Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer

Abstract

Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumour initiation and progression. The stromal microenvironment is important in maintaining normal tissue homeostasis or promoting tumour development. A plethora of immune cells (i.e., lymphocytes, macrophages, mast cells, monocytes, myeloid-derived suppressor cells, Treg cells, dendritic cells, neutrophils, eosinophils, natural killer (NK) and natural killer T (NKT) cells) are components of gastric cancer microenvironment. Mast cell density is increased in gastric cancer and there is a correlation with angiogenesis, the number of metastatic lymph nodes and the survival of these patients. Mast cells exert a protumorigenic role in gastric cancer through the release of angiogenic (VEGF-A, CXCL8, MMP-9) and lymphangiogenic factors (VEGF-C and VEGF-F). Gastric mast cells express the programmed death ligands (PD-L1 and PD-L2) which are relevant as immune checkpoints in cancer. Several clinical undergoing trials targeting immune checkpoints could be an innovative therapeutic strategy in gastric cancer. Elucidation of the role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization.

Keywords: angiogenesis; cancer; gastric cancer; immune cells; inflammation; lymphangiogenesis; mast cells.

Figure 1

Representation of the immune landscape of human gastric cancer. The immune network in gastric cancer is a complex and dynamic system characterized by multiple interactions between a wide spectrum of immune cells, their mediators and tumour cells. Tumour-associated macrophages (TAM), M2 macrophages, tumour-associated mast cells, basophils, monocytes, polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs), monocyte-derived suppressor cells (M-MDSCs), Tregs, Th2 cells, tumour-associated neutrophils (TAN), immature DCs (iDCs), Th17 cells and their mediators play protumorigenic roles. M1 macrophages, cytotoxic CD8⁺ T cells, NK cells, Th1 cells, mature DCs (mDCs) and their mediators play an anti-tumorigenic role in gastric cancer. VEGF-A and CXCL8 produced by tumour cells can activate tumour angiogenesis. Mast cells and macrophages are major producers of lymphangiogenic factors (VEGF-C and VEGF-D). The anti-tumorigenic role of Th9 cells, type I NKT cells and γδ T cells (grey and dashed lines) have been demonstrated in several other human cancers or are under investigation in gastric cancer. There is increasing evidence that eosinophils play an anti-tumorigenic role in different cancers [162,163,164]. The protumorigenic role of circulating Tfh cells [165] and of type II NKT cells has been preliminarily shown in gastric cancer or in several other human tumours, respectively (grey and dashed lines).

Figure 2

(A) Primary gastric cancer tissue immunostained with an anti-tryptase antibody demonstrates the presence of several mast cells in red (single arrow). Big arrow indicates a blood vessel with a red blood cell in its lumen (40 ×). (B) Metastatic lymph node from primary gastric cancer immunostained with an anti-tryptase antibody. Single arrows indicate red stained mast cells; the big arrow indicates a lymphocyte and the double arrow indicates a blood vessel (40 ×). Reprinted from Ammendola et al. (Int. J. Mol. Sci. 17: E1905, 2016). Bars: A and B = 100 μm.