Comparative Study of the Role of Interepithelial Mucosal Mast Cells in the Context of Intestinal Adenoma-Carcinoma Progression

Abstract

Mast cells (MCs) are crucial players in the relationship between the tumor microenvironment (TME) and cancer cells and have been shown to influence angiogenesis and progression of human colorectal cancer (CRC). However, the role of MCs in the TME is controversially discussed as either pro- or anti-tumorigenic. Genetically engineered mouse models (GEMMs) are the most frequently used in vivo models for human CRC research. In the murine intestine there are at least three different MC subtypes: interepithelial mucosal mast cells (ieMMCs), lamina proprial mucosal mast cells (lpMMCs) and connective tissue mast cells (CTMCs). Interepithelial mucosal mast cells (ieMMCs) in (pre-)neoplastic intestinal formalin-fixed paraffin-embedded (FFPE) specimens of mouse models (total lesions n = 274) and human patients (n = 104) were immunohistochemically identified and semiquantitatively scored. Scores were analyzed along the adenoma-carcinoma sequence in humans and 12 GEMMs of small and large intestinal cancer. The presence of ieMMCs was a common finding in intestinal adenomas and carcinomas in mice and humans. The number of ieMMCs decreased in the course of colonic adenoma-carcinoma sequence in both species (p < 0.001). However, this dynamic cellular state was not observed for small intestinal murine tumors. Furthermore, ieMMC scores were higher in GEMMs with altered Wnt signaling (active β-catenin) than in GEMMs with altered MAPK signaling and wildtypes (WT). In conclusion, we hypothesize that, besides stromal MCs (lpMMCs/CTMCs), particularly the ieMMC subset is important for onset and progression of intestinal neoplasia and may interact with the adjacent neoplastic epithelial cells in dependence on the molecular environment. Moreover, our study indicates the need for adequate GEMMs for the investigation of the intestinal immunologic TME.

High Intraepithelial Mast Cell Density in Warthin’s Tumor

“…In tumors, they may contribute to tumor growth, angiogenesis, and immune suppression. Based on the data published so far, it was concluded that IEMCs appear only in pathological conditions (28).…”

Lysophosphatidylinositol Promotes Chemotaxis and Cytokine Synthesis in Mast Cells with Differential Participation of GPR55 and CB2 Receptors

“…Our data show important chemotactic effects of LPI on a cell culture that renders cells closely resembling mucosal MCs [ 47 ]. Although MCs with a connective tissue phenotype (i.e., expressing tryptase) have been found to be associated with tumors and tumor-associated MCs seem to suffer important changes to their phenotype due to conditions prevalent in the tumor environment [ 29 ], mucosal-type MCs have been importantly related to colon cancer [ 48 ] and to adenoma–carcinoma progression [ 49 ]. Future research should be conducted to analyze the effects that the LPI/GPR55 axis exerts on connective tissue MCs and whether this is related to the pro- and anti-tumoral roles that have been described for MCs.…”

Unlocking the Potential of the Human Microbiome for Identifying Disease Diagnostic Biomarkers

“…In addition to microbiome-based biomarkers, there is also an emerging interest in mast cells (MCs) [ 82 , 83 , 84 , 85 ], microRNAs (miRNAs) [ 86 , 87 ], imaging, and machine-learning models [ 42 ] as non-invasive disease diagnostic and prognostic biomarkers that promise to shape the future of precision medicine. Sometimes, there is a crosstalk between the human microbiota and other genetic or chemical biomarkers.…”