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.

Mast Cells: Fascinating but Still Elusive after 140 Years from Their Discovery

“…There is increasing evidence that mast cells and their mediators can be involved in several aspects of tumor initiation and growth [21,39,69,70]. However, their impact on experimental and human tumors remains controversial [22,23].…”

“…Sammarco and collaborators investigated the role played by mast cells in the modulation of angiogenesis and lymphangiogenesis in human gastric cancer [21]. They report that mast cell density is increased in gastric cancer and there is a correlation with angiogenesis [72,73].…”

“…With the appreciation of these cells as major potential sources of a myriad of cytokines and chemokines, it became evident in the 1990s that mast cells may express immunoregulatory functions [14,15]. During the last decades, it was demonstrated that mast cells can also produce different proangiogenic [16][17][18] and lymphangiogenic factors [19,20], suggesting that they may actually play a role in tumor initiation and growth [21][22][23][24]. Moreover, these cells can be activated by different viral [25,26] and bacterial proteins [27,28] and thereby represent a potentially important cell during microbial infections.…”

“…Kim and coworkers demonstrate that bone-marrow-derived mast cells from mice with a genetic deletion of Aldh2 have increased proliferation and IL-6 production after activation by stem cell factor (SCF), as well as when co-stimulated with SCF and an antigen [68]. These findings provide insight into the regulation of mast cell responsiveness in relation to alcohol-associated flushing.There is increasing evidence that mast cells and their mediators can be involved in several aspects of tumor initiation and growth [21,39,69,70]. However, their impact on experimental and human tumors remains controversial [22,23].…”

“…By comparing the transcriptomic profile of colon cancer-co-cultured mast cells versus control mast cells, they identify several deregulated genes which can contribute to cancer development. This experimental model could represent a novel approach to investigate the role of mast cells in tumorigenesis [71].Sammarco and collaborators investigated the role played by mast cells in the modulation of angiogenesis and lymphangiogenesis in human gastric cancer [21]. They report that mast cell density is increased in gastric cancer and there is a correlation with angiogenesis [72,73].…”