocyte-derived macrophages recruited and reprogrammed by tumor cells serve as a major source of angiogenic factors boosting the angiogenic switch. Tumor endothelium releases angiopoietin-2 and further facilitates recruitment of TIE2 receptor expressing monocytes (TEM) into tumor sites. Tumor-associated macrophages (TAM) sense hypoxia in avascular areas of tumors, and react by production of angiogenic factors such as VEGFA. VEGFA stimulates chemotaxis of endothelial cells (EC) and macrophages. In some tumors, TAM appeared to be a major source of MMP9. Elevated expression of MMP9 by TAM mediates extracellular matrix (ECM) degradation and the release of bioactive VEGFA. Other angiogenic factors released by TAM include basic fibroblast growth factor (bFGF), thymidine phosphorylase (TP), urokinase-type plasminogen activator (uPA), and adrenomedullin (ADM). The same factors used by macrophages for the induction of angiogenesis [like vascular endothelial growth factor A (VEGF-A) and MMP9] support lymphangiogenesis. TAM can express LYVE-1, one of the established markers of lymphatic endothelium. TAM support tumor lymphangiogenesis not only by secretion of pro-lymphangiogenic factors but also by trans-differentiation into lymphatic EC. New pro-angiogenic factor YKL-40 belongs to a family of mammalian chitinase-like proteins (CLP) that act as cytokines or growth factors. Human CLP family comprises YKL-40, YKL-39, and SI-CLP. Production of all three CLP in macrophages is antagonistically regulated by cytokines. It was recently established that YKL-40 induces angiogenesis in vitro and in animal tumor models. YKL-40-neutralizing monoclonal antibody blocks tumor angiogenesis and progression. The role of YKL-39 and SI-CLP in tumor angiogenesis and lymphangiogenesis remains to be investigated.

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

“…These soluble stimuli include IL-8, IL-10, adrenomedullin (ADM), TNF-a, TGF-b, VEGFs, uPA, colony stimulating factor 1 (CSF-1), and chemokine (C-C motif) ligand 2 (CCL2). 21,22,44 In the present study, we proved that LPS facilitates pancreatic cancer cell invasion, while MCM promotes both pancreatic cancer cell growth and invasion. Both LPS and MCM repressed PP2Ac expression in pancreatic cancer cells in vitro, suggesting PP2Ac regulation could be involved in inflammation-driven pancreatic cancer progression.…”

“…Quality control of MCM was performed by evaluating secretion of the cytokines interleukin-8 (IL-8) and tumor necrosis factor-a (TNF-a) ( Figure 1C). 20,21,22 MCM promoted pancreatic cancer cell growth slightly ( Figure 1D) and stimulated invasion remarkably ( Figure 1E). These in vitro data suggest that inflammation could be a favorable factor for pancreatic cancer progression by accelerating cell growth and invasion.…”

High YKL-40 is associated with poor survival in patients with renal cell carcinoma: a novel independent prognostic marker

“…Classically activated M1 macrophages have been linked to protective role against the tumor, while M2 macrophages seem to have a tumour-supporting role [26]. Intriguingly, YKL-40 is acknowledged as a marker of alternatively activated M2 macrophages, which have been shown to suppress adaptive tumor-specific immune response and promote tumor growth, angiogenesis, invasion, metastasis and stroma remodeling [26,27]. Further, YKL-40 seems to be a pro-angiogenic factor itself as it has been shown to induce VEGF expression in U87 glioblastoma cells and angiogenesis in vitro and in vivo [27][28][29].…”

“…Intriguingly, YKL-40 is acknowledged as a marker of alternatively activated M2 macrophages, which have been shown to suppress adaptive tumor-specific immune response and promote tumor growth, angiogenesis, invasion, metastasis and stroma remodeling [26,27]. Further, YKL-40 seems to be a pro-angiogenic factor itself as it has been shown to induce VEGF expression in U87 glioblastoma cells and angiogenesis in vitro and in vivo [27][28][29]. In the study by Faibish et al blocking YKL-40 with monoclonal antibody was demonstrated to suppress tumor growth and angiogenesis [30].…”

Modern concepts of factors for gastric cancer progression

“…Макрофаги являются производными моноцитов, активируются хемокинами, секрети-руемыми многими опухолевыми клетками [67]. Хемокины инду-цируют продукцию макрофагами ангиогенных факторов, VEGF и ММР, разрушающих клеточный матрикс и способствующих миграции опухолевых и лимфоидных клеток [50,54,68,69]. Раз-личают М1 макрофаги, ассоциированные с острым воспалением и противоопухолевой активностью, и М2 макрофаги, связанные с опухолевой прогрессией [50,64,67,69,70].…”