The enzyme histidine decarboxylase (HDC) converts L-histidine to histamine, a biogenic amine that functions in numerous physiologic processes, but has increasingly been linked to immune regulation. Work from our laboratory using HDC-EGFP BAC transgenic reporter mice has demonstrated that HDC is highly expressed in CD11b+Ly6G+ immature myeloid cells (IMCs) that exhibit cell surface markers similar to myeloid-derived suppressor cells (MDSCs) or tumor-associated neutrophils (TAN). These HDC-expressing cells are recruited early on in an AOM/DSS model of colorectal carcinogenesis. HDC-/- mice that are deficient in histamine production exhibit markedly increased inflammatory responses to AOM/DSS and thus increased colon carcinogenesis, due largely to deficient myeloid maturation. HDC-/- mice show increased circulating CD11b+Ly6G+ IMCs and decreased mature neutrophils and macrophages, due to a requirement for histamine for normal maturation and differentiation of CD11b+Ly6G+ myeloid progenitors. Transplant of HDC deficient bone marrow to wild type recipients results in increased CD11b+Ly6G+ cell mobilization and reproduces the cancer susceptibility phenotype. CD11b+Ly6G+ IMCs from HDC-KO mice show increased proinflammatory cytokine expression and induce greater growth of colon cancer xenografts. IMCs accumulate in early stages of mouse and human colonic neoplasia, due to downregulation of HDC gene expression by cancer cells leading to inhibition of myeloid cell maturation, suggesting a novel mechanism by which tumors promote an active tumor microenvironment. Taken together, these data indicate key roles for HDC/histamine in myeloid cell differentiation, and CD11b+Ly6G+ IMCs in early colon cancer development. We are proposing four specific aims: (1) Are HDC-expressing CD11b+Gr1+ cells myeloid precursors that give rise to mature monocytes and granulocytes and other cell types? We will utilize HDC-BAC-Cre-ERTM mice developed in our laboratory to trace the development and differentiation of the myeloid cell lineage, both in vitro and in vivo. (2) How are HDC-expressing IMCs recruited during carcinogenic stimuli? We will examine the role of IL-1beta, IL-6, and RAGE ligands (S100A8/A9), and test the effect of IL-1beta blockade and RAGE deletion on IMC recruitment. (3) How do tumors downregulate HDC to inhibit myeloid cell differentiation and maturation? We will examine changes in methylation of the HDC CpG promoter sites during co-culture of IMCs with tumor cells, and explore the possible role of TGF-beta in modulating myeloid cell differentiation. (4) Are HDC-expressing IMC cells critical to the initiation and promotion of colorectal cancer? HDC-BAC-Cre-ERTM mice will be crossed to Ikkbeta F/F and DTR F/F mice, and we will also explore the importance of histamine in carcinogenesis.
Chronic inflammation is a major cause of cancer, but the immune cell types that contribute to cancer progression have not been defined. Histamine, a secreted substance that contributes to allergies, appears to be primarily generated in the body in immature white blood cells by an enzyme called histidine decarboxylase or HDC. An absence of this enzyme leads to reduced histamine formation and interestingly an increased susceptibility to cancer. We have generated mice that express a fluorescent protein (green fluorescent protein or GFP) and an enzyme (Cre recombinase) in their white blood cells that make HDC, and thus we can tag or follow these cells, In addition, we have mice that are deficient in histamine production (HDC knockout mice). Using these mouse models, we plan to study the white blood cells that make histamine and determine how they are recruited to early cancer sites and how these white blood cells drive early cancer formation. Understanding the role of these immature, histamine producing white blood cells may lead to a number of cancer prevention or treatment strategies.
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