Cysteinyl leukotriene 1 receptor influences intestinal polyp incidence in a gender-specific manner in the ApcMin/+ mouse model

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 ApcMin/+ mouse model of familial adenomatous polyposis/sporadic colorectal cancer to investigate the role of CysLTR1 in intestinal tumorigenesis by crossing ApcMin/+ 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 ...
Source: Carcinogenesis - Category: Cancer & Oncology Authors: Tags: Original Manuscript Source Type: research