| 1. |
- Bellamkonda, Kishan, et al.
(författare)
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Montelukast, a CysLT1 receptor antagonist, reduces colon cancer stemness and tumor burden in a mouse xenograft model of human colon cancer
- 2018
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835. ; 437, s. 13-24
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is implicated in the etiology of sporadic colon cancer (CC), which is one of the leading causes of cancer-related deaths worldwide. Here, we report that inhibition of the inflammatory receptor CysLT1 through its antagonist, montelukast, is beneficial in minimizing stemness in CC and thereby minimizing tumor growth in a mouse xenograft model of human colon cancer. Upon treatment with montelukast, colonospheres derived from HT-29 and SW-480 human colon cancer cells exhibited a significant phenotypic change coupled with the downregulation of mRNA and protein expression of cancer stem cell (CSC) markers ALDH1 and DCLK1. Moreover, montelukast reduced the size of HT-29 cell-derived tumors in mice. The reduction in tumor size was associated with decreased levels of ALDH1A1, DCLK1, BCL2 mRNA and macrophage infiltration into the tumor tissue. Interestingly, this treatment elevated levels of the tumor suppressor 15-PGDH while reducing COX-2 expression. Our data highlight the association of CysLT1R with CSCs and demonstrate that inhibition of CysLT1R could prove beneficial in minimizing CSC-induced tumor growth. This work advances the notion that targeting CSCs is a promising approach to improve outcomes in those afflicted with colon cancer.
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| 2. |
- Osman, Janina, et al.
(författare)
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Cysteinyl leukotriene receptor 1 facilitates tumorigenesis in a mouse model of colitis-associated colon cancer
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:21, s. 34773-34786
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Tidskriftsartikel (refereegranskat)abstract
- Cysteinyl leukotriene receptor 1 (CysLT1R) has been shown to be up-regulated in the adenocarcinomas of colorectal cancer patients, which is associated with a poor prognosis. In a spontaneous model of colon cancer, CysLT1R disruption was associated with a reduced tumor burden in double-mutant female mice (ApcMin/+/Cysltr1-/-) compared to ApcMin/+ littermates. In the current study, we utilized a genetic approach to investigate the effect of CysLT1R in the induced azoxymethane/dextran sulfate sodium (AOM/DSS) model of colitis-associated colon cancer. We found that AOM/DSS female mice with a global disruption of the Cysltr1 gene (Cysltr1-/-) had a higher relative body weight, a more normal weight/length colon ratio and smaller-sized colonic polyps compared to AOM/DSS wild-type counterparts. The Cysltr1-/- colonic polyps exhibited low-grade dysplasia, while wild-type polyps had an adenoma-like phenotype. The Cysltr1-/- colonic polyps exhibited significant decreases in nuclear β-catenin and COX-2 protein expression, while the normal crypts surrounding the polyps exhibited increased Mucin 2 expression. Furthermore, Cysltr1-/- mice exhibited an overall reduction in inflammation, with a significant decrease in proinflammatory cytokines, polyp 5-LOX expression and infiltration of CD45 leukocytes and F4/80 macrophages. In conclusion, the present genetic approach in an AOM/DSS model further supports an important role for CysLT1R in colon tumorigenesis.
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| 3. |
- Savari, Sayeh, et al.
(författare)
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Cysteinyl leukotriene 1 receptor influences intestinal polyp incidence in a gender-specific manner in the ApcMin/+ mouse model
- 2016
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 37:5, s. 491-499
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Tidskriftsartikel (refereegranskat)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 (5-LOX), is associated with poor prognosis in patients with colorectal adenocarcinomas. Apc mutation is an early event in the development of sporadic and hereditary (FAP) colorectal cancer. We utilized the Apc(Min/+) mouse model of FAP/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 to 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 to control littermates. The female double-mutant phenotype was accompanied with decreased systemic inflammation, as evidenced by significantly reduced serum levels of PGE2 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.
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