Role of prostaglandin D2 receptor DP as a suppressor of tumor hyperpermeability and angiogenesis in vivo
Role of prostaglandin D2 receptor DP as a suppressor of tumor hyperpermeability and angiogenesis in vivo
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DOI：
10.1073/pnas.0805171105
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发表时间：
2008-12-16
影响因子：
11.1
通讯作者：
Sessa, William C.
中科院分区：
文献类型：
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作者：
Murata, Takahisa;Lin, Michelle I.;Sessa, William C.
虽然已知cox依赖性前列腺素（PGs）的产生对肿瘤血管生成和生长至关重要，但PGD(2)的作用仍然几乎未知。我们发现PGD(2)受体（DP）缺乏会促进肿瘤进展并伴有异常血管扩张。在肿瘤中，血管生成内皮细胞高度表达DP受体，其缺乏会加速血管渗漏和血管生成。合成DP激动剂BW245C在WT小鼠中显著抑制肿瘤生长和肿瘤高通透性，但在DP缺乏小鼠中没有作用。在角膜血管生成实验和改良的Miles实验中，在cox -2活跃的情况下，宿主DP缺乏增强了血管生成和血管高通透性，而外源性BW245C强烈抑制了WT小鼠的血管生成特性。在体外实验中，BW245C不影响血管生成所必需的内皮迁移和管形成过程；然而，它通过增加细胞内cAMP的产生，强烈地改善内皮屏障功能。我们的研究结果发现PGD(2)/DP受体是肿瘤血管通透性的新调节剂，表明DP激动剂可能被开发为治疗癌症的潜在疗法。
Although COX-dependent production of prostaglandins (PGs) is known to be crucial for tumor angiogenesis and growth, the role of PGD(2) remains virtually unknown. Here we show that PGD(2) receptor (DP) deficiency enhances tumor progression accompanied by abnormal vascular expansion. In tumors, angiogenic endothelial cells highly express DP receptor, and its deficiency accelerates vascular leakage and angiogenesis. Administration of a synthetic DP agonist, BW245C, markedly suppresses tumor growth as well as tumor hyperpermeability in WT mice, but not in DP-deficient mice. In a corneal angiogenesis assay and a modified Miles assay, host DP deficiency potentiates angiogenesis and vascular hyperpermeability under COX-2-active situation, whereas exogenous administration of BW245C strongly inhibits both angiogenic properties in WT mice. In an in vitro assay, BW245C does not affect endothelial migration and tube formation, processes that are necessary for angiogenesis; however, it strongly improves endothelial barrier function via an increase in intracellular cAMP production. Our results identify PGD(2)/DP receptor as a new regulator of tumor vascular permeability, indicating DP agonism may be exploited as a potential therapy for the treatment of cancer.