Jackson Shaun W, Hoshi Tomokazu, Wu Yan, Sun Xiaofeng, Enjyoji Keiichi, Cszimadia Eva, Sundberg Christian, Robson Simon C
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Am J Pathol. 2007 Oct;171(4):1395-404. doi: 10.2353/ajpath.2007.070190. Epub 2007 Sep 6.
CD39/ecto-nucleoside triphosphate diphosphohydrolase-type-1 (ENTPD1) is the dominant vascular ecto-nucleotidase that catalyzes the phosphohydrolysis of extracellular nucleotides in the blood and extracellular space. This ecto-enzymatic process modulates endothelial cell, leukocyte, and platelet purinergic receptor-mediated responses to extracellular nucleotides in the setting of thrombosis and vascular inflammation. We show here that deletion of Cd39/Entpd1 results in abrogation of angiogenesis, causing decreased growth of implanted tumors and inhibiting development of pulmonary metastases. Qualitative abnormalities of Cd39-null endothelial cell adhesion and integrin dysfunction were demonstrated in vitro. These changes were associated with decreased activation of focal adhesion kinase and extracellular signaling-regulated kinase-1 and -2 in endothelial cells. Our data indicate novel links between CD39/ENTPD1, extracellular nucleotide-mediated signaling, and vascular endothelial cell integrin function that impact on angiogenesis and tumor growth.
CD39/外核苷三磷酸二磷酸水解酶-1型（ENTPD1）是主要的血管外核苷酸酶，可催化血液和细胞外空间中细胞外核苷酸的磷酸水解。这种外酶促过程在血栓形成和血管炎症的情况下调节内皮细胞、白细胞和血小板嘌呤能受体介导的对细胞外核苷酸的反应。我们在此表明，Cd39/Entpd1的缺失导致血管生成的废除，导致植入肿瘤的生长减少并抑制肺转移的发展。体外证实了Cd39基因缺失的内皮细胞粘附和整合素功能障碍的定性异常。这些变化与内皮细胞中粘着斑激酶和细胞外信号调节激酶-1和-2的激活减少有关。我们的数据表明，CD39/ENTPD1、细胞外核苷酸介导的信号传导和血管内皮细胞整合素功能之间存在新的联系，这些联系会影响血管生成和肿瘤生长。
