Cysteinyl leukotriene receptor 1 facilitates tumorigenesis in a mouse model of colitis-associated colon cancer.

Janina Osman,Anita Sjölander,Sayeh Savari,Naveen Kumar Chandrashekar,Desiree Douglas,Kishan Bellamkonda

doi:10.18632/oncotarget.16718

Janina Osman, Anita Sjölander + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.16718

Copy DOI

Journal: Oncotarget	Publication Date: Mar 30, 2017
Citations: 27	License type: cc-by

Affiliation: Skåne University Hospital

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.

Highlights

Patients suffering from inflammatory bowel disease (IBD) have an approximately 2- to 5-fold increased risk of developing colorectal cancer compared to age-matched healthy individuals
We have shown that the LTD4-induced CysLT1R signaling is important in promoting colorectal tumorigenesis by increasing the expression of proteins associated with cell survival (COX-2 and Cyclin D1) and increased proliferation and migration (β-catenin) in xenograft colon cancer and colon cancer cell lines [18,19,20]
The azoxymethane/dextran sulfate sodium (AOM/dextran sodium sulfate (DSS)) Cysteinyl leukotriene receptor 1 (Cysltr1)−/− mice euthanized at the early and late (CAC) endpoints had a significantly decreased colon weight/length ratio compared to their wild-type counterparts (Figure 1B and 1G)

Summary

Introduction

Patients suffering from inflammatory bowel disease (IBD) have an approximately 2- to 5-fold increased risk of developing colorectal cancer compared to age-matched healthy individuals. IBD involves chronic inflammation of the intestinal tract and includes ulcerative colitis (UC) and Crohn’s disease (CD) [1]. The risk factors of developing colorectal cancer in IBD patients include a family history of colorectal cancer, early age of onset of colitis and the concomitant presence of primary sclerosing cholangitis. In accordance with the link between chronic intestinal inflammation and the development of colorectal cancer, studies have shown that the treatment of IBD patients with anti-inflammatory amino salicylates reduces the risk of developing colorectal cancer [3]. In the azoxymethane/dextran sodium sulfate model of colitis-associated colorectal cancer (CAC), 5-amino salicylic acid has been shown to reduce the number of dysplastic lesions [4]

Methods

Results

Conclusion