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- W3026619841 abstract "Colorectal cancer (CRC) remains one of the most common and deadliest malignancies in USA, including in Florida. CRC includes hereditary, sporadic, and colitis-associated cancer (CAC). CAC often shows rapid progression, poor response to treatment, and high mortality. In CAC, tumors are formed in the context of chronic inflammation, but ultimately the immune populations in colonic tumors acquire a suppressive phenotype. Among such populations, myeloid-derived suppressive cells (MDSCs), consisting of polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs, accumulate in the tumors and promote a tumor-suppressive microenvironment, together with tumor-associated macrophages. Numerous questions remain unanswered in regard to the biology and regulation of myeloid-suppressive populations in CAC. We found that the levels of the ubiquitin ligase Hectd3 were reduced in human inflamed ulcerative colitis (UC) tissues and in colonic tumors versus healthy matched colonic tissues. Hectd3 KO mice developed more severe dextran sodium sulfate (DSS)-induced colitis and larger and more numerous colonic tumors in the azoxymethane (AOM)/DSS model of CAC. Bone marrow chimera experiments demonstrated that both the hematopoietic and nonhematopoietic compartments play roles in the phenotype, in DSS colitis and in AOM/DSS CAC model. During DSS-induced colitis we found that genes for several proinflammatory cytokines were upregulated in the colons of Hectd3 KO mice, including IL6, IL11 and G-CSF, as well for Lipocalin-2, associated with inflammation. However, in the colonic tumors of Hectd3 KO mice, the CD11b+ CD11c- myeloid cells were elevated and showed increased Arginase 1 and iNOS levels and frequencies, suggestive of a suppressive phenotype. We hypothesize that absence of Hectd3 promotes a highly inflammatory phenotype in the colon, and further an immune-suppressive phenotype in the colonic tumors through regulation of specific signaling pathways in myeloid populations. Citation Format: Ashley Zuniga, Upasana Parthasarath, Jonathan Cho, Theodore Drashansky, Eric Helm, Kyle Lorentsen, Zhen He, Christian Jobin, Dorina Avram. Hectd3 protects against colitis and colon cancer development through maintenance of homeostatic immune environment in the gut [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A25." @default.
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- W3026619841 date "2020-04-01" @default.
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- W3026619841 title "Abstract A25: Hectd3 protects against colitis and colon cancer development through maintenance of homeostatic immune environment in the gut" @default.
- W3026619841 doi "https://doi.org/10.1158/2326-6074.tumimm18-a25" @default.
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