Expression of P2X7 Receptor Increases In Vivo Tumor Growth
Expression of P2X7 Receptor Increases In Vivo Tumor Growth
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DOI：
10.1158/0008-5472.can-11-1947
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发表时间：
2012-06-15
期刊：
影响因子：
11.2
通讯作者：
Di Virgilio, Francesco
中科院分区：
文献类型：
--
作者：
Adinolfi, Elena;Raffaghello, Lizzia;Di Virgilio, Francesco
P2X7 受体是一种 ATP 门控离子通道，以其细胞毒活性而闻名。然而，最近的证据表明 P2X7 在细胞增殖中发挥作用。在这里，我们发现 P2X7 在体内表现出显着的生长促进作用。表达 P2X7 的人胚胎肾细胞在体内表现出比对照细胞更具致瘤性和变性表型，并且通过瘤内注射 P2X7 抑制剂氧化的 ATP 显着降低了这些肿瘤的生长速度和大小。表达 P2X7 的肿瘤加速生长的特点是增殖增加、细胞凋亡减少和高水平的激活转录因子 NFATc1。这些肿瘤还表现出比对照肿瘤更发达的血管网络，并分泌大量的 VEGF。通过瘤内注射 VEGF 阻断抗体阿瓦斯汀（贝伐珠单抗）、药物 P2X7 阻断或体内 P2X7 沉默，阻断表达 P2X7 的肿瘤的生长和新生血管生成。免疫组织化学显示 P2X7 在几种人类癌症中呈强阳性。总之，我们的研究结果提供了 P2X7 促进体内肿瘤生长的直接证据。癌症研究； 72(12)； 2957-69。 (C)2012 AACR。
The P2X7 receptor is an ATP-gated ion channel known for its cytotoxic activity. However, recent evidence suggests a role for P2X7 in cell proliferation. Here, we found that P2X7 exhibits significant growth-promoting effects in vivo. Human embryonic kidney cells expressing P2X7 exhibited a more tumorigenic and anaplastic phenotype than control cells in vivo, and the growth rate and size of these tumors were significantly reduced by intratumoral injection of the P2X7 inhibitor-oxidized ATP. The accelerated growth of P2X7-expressing tumors was characterized by increased proliferation, reduced apoptosis, and a high level of activated transcription factor NFATc1. These tumors also showed a more developed vascular network than control tumors and secreted elevated amounts of VEGF. The growth and neoangiogenesis of P2X7-expressing tumors was blocked by intratumoral injection of the VEGF-blocking antibody Avastin (bevacizumab), pharmacologic P2X7 blockade, or P2X7 silencing in vivo. Immunohistochemistry revealed strong P2X7 positivity in several human cancers. Together, our findings provide direct evidence that P2X7 promotes tumor growth in vivo. Cancer Res; 72(12); 2957-69. (C)2012 AACR.