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Published on: July 20, 2019
Suppression of cytokine-inducible nitric oxide synthesis during intraperitoneal Meth A tumor growth
Oh-Deog Kwon1, Chang-Yeol Yim, Kyu-Shik Jeong
1University of Utah Cancer Immunotherapy Program, Department of Internal Medicine of the University of Utah School of Medicine, Salt Lake City, 84132, USA.
Abstract:
Nitric oxide (NO*) synthesis is induced within many tumors. The time course of NO* synthesis was evaluated during intra-peritoneal Meth A fibrosarcoma progression. While increasing macrophage recruitment into ascites was noted, inducible nitric oxide synthase (iNOS) antigen and function peaked between days 3-6 after tumor implantation. The capacity of cells to respond to LPS and IFNgamma stimulation was markedly depressed on day 9 and 11. Cellular proliferation correlated in an inverse fashion with levels of NO* synthesis. Electron paramagnetic resonance spectroscopy and nitrotyrosine immunostaining failed to show accumulation of characteristic target cell lesions induced by NO*. These findings lead us to conclude that NO* production was increasingly suppressed during Meth A tumor progression. Depression of NO* production did not correlate with levels of the inhibitory cytokines TGFbeta and IL-10, but could be partially overcome by addition of sepiapterin (a tetrahydrobiopterin prodrug). Thus, depletion of essential co-factors necessary for iNOS function may contribute to depressed NO* responses during cancer progression.
Insights
Nitric oxide (NO) synthesis decreases during Meth A fibrosarcoma tumor progression. This suppression may stem from essential co-factor depletion impacting inducible nitric oxide synthase (iNOS) function.
Area of Science:
- Immunology
- Cancer Biology
- Biochemistry
Background:
- Nitric oxide (NO) synthesis is upregulated in various tumors.
- Understanding NO's role in tumor progression is crucial for therapeutic development.
Purpose of the Study:
- To investigate the temporal dynamics of NO synthesis during Meth A fibrosarcoma progression.
- To identify factors contributing to altered NO production in the tumor microenvironment.
Main Methods:
- Monitoring macrophage recruitment and inducible nitric oxide synthase (iNOS) activity in ascites.
- Assessing cellular responsiveness to lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma).
- Utilizing electron paramagnetic resonance spectroscopy and nitrotyrosine immunostaining.
Main Results:
- iNOS antigen and function peaked between days 3-6 post-implantation, followed by a decline.
- Cellular response to LPS and IFN-gamma was significantly impaired by day 9.
- Cellular proliferation showed an inverse correlation with NO synthesis levels.
- No characteristic NO-induced target cell lesions were detected.
Conclusions:
- NO production is progressively suppressed during Meth A tumor progression.
- This suppression is not directly linked to inhibitory cytokines TGF-beta and IL-10.
- Sepiapterin supplementation partially restored NO production, suggesting co-factor depletion (tetrahydrobiopterin) as a contributing factor.
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