Isenberg Jeff S, Hyodo Fuminori, Ridnour Lisa A, Shannon Caitlin S, Wink David A, Krishna Murali C, Roberts David D
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Neoplasia. 2008 Aug;10(8):886-96. doi: 10.1593/neo.08264.
Nitric oxide (NO) plays important physiological roles in the vasculature to regulate angiogenesis, blood flow, and hemostasis. In solid tumors, NO is generally acknowledged to mediate angiogenic responses to several growth factors. This contrasts with conflicting evidence that NO can acutely increase tumor perfusion through local vasodilation or diminish perfusion by preferential relaxation of peripheral vascular beds outside the tumor. Because thrombospondin 1 (TSP1) is an important physiological antagonist of NO in vascular cells, we examined whether, in addition to inhibiting tumor angiogenesis, TSP1 can acutely regulate tumor blood flow. We assessed this activity of TSP1 in the context of perfusion responses to NO as a vasodilator and epinephrine as a vasoconstrictor. Nitric oxide treatment of wild type and TSP1 null mice decreased perfusion of a syngeneic melanoma, whereas epinephrine transiently increased tumor perfusion. Acute vasoactive responses were also independent of the level of tumor-expressed TSP1 in a melanoma xenograft, but recovery of basal perfusion was modulated by TSP1 expression. In contrast, overexpression of truncated TSP1 lacking part of its CD47 binding domain lacked this modulating activity. These data indicate that TSP1 primarily regulates long-term vascular responses in tumors, in part, because the tumor vasculature has a limited capacity to acutely respond to vasoactive agents.
一氧化氮（NO）在脉管系统中发挥着重要的生理作用，以调节血管生成、血流和止血。在实体瘤中，一般认为NO介导对多种生长因子的血管生成反应。这与相互矛盾的证据形成对比，即NO可通过局部血管舒张急性增加肿瘤灌注，或通过优先舒张肿瘤外的外周血管床减少灌注。由于血小板反应蛋白1（TSP1）是血管细胞中NO的重要生理拮抗剂，我们研究了TSP1除了抑制肿瘤血管生成外，是否还能急性调节肿瘤血流。我们在对作为血管舒张剂的NO和作为血管收缩剂的肾上腺素的灌注反应背景下评估了TSP1的这种活性。用一氧化氮处理野生型和TSP1基因敲除小鼠可降低同基因黑色素瘤的灌注，而肾上腺素可短暂增加肿瘤灌注。急性血管活性反应也与黑色素瘤异种移植中肿瘤表达的TSP1水平无关，但基础灌注的恢复受TSP1表达的调节。相反，缺乏部分CD47结合域的截短TSP1的过表达缺乏这种调节活性。这些数据表明，TSP1主要调节肿瘤中的长期血管反应，部分原因是肿瘤血管系统对血管活性药物的急性反应能力有限。
