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

SIMPLE SUMMARY: The role of mast cells in the tumor microenvironment (TME) remains controversial but has become increasingly evident and explored as a possible therapeutic target. In this study, we investigated the underexplored mast cell heterogeneity of intestinal cancer by applying standardized mast cell subtyping during adenoma-carcinoma progression. We immunohistochemically evaluated and scored the occurrence of interepithelial mucosal mast cells (ieMMCs) in tumors of frequently employed genetically engineered mouse models and in human colonic adenomas and carcinomas. We found a decrease of ieMMCs from colonic low-grade adenomas to carcinomas. Moreover, mouse models based on altered Wnt signaling showed higher ieMMC scores than models based on altered MAPK signaling. Our descriptive study indicates that ieMMCs play a special role in the molecular TME related to adenoma-carcinoma progression. Furthermore, it emphasizes the need for adequate immunohistochemical methodology and experimental setup when investigating the functional role of mast cell populations of the TME. 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.