Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 138, Issue 11, Pages 2678-2687Publisher
WILEY
DOI: 10.1002/ijc.29997
Keywords
nitric oxide; nitric oxide synthase; inducible expression; MRI; tumour vessel maturation
Categories
Funding
- Association for International Cancer Research (AICR) [09-0310]
- Biotechnology and Biological Sciences Research Council [S20430
- ]
- Medical Research Council (MRC)
- St. George's Hospital Medical School
- Biotechnology and Biological Sciences Research Council [S20430] Funding Source: researchfish
- Cancer Research UK [16464] Funding Source: researchfish
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Nitric oxide (NO) is a free radical signalling molecule involved in various physiological and pathological processes, including cancer. Both tumouricidal and tumour promoting effects have been attributed to NO, making its role in cancer biology controversial and unclear. To investigate the specific role of tumour-derived NO in vascular development, C6 glioma cells were genetically modified to include a doxycycline regulated gene expression system that controls the expression of an antisense RNA to inducible nitric oxide synthase (iNOS) to manipulate endogenous iNOS expression. Xenografts of these cells were propagated in the presence or absence of doxycycline. Susceptibility magnetic resonance imaging (MRI), initially with a carbogen (95% O-2/5% CO2) breathing challenge and subsequently an intravascular blood pool contrast agent, was used to assess haemodynamic vasculature (Delta R-2*) and fractional blood volume (fBV), and correlated with histopathological assessment of tumour vascular density, maturation and function. Inhibition of NO production in C6 gliomas led to significant growth delay and inhibition of vessel maturation. Parametric fBV maps were used to identify vascularised regions from which the carbogen-induced Delta R-2* was measured and found to be positively correlated with vessel maturation, quantified ex vivo using fluorescence microscopy for endothelial and perivascular cell staining. These data suggest that tumour-derived iNOS is an important mediator of tumour growth and vessel maturation, hence a promising target for anti-vascular cancer therapies. The combination of Delta R-2* response to carbogen and fBV MRI can provide a marker of tumour vessel maturation that could be applied to non-invasively monitor treatment response to iNOS inhibitors.
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