title: Cysteinyl leukotriene 1 receptor influences intestinal polyp incidence in a gender-specific manner in the ApcMin/+ mouse model.
abstract: There is emerging literature emphasizing the role of inflammatory eicosanoids, including prostaglandins and leukotrienes, in cancer development. Increased expression of both the cysteinyl leukotriene receptor 1 (CysLTR1) and the enzyme responsible for the production of leukotrienes, 5-lipoxygenase, is associated with poor prognosis in patients with colorectal adenocarcinomas. Apc mutation is an early event in the development of sporadic and hereditary (familial adenomatous polyposis) colorectal cancer. We utilized the Apc(Min/+) mouse model of familial adenomatous polyposis/sporadic colorectal cancer to investigate the role of CysLTR1 in intestinal tumorigenesis by crossing Apc(Min/+) mice with mice lacking the Cysltr1 gene. We could observe a reduced tumor burden in the small intestine of double-mutant female (Cysltr1 (-/-) Apc (Min/+) ) but not double-mutant male mice, compared with gender-matched single-mutant (Cysltr1 (+/+) Apc (Min/+) ) mice. This reduction was in a Cysltr1-dependent manner, female double-mutant mice having significantly reduced tumor formation compared with control littermates. The female double-mutant phenotype was accompanied with decreased systemic inflammation, as evidenced by significantly reduced serum levels of prostaglandin E2 and CysLTs, as well as increased CD3(+)CD8(+) T-cell tumor infiltration. Furthermore, the reduced formation of polyps in double-mutant (Cysltr1 (-/-) Apc (Min/+) ) female mice could in part be explained by the cytotoxic action of CD3(+)CD8(+) T cells in the polyp and reduced nuclear accumulation of β-catenin in the epithelium of small intestinal polyps. Our results stress the important role that CysLTR1 plays in colorectal cancer and its potential as a therapeutic target in cancer therapy.
authors.forename: Sayeh
authors.initials: S
authors.lastname: Savari
authors.forename: Naveen Kumar
authors.initials: NK
authors.lastname: Chandrashekar
authors.forename: Janina
authors.initials: J
authors.lastname: Osman
authors.forename: Desiree
authors.initials: D
authors.lastname: Douglas
authors.forename: Kishan
authors.initials: K
authors.lastname: Bellamkonda
authors.forename: Gunilla
authors.initials: G
authors.lastname: Jönsson
authors.forename: Maria
authors.initials: M
authors.lastname: Juhas
authors.affiliation: Laboratory of Inflammation Biology, Department of Cellular and Molecular Research, National Cancer Centre Singapore, 9 Hospital Drive, Singapore 169612, Singapore and Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Gedas
authors.initials: G
authors.lastname: Greicius
authors.affiliation: Laboratory of Inflammation Biology, Department of Cellular and Molecular Research, National Cancer Centre Singapore, 9 Hospital Drive, Singapore 169612, Singapore and Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Pettersson
authors.forename: Anita
authors.initials: A
authors.lastname: Sjölander
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000097:blood / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007417:Intestinal Polyps / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics; D018077:Receptors, Leukotriene / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; C524626:Muc2 protein, mouse; D055262:Mucin-2; D018077:Receptors, Leukotriene; C000613192:adenomatous polyposis coli protein, mouse; D051176:beta Catenin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D015232:Dinoprostone; C083169:leukotriene D4 receptor