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

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Author

  • Sayeh Savari
  • Naveen Kumar Chandrashekar
  • Janina Osman
  • Desiree Douglas
  • Kishan Bellamkond
  • Gunilla Jönsson
  • Maria Juhas
  • Gediminas Greicius
  • Sven Pettersson
  • Anita Sjölander

Summary, in English

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.

Department/s

  • Cell Pathology, Malmö
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2016-03-15

Language

English

Pages

491-499

Publication/Series

Carcinogenesis

Volume

37

Issue

5

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Cell and Molecular Biology

Status

Published

Research group

  • Cell Pathology, Malmö

ISBN/ISSN/Other

  • ISSN: 0143-3334