title: Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells.
abstract: Histidine decarboxylase (HDC), the unique enzyme responsible for histamine generation, is highly expressed in myeloid cells, but its function in these cells is poorly understood. Here we show that Hdc-knockout mice show a high rate of colon and skin carcinogenesis. Using Hdc-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the Hdc promoter, we show that Hdc is expressed primarily in CD11b(+)Ly6G(+) immature myeloid cells (IMCs) that are recruited early on in chemical carcinogenesis. Transplant of Hdc-deficient bone marrow to wild-type recipients results in increased CD11b(+)Ly6G(+) cell mobilization and reproduces the cancer susceptibility phenotype of Hdc-knockout mice. In addition, Hdc-deficient IMCs promote the growth of tumor allografts, whereas mouse CT26 colon cancer cells downregulate Hdc expression through promoter hypermethylation and inhibit myeloid cell maturation. Exogenous histamine induces the differentiation of IMCs and suppresses their ability to support the growth of tumor allografts. These data indicate key roles for Hdc and histamine in myeloid cell differentiation and CD11b(+)Ly6G(+) IMCs in early cancer development.
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Center, Columbia University, New York, New York, USA.
authors.forename: Xiang Dong
authors.initials: XD
authors.lastname: Yang
authors.forename: Walden
authors.initials: W
authors.lastname: Ai
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.forename: Guangchun
authors.initials: G
authors.lastname: Jin
authors.forename: Heuijoon
authors.initials: H
authors.lastname: Park
authors.forename: Benjamin
authors.initials: B
authors.lastname: Shykind
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Diacovo
authors.forename: Andras
authors.initials: A
authors.lastname: Falus
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics*; D039481:CD11b Antigen / Q000235:genetics*; D002454:Cell Differentiation; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D003110:Colonic Neoplasms / Q000453:epidemiology* / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006632:Histamine / Q000172:deficiency*; D006640:Histidine Decarboxylase / Q000172:deficiency* / Q000235:genetics*; D007249:Inflammation / Q000139:chemically induced* / Q000150:complications; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012878:Skin Neoplasms / Q000453:epidemiology* / Q000473:pathology; D014184:Transplantation, Homologous / Q000473:pathology
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C480309:Ly6G antigen, mouse; D049452:Green Fluorescent Proteins; D006632:Histamine; D006640:Histidine Decarboxylase