Roberts David D, Isenberg Jeffery S, Ridnour Lisa A, Wink David A
Laboratory of Pathology and Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2007 Feb 1;13(3):795-8. doi: 10.1158/1078-0432.CCR-06-1758.
Nitric oxide (NO) plays a central role in angiogenesis as a mediator of signaling by vascular endothelial growth factor and other angiogenic factors. Low concentrations of NO produced in response to angiogenic factors stimulate angiogenesis, whereas higher concentrations typical of inflammatory responses inhibit angiogenesis. The proangiogenic activity of NO is mediated by activation of soluble guanylyl cyclase, leading to cyclic guanosine 3',5'-monophosphate accumulation and activation of its target kinases and ion channels. The four angiogenesis inhibitors currently approved for clinical use target components of the signaling cascade upstream of NO. New research has identified components downstream of NO as the primary target of the endogenous angiogenesis inhibitor thrombospondin-1 and has shown that circulating levels of thrombospondin-1 are sufficient to limit angiogenic responses by antagonizing NO signaling. This provides new insights into the significance of the widespread loss of thrombospondin-1 expression during malignant progression. Although clinical trials suggest that blocking NO signaling can inhibit tumor angiogenesis, this approach also inactivates inhibitory signaling from thrombospondin-1. We discuss the implications of the balance between these pathways for applying thrombospondin-1 mimetics and redox modifiers as cancer therapeutics.
一氧化氮（NO）作为血管内皮生长因子和其他血管生成因子信号传导的介质，在血管生成中起着核心作用。响应血管生成因子产生的低浓度NO刺激血管生成，而炎症反应中典型的较高浓度则抑制血管生成。NO的促血管生成活性由可溶性鸟苷酸环化酶的激活介导，导致环磷酸鸟苷积累及其靶激酶和离子通道的激活。目前批准用于临床的四种血管生成抑制剂靶向NO上游信号级联的组成部分。新的研究已确定NO下游的组成部分是内源性血管生成抑制剂血小板反应蛋白-1的主要靶点，并表明血小板反应蛋白-1的循环水平足以通过拮抗NO信号来限制血管生成反应。这为恶性进展过程中血小板反应蛋白-1表达广泛丧失的意义提供了新的见解。尽管临床试验表明阻断NO信号可以抑制肿瘤血管生成，但这种方法也会使来自血小板反应蛋白-1的抑制信号失活。我们讨论了这些途径之间的平衡对于应用血小板反应蛋白-1模拟物和氧化还原调节剂作为癌症治疗方法的意义。
