IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization

Abstract

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.

The prognostic value of immune infiltration signature and its potential mechanism in gastric cancer

“…Therefore, same as cellular immunity, humoral immunity dominated by plasma cells may play an important role in inhibiting the development of digestive system tumors,but there are few studies focus on this area, the mechanism is worthy for further research. A long-term follow-up study con rmed that macrophage was a key factor in the progression of non-cancerous gastric adenomas to GC [28], and another animal experiment validated that the number of macrophages were positively correlated with gastric tumor growth [29]. We found that both Macrophage M0 and M1 were enriched in tumor tissues in both cohorts, but M2 macrophages proportion in two cohorts was inconsistent.…”

“…Moreover, some retrospective studies have shown that submucosal mast cells adjacent to the tumor are involved in advanced disease and metastasis of human GC [38,39]. In 2019, an article published on Nature Communication revealed that the inactivation of mast cells in gastric cancer tissue effectively inhibited the accumulation of tumor-associated macrophages, reducing tumor cell proliferation and angiogenesis [29]. Interestingly, we found that the M2 macrophages and activated mast cells were strongly associated with poor prognosis, suggested that these cells can be promising GC treatment targets.…”

Natural IgE promotes epithelial hyperplasia and inflammation-driven tumour growth

“…Interestingly, contrary to many other cancers, RNAseq data in these two cancers suggests a negative correlation between FCER1A and overall survival (KMplotter24). A recent study also revealed increased mast cell density in human gastric tumours and in the corresponding mouse models, and that mast cell degranulation was driving tumour growth25. It should be noted that in this study mast cell numeration was done using toluidine blue in this study, which also stains basophils.…”

The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment

“…When the body is infected or repairs wounds, it permanently activates and chemotactically accumulates a large number of white blood cells (such as macrophages, neutrophils, lymphocytes, and dendritic cells) at the site of injury by releasing cytokines/chemokines (such as interleukin-6/10 (IL-6/10) [38,39] and tumor necrosis factor-α (TNF-α)) [40], growth factors (transforming growth factor-β (TGF-β)) [41], matrix metalloproteinases (MMPs) [42], vascular endothelial growth factor (VEGF) [43], reactive oxygen species (ROS) metabolites, and other substances [44]. These inflammatory cytokines not only recruit inflammatory cells to amplify inflammation at the tumor site [45] but also form a new environment [46], leading to the destruction and atrophy of normal tissues [47] and promoting mass production of the tumor matrix and blood vessels [48]. These factors play an essential role in the occurrence and development of tumors and promote the growth and metastasis of tumors.…”