Mast cells promote small bowel cancer in a tumor stage-specific and cytokine-dependent manner

Abstract

SignificanceWe show that distinct subsets of mast cells (MCs) expand with sequential oncogenic events in small bowel cancer. Mucosal mast cells (MMCs) previously detected early during Trichinella spiralis infection expand in adenomatous polyps in an IL-10–dependent manner. Connective tissue mast cells (CTMCs), earlier shown to expand during the resolution of inflammation following clearance of T. spiralis, are independent of IL-10 and associate with the transition of polyps to adenocarcinoma. IL-33 upregulates the CTMC lineage-specific protease murine mast cell protease 6 (mMCP6). Ablation of mMCP6 attenuates tumor growth. Thus, tissue sentinel cells respond to oncogenic events and cellular transformation in effect to help promote cancer. Delineating the types of MCs present at various stages of disease offers actionable cellular targets for therapeutic intervention in disease progression.

Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

“…In small intestinal cancers, MCs expand in benign polyps in the presence of IL-10, IL-13, and IL-33 as well as ILC2 cells. The presence of these MCs is maintained in an IL-10 dependent manner-overexpression of IL-10 greatly expanded MC populations in these polyps [59]. The presence of IL-10 in conjunction with MC chemokines and alarmins such as IL-33 explains the pro-cancer, pro-inflammatory role MCs can play in certain cancers; in the context of small bowel cancers, MC protease expression resembled MMCs but included CTMC-related mast cell proteases too [59].…”

“…The presence of these MCs is maintained in an IL-10 dependent manner-overexpression of IL-10 greatly expanded MC populations in these polyps [59]. The presence of IL-10 in conjunction with MC chemokines and alarmins such as IL-33 explains the pro-cancer, pro-inflammatory role MCs can play in certain cancers; in the context of small bowel cancers, MC protease expression resembled MMCs but included CTMC-related mast cell proteases too [59]. When the polyps switched to an invasive phenotype, CTMCs expressing both MMC and CTMC proteases expanded, demonstrating cancer's ability to alter MC activity toward a pathogenic, pro-cancer function [59].…”

IL-9 and IL-9-producing cells in tumor immunity

“…The protease released by activated mast cells is the key factor in inducing angiogenesis, which may promote tumor angiogenesis and tumor growth [95]. Moreover, it has been reported that mast cells promote small bowel cancer progression in a tumor stage-specific and cytokine-dependent manner [96]. The role of IL-9 and IL-9 producing cells in antitumor immunity is summarized in Fig.…”

Mast cells-derived MiR-223 destroys intestinal barrier function by inhibition of CLDN8 expression in intestinal epithelial cells

“…Interestingly, the hallmark of IBD is a dysregulated intestinal immune response in which mast cells (MCs) accumulate in the inflamed gut of IBD patients [2]. Meanwhile, the report by Vivinus et al [3] showed that increased MCs numbers were counted in the colon of both Crohn's Disease (CD) and Ulcerative colitis (UC) patients compared to that in healthy controls, while activation of MCs are suggested by increased expression or release of MCs mediators in the mucosa, including proteases [4], histamine [5], chemokines and cytokines [6], leading to the attraction of inflammatory cells, changes in barrier function, tissue remodeling etc. However, the specific function of MCs in IBD development remains to be elucidated, especially the aberrant interactions between MCs and IECs or others underlying resident cells, which is fundamental for immunopathological regulation.…”