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

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.

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

Mast cells (MCs) are tissue resident sentinels that mature and orchestrate inflammation in response to infection and allergy. While they are also frequently observed in tumors, the contribution of MCs to carcinogenesis remains unclear. Here, we show that sequential oncogenic events in gut epithelia expand different types of MCs in a temporal-, spatial-, and cytokine-dependent manner.

T-cell Expression of IL10 Is Essential for Tumor Immune Surveillance in the Small Intestine.

IL10 is attributed with immune-suppressive and anti-inflammatory properties, which could promote or suppress cancer in the gastrointestinal tract. Loss of IL10 exacerbates colonic inflammation, leading to colitis and cancer. Consistent with this, transfer of IL10-competent regulatory T cells (Treg) into mice with colitis or hereditary polyposis protects against disease, while IL10-deficient mice are predisposed to polyposis with increased colon polyp load.

Oral interleukin-10 alleviates polyposis via neutralization of pathogenic T-regulatory cells.

Immune dysregulation drives the pathogenesis of chronic inflammatory, autoimmune, and dysplastic disorders. While often intended to address localized pathology, most immune modulatory therapies are administered systemically and carry inherent risk of multiorgan toxicities. Here, we demonstrate, in a murine model of spontaneous gastrointestinal polyposis, that site-specific uptake of orally administered IL10 microparticles ameliorates local and systemic disease to enhance survival.

Current status of interleukin-10 and regulatory T-cells in cancer.

Purpose Of Review: Tumor growth elicits antigen-specific cytotoxic as well as immune suppressive responses. Interleukin-10 (IL-10) is a key immune-suppressive cytokine produced by regulatory T-cells and by helper T-cells. Here, we review pleiotropic functions of IL-10 that impact the immune pathology of cancer.

Adenomatous polyps are driven by microbe-instigated focal inflammation and are controlled by IL-10-producing T cells.

Interleukin (IL)-10 is elevated in cancer and is thought to contribute to immune tolerance and tumor growth. Defying these expectations, the adoptive transfer of IL-10-expressing T cells to mice with polyposis attenuates microbial-induced inflammation and suppresses polyposis. To gain better insights into how IL-10 impacts polyposis, we genetically ablated IL-10 in T cells in APC(Δ468) mice and compared the effects of treatment with broad-spectrum antibiotics.

Quantitative magnetic resonance imaging in the transgenic APC(Δ468) mouse model of hereditary colon cancer.

In this study, we investigated the use of high-resolution magnetic resonance imaging (MRI) methods for in vivo detection and quantitative characterization of colorectal tumors in the transgenic APC(Δ468) mouse model. High-resolution T(1)-weighted (T(1)W) images, T(2)-weighted (T(2)W) images, and dynamic contrast-enhanced (DCE) measurements were performed using a 7.0 T small-animal imaging system (N = 10).

Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.

The role of regulatory T cells (T(regs)) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T(regs) have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T(reg) subsets.

Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APCDelta468 mice.

Arachidonic acid metabolism has been implicated in colon carcinogenesis, but the role of hematopoietic 5-lipoxygenase (5LO) that may impact tumor immunity in development of colon cancer has not been explored. Here we show that tissue-specific deletion of the 5LO gene in hematopoietic cells profoundly attenuates polyp development in the APC(Δ468) murine model of colon polyposis. In vitro analyses indicated that mast cells in particular utilized 5LO to limit proliferation of intestinal epithelial cells and to mobilize myeloid-derived suppressor cells (MDSCs).