Cell Intrinsic Deregulated ß-Catenin Signaling Promotes Expansion of Bone Marrow Derived Connective Tissue Type Mast Cells, Systemic Inflammation, and Colon Cancer

Abstract

Mast cells constitutively express ß-catenin and expand in solid tumors such as colon and skin cancer. However, the role of ß-catenin signaling in mast cells and the cause or effect of mast cell expansion and tumor growth has yet to be established. In earlier studies we used mast cell depletion and protease staining approaches, to provide evidence for a causative role of mast cells in small bowel polyposis, and related specific phenotypes and distributions of tumor infiltrating mast cells to stages of tumor growth. Here we report that, stabilization of ß-catenin expands mast cells to promote high incidence of colon polyposis and infrequent small bowel polyps and skin cancer. Expression of a dominant acting ß-catenin in mast cells (5CreCAT) stimulated maturation and expression of granule stored proteases. Both mucosal and connective tissue type mast cells accumulated in colonic small bowel polyps independent of gender, and mice developed chronic systemic inflammation with splenomegaly. Reconstitution of polyposis-prone mice with bone marrow from 5CreCAT mice resulted in focal expansion of connective tissue like mast cells, which are normally rare in benign polyps and characteristically expand during adenoma-to-carcinoma transition. Our findings highlight a hitherto unknown contribution of ß-catenin signaling in mast cells to their maturation and to increased risk of colon cancer.

Helper innate lymphoid cells as cell therapy for cancer

“…Another study using the B16 murine melanoma model found that ILC2 cells expanded by IL‐33 promoted tumour growth by inhibiting the activation and cytotoxicity of NK cells [54]. In a spontaneous mouse model of colon cancer, Saadalla et al described increased numbers of ILC2 cells in colon adenomas as compared to adjacent healthy tissue, although the impact of these ILC2 cells on cancer progression was not addressed [55]. Consistent with ILC2 accumulation in colon cancer, IL‐33 expression was shown to be elevated in mouse intestinal polyps [56], and was also detected in human colon cancer epithelial cells [57, 58].…”

“…cancer progression was not addressed [55]. Consistent with ILC2 accumulation in colon cancer, IL-33 expression was shown to be elevated in mouse intestinal polyps [56], and was also detected in human colon cancer epithelial cells [57,58].…”

The emerging role of mast cells in skin cancers: involved cellular and molecular mechanisms

“…Chronic activation of ß‐catenin in rodent MCs has been reported to be associated with the development of skin cancers. However, the molecular mechanism needs to be clarified 64 . Although an increased number of MCs and their positive correlation with the progression of tumors have been reported in the majority of papers, the accumulation of MCs in different tumor types may act in favor of a better prognosis.…”

“…However, the molecular mechanism needs to be clarified. 64 Although an increased number of MCs and their positive correlation with the progression of tumors have been reported in the majority of papers, the accumulation of MCs in different tumor types may act in favor of a better prognosis. For instance, higher numbers of MCs in OSCC correlate negatively with lymph node metastasis.…”

The Regulation of Intestinal Inflammation and Cancer Development by Type 2 Immune Responses

“…In turn, MC directly promoted tumor cell proliferation [ 176 ]. Like stem cells, MC also express beta-catenin, an important pro-proliferative molecule that is activated in response to Wnt ligands secreted by colonic tumor cells [ 177 ]. Strikingly, the activation of beta-catenin in MCs was shown to induce the formation of colonic polyps.…”