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  • 1
    Keywords: SURVIVAL ; TUMOR PROGRESSION ; COLON-CANCER ; PROGNOSTIC-SIGNIFICANCE ; INFLAMMATORY-BOWEL-DISEASE ; PHOSPHOINOSITIDE 3-KINASE ; PRIMARY COLORECTAL-CANCER ; PIK3CA MUTATIONS ; CHRONIC ULCERATIVE-COLITIS ; BETA-CATENIN ACTIVATION
    Abstract: PURPOSE: To understand signaling pathways that shape inflamed tissue and predispose to cancer is critical for effective prevention and therapy for chronic inflammatory diseases. We have explored phosphoinositide 3-kinase (PI3K) activity in human inflammatory bowel diseases and mouse colitis models. EXPERIMENTAL DESIGN: We conducted immunostaining of phosphorylated AKT (pAKT) and unbiased high-throughput image acquisition and quantitative analysis of samples of noninflamed normal colon, colitis, dysplasia, and colorectal cancer. Mechanistic insights were gained from ex vivo studies of cell interactions, the piroxicam/IL-10(-/-) mouse model of progressive colitis, and use of the PI3K inhibitor LY294002. RESULTS: Progressive increase in densities of pAKT-positive tumor-associated macrophages (TAM) and increase in densities of mast cells in the colonic submucosa were noted with colitis and progression to dysplasia and cancer. Mast cells recruited macrophages in ex vivo migration assays, and both mast cells and TAMs promoted invasion of cancer cells. Pretreatment of mast cells with LY294002 blocked recruitment of TAMs. LY294002 inhibited mast cell and TAM-mediated tumor invasion, and in mice, blocked stromal PI3K, colitis, and cancer. CONCLUSION: The PI3K/AKT pathway is active in cells infiltrating inflamed human colon tissue. This pathway sustains the recruitment of inflammatory cells through a positive feedback loop. The PI3K/AKT pathway is essential for tumor invasion and the malignant features of the piroxicam/IL-10(-/-) mouse model. LY294002 targets the PI3K pathway and hinders progressive colitis. These findings indicate that colitis and progression to cancer are dependent on stromal PI3K and sensitive to treatment with LY294002. Clin Cancer Res; 19(9); 2342-54. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 23487439
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  • 2
    Abstract: Melanoma is an aggressive skin cancer, however it is immunogenic. The size of the primary tumor is associated with the nodal metastases. Our goals were to characterize melanoma-associated antigens (MAAs) and tumor-infiltrating T-lymphocytes (TILs) subsets in the few very large tumors (VLTs) developing in ret transgenic mice of melanoma. Tumors 〉700mg (VLTs) were investigated for MAAs and subsets of TILs. Immunohistochemistry and flow cytometry-based studies were performed to determine the infiltration patterns of T-lymphocytes in VLTs. It was observed that zinc fixative restores the antigenicity of the cell-surface markers of lymphocyte subpopulations without the need of antigen retrieval, whereas formalin-based fixative fails to restore the antigenicity in the presence of antigen retrieval in the immunohistochemistry. VLTs from ret mice express MAAs, such as Tyrosinase, TRP-1, TRP-2 and gp-100. The mean+/-standard deviation (S.D.) T-cell infiltration per 400 times-high power field in VLTs; CD4+ (2.33+/-1.3), CD8+ (2.00+/-1.0), and CD4+ Foxp3+ (2.5+/-0.5) regulatory T cells infiltration was exclusively restricted to the tumor stroma. Moreover, our flow cytometry-based data reveal that % mean+/-S.D. naive CD3+ CD4+ T cell infiltration (32.8+/-4.0%) was significantly larger than effector (25.8+/-2.8%, p〈0.01) and central memory cells (16.1+/-3.7%, p〈0.001) in VLTs. Similarly, between CD3+ CD8+ T cells, naive cells infiltrate (57.7+/-2.3%) in a significantly larger frequency than effector (5.0+/-0.4%, p〈0.0001) and central memory cell (4.8+/-1.7%, p〈0.0001) subsets. These results suggest that the VLTs from ret mice display lowered infiltration ratios between memory and naive T cells, which could be associated with the relatively large growth of VLTs.
    Type of Publication: Journal article published
    PubMed ID: 27397900
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  • 3
    Keywords: MICE ; SUPPRESSION ; COLORECTAL-CANCER ; GRANZYME-B ; inflammation ; INTERLEUKIN-10 ; MAST-CELLS ; HELPER-CELLS ; TH17 CELLS ; LINEAGE DIFFERENTIATION
    Abstract: 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. We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and RORgammat. T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORgammat gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor-alpha in polyp-prone mice reduced polyp number but not to the same extent as loss of RORgammat. Surprisingly, loss of IL-17A had a dual effect: IL-17A-deficient mice had fewer polyps but continued to have RORgammat(+) T(regs) and developed invasive cancer. Thus, we conclude that RORgammat has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.
    Type of Publication: Journal article published
    PubMed ID: 23241743
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