文章：

一氧化氮在肿瘤进展中的作用

The role of nitric oxide in tumour progression

原文发布日期：2006-07-01

DOI: 10.1038/nrc1910

类型: Review Article

开放获取: 否

要点：

1. Nitric oxide (NO) is synthesized by nitric oxide synthases (NOSs), which are ubiquitously expressed in malignant tumours. NO regulates several physiological processes through the soluble-guanylyl-cyclase–cGMP pathway and S-nitrosylation, and has cytotoxic and genotoxic effects at high concentrations.
2. Tumour-cell-derived NO promotes tumour progression by induction of tumour-cell invasion, proliferation and the expression of angiogenic factors. The inducible isoform of NOS (iNOS), which produces high concentrations of NO, mediates neoplastic transformation in oncogene- and chemical-induced tumorigenesis models, although conflicting results are reported in the literature. Conversely, the transfection of iNOS-expressing constructs into NO-sensitive tumour cells inhibits tumour growth and metastasis.
3. Host stromal-cell-derived NO, which is synthesized by iNOS, inhibits growth of NO-sensitive tumours but promotes growth of NO-resistant tumours.
4. NO that is predominantly synthesized by endothelial NOS (eNOS) in vascular endothelial cells promotes angiogenesis directly and functions both upstream and downstream of angiogenic stimuli. Moreover, NO mediates recruitment of perivascular cells and, therefore, remodelling and maturation of blood vessels. NO that is synthesized by eNOS promotes tumour progression through the maintenance of blood flow, induction of vascular hyperpermeability and reduction of leukocyte–endothelial interactions.
5. Induction of NO signalling can induce direct tumour-cell cytotoxicity or sensitize tumour cells to other treatments such as radiation. Conversely, blockade of NO signalling can inhibit neoplastic transformation, tumour angiogenesis and blood flow.
6. Expression, activity and localization of NOS isoforms, concentration and duration of NO exposure, and cellular sensitivity to NO are important determinants of NO function. Further in vivo tumour studies with high spatial and temporal resolution should resolve conflicting issues in NO biology and guide the manipulation of NO signalling for future clinical use.

要点翻译：

1. 一氧化氮（NO）由一氧化氮合酶（NOSs）合成，这类酶在恶性肿瘤中普遍表达。NO通过可溶性鸟苷酸环化酶-cGMP通路和S-亚硝基化作用调控多种生理过程，高浓度时具有细胞毒性和遗传毒性。
2. 肿瘤细胞来源的NO通过诱导肿瘤细胞侵袭、增殖及血管生成因子表达促进肿瘤进展。诱导型NOS（iNOS）可产生高浓度NO，在癌基因和化学诱发性肿瘤模型中介导肿瘤转化，但文献报道存在矛盾结果。相反，将表达iNOS的载体转染至NO敏感型肿瘤细胞可抑制肿瘤生长和转移。
3. 由iNOS合成的宿主基质细胞来源NO能抑制NO敏感型肿瘤生长，但促进NO耐药型肿瘤生长。
4. 血管内皮细胞中主要由内皮型NOS（eNOS）合成的NO直接促进血管生成，并在血管生成刺激因子的上下游发挥作用。此外，NO介导血管周细胞募集，从而参与血管重塑与成熟。eNOS合成的NO通过维持血流、诱导血管高渗透性和减少白细胞-内皮相互作用促进肿瘤进展。
5. 诱导NO信号通路可直接引发肿瘤细胞毒性，或增强肿瘤细胞对其他疗法（如放疗）的敏感性。相反，阻断NO信号通路可抑制肿瘤转化、肿瘤血管生成及血流。
6. NOS亚型的表达、活性与定位，NO暴露的浓度与持续时间，以及细胞对NO的敏感性是决定NO功能的关键因素。开展具有高时空分辨率的体内肿瘤研究将解决NO生物学中的矛盾问题，为未来临床调控NO信号通路提供指导。

英文摘要：

Nitric oxide (NO) and nitric oxide synthases are ubiquitous in malignant tumours and are known to exert both pro- and anti-tumour effects. We summarize our current understanding of the role of NO in tumour progression, especially in relation to angiogenesis and vascular functions. We also discuss potential strategies for cancer treatment that modulate NO production and/or its downstream signalling pathways.

摘要翻译： 

一氧化氮（NO）及一氧化氮合酶在恶性肿瘤中广泛存在，并表现出促瘤和抑瘤的双重作用。我们总结了目前对NO在肿瘤进展中作用的理解，特别是其与血管生成和血管功能的关系；同时探讨了通过调节NO生成和/或其下游信号通路进行癌症治疗的潜在策略。

原文链接：

The role of nitric oxide in tumour progression