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Real-time Imaging of Myeloid Cells Dynamics in ApcMin/+ Intestinal Tumors by Spinning Disk Confocal Microscopy
Published on: October 6, 2014
Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the Apc(Min/+) mouse
D J Scott1, M A Hull, E J Cartwright
1Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds, England, UK.
Background & Aims:
The role of the inducible isoform of nitric oxide synthase (Nos2 or iNOS) in intestinal tumorigenesis is unclear. Conflicting data also exist regarding the ability of Nos2 to modulate expression and/or activity of cyclooxygenase 2 (Cox-2), which promotes intestinal tumorigenesis. Therefore, we determined the effect of a null Nos2 genotype on intestinal tumorigenesis and Cox-2 expression/activity in the Apc(Min/+) mouse model of familial adenomatous polyposis.
Methods:
Apc(Min/+)Nos2(-/-) mice were generated by successive crosses between C57BL/6-Apc(Min/+) and C57BL/6-Nos2(tm1Lau) mice. Adenoma characteristics of age-matched Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) mice were compared. The level and cellular localization of Nos2 messenger RNA (mRNA) expression in Apc(Min/+)Nos2(+/+) mouse intestine was determined. Cox-2 expression and activity were measured in both intestinal tissue and bone marrow-derived macrophages in vitro.
Results:
Apc(Min/+)Nos2(-/-) mice developed significantly more intestinal adenomas than Apc(Min/+)Nos2(+/+) littermates. Epithelial cell Nos2 mRNA expression was decreased in adenomas compared with histologically normal Apc(Min/+)Nos2(+/+) intestine. There was no significant difference in Cox-2 expression or activity in either intestine or bone marrow-derived macrophages from Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) animals.
Conclusions:
Nos2 plays an antineoplastic role in the Apc(Min/+) mouse model of familial adenomatous polyposis. Nos2 does not modulate Cox-2 expression or activity in the Apc(Min/+) mouse.
Insights
The inducible nitric oxide synthase (Nos2) gene acts to prevent intestinal tumors in a mouse model. Nos2 deficiency increased adenoma formation and did not affect cyclooxygenase 2 (Cox-2) levels.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- The role of inducible nitric oxide synthase (Nos2) in intestinal cancer is not well understood.
- Conflicting data exist regarding Nos2's influence on cyclooxygenase 2 (Cox-2), a known tumor promoter.
Purpose of the Study:
- To investigate the effect of a null Nos2 genotype on intestinal tumorigenesis.
- To determine if Nos2 influences Cox-2 expression and activity in the Apc(Min/+) mouse model.
Main Methods:
- Generated Apc(Min/+)Nos2(-/-) mice.
- Compared adenoma characteristics between Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) mice.
- Assessed Nos2 mRNA, Cox-2 expression, and Cox-2 activity in intestinal tissue and macrophages.
Main Results:
- Apc(Min/+)Nos2(-/-) mice exhibited significantly more intestinal adenomas than controls.
- Nos2 mRNA expression was lower in adenomas compared to normal tissue.
- No significant differences in Cox-2 expression or activity were observed between genotypes.
Conclusions:
- Nos2 plays an anti-neoplastic role in this mouse model of intestinal polyposis.
- Nos2 does not modulate Cox-2 expression or activity in the Apc(Min/+) mouse model.
