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首页> 外文期刊>International Journal of Cancer =: Journal International du Cancer >Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system
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Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system

机译：使用四环素调节表达系统研究肿瘤细胞衍生in Inos在肿瘤生长和脉管系统中的作用

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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.
机译：一氧化氮（NO）是涉及各种生理和病理过程的自由基信号分子，包括癌症。肿瘤和肿瘤促进作用都归因于否，使其在癌症生物学中的作用争议且不清楚。为了探讨肿瘤衍生的NO在血管发育中的特定作用，遗传修饰C6胶质瘤细胞以包括一种强囊素调节基因表达系统，其控制反义RNA对诱导型一氧化氮合酶（InOS）的表达以操纵内源性InOS表达。这些细胞的异种移植物在不存在或不存在下繁殖。易感性磁共振成像（MRI）最初用肉毒原（95％O-2/5％CO 2）呼吸攻击和随后是血管内血吸造影剂，用于评估血管动力学脉管系统（DELTA R-2 *）和分数血液体积（FBV），与肿瘤血管密度的组织病理学评估相关，成熟和功能相关。在C6胶质瘤中抑制不产生的产生导致显着的生长延迟和血管成熟的抑制作用。参数化FBV地图用于鉴定测量肌肉引起的ΔR-2 *的血管化区域，发现使用荧光显微镜对内皮和血管细胞染色来呈血管成熟的呈正相关。这些数据表明肿瘤衍生的InOS是肿瘤生长和血管成熟的重要介质，因此是抗血管癌治疗的有希望的靶标。 Delta R-2 *对碳酸根和FBV MRI的反应的组合可以提供肿瘤血管成熟的标记，其可以应用于对INOS抑制剂的非侵入性监测治疗响应。

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