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Glioma tumourgenicity is decreased by iNOS knockout: experimental studies using the C6 striatal implantation glioma
S Yamaguchi1, H S Bell, J Shinoda
1Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Abstract:
Nitric oxide synthase (NOS) has recently been shown to be an important pathophysiological regulator in experimental implantation glioma since manipulation of NOS can significantly alter tumoural blood flow and inhibit tumour growth. In this study we investigated the role of iNOS (inducible NOS) in glioma tumourogenisis using the rodent C6 striatal implantation model. We produced genetically engineered C6 clones that do not express iNOS activity even after stimulation with a mixture of lipopolysaccaride (LPS) and tumour necrosis factor (TNF)-alpha. These iNOS knockout cells showed a similar growth rate to control cells in vivo at 5 days. We then performed an in vivo implantation glioma study using either the iNOS knockout clone or two genetically engineered control C6 clones. There was a significant reduction (p < 0.01) of tumour mass with the iNOS knockout clone 28 days after the implantation. Immunocytochemistry indicated infiltrates of CD3 positive T cells and macrophages in the controls and the iNOS knockout group. These studies indicate that iNOS expression by tumour parenchymal cells is a critical factor for tumour growth with this model. The mechanisms that cause failure of tumour growth need clarification prior to considering that specific iNOS inhibitors might be candidates for adjuvant treatment of malignant glioma.
Insights
Inducible nitric oxide synthase (iNOS) plays a critical role in glioma tumor growth. Inhibiting iNOS in tumor cells significantly reduced tumor mass in a rodent model, suggesting potential therapeutic strategies.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Immunology
Background:
- Nitric oxide synthase (NOS) regulates pathophysiological processes in experimental glioma.
- Manipulation of NOS affects tumor blood flow and growth.
Purpose of the Study:
- Investigate the role of inducible nitric oxide synthase (iNOS) in glioma tumourogenesis.
- Utilize a rodent C6 striatal implantation model for in vivo studies.
Main Methods:
- Generated genetically engineered C6 glioma clones lacking iNOS expression.
- Compared tumor growth and characteristics between iNOS knockout and control C6 clones in vivo.
- Performed immunocytochemistry to analyze cellular infiltrates.
Main Results:
- iNOS knockout C6 cells exhibited similar initial growth rates to controls.
- A significant reduction in tumor mass (p < 0.01) was observed with iNOS knockout clones at 28 days.
- Both groups showed infiltrates of CD3 positive T cells and macrophages.
Conclusions:
- iNOS expression by tumor parenchymal cells is critical for glioma growth in this model.
- Further research is needed to clarify mechanisms behind impaired tumor growth.
- iNOS inhibitors may be candidates for adjuvant therapy in malignant glioma.
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