Section of General Pathology, Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy.
Cancer Res. 2012 Jun 15;72(12):2957-69. doi: 10.1158/0008-5472.CAN-11-1947. Epub 2012 Apr 13.
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.
P2X7 受体是一种 ATP 门控离子通道，以其细胞毒性活性而闻名。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 在体内表现出显著的促生长作用。在体内，表达 P2X7 的人胚肾细胞比对照细胞表现出更强的致瘤性和间变性表型，并且通过向肿瘤内注射 P2X7 抑制剂氧化 ATP，这些肿瘤的生长速度和大小显著降低。表达 P2X7 的肿瘤的加速生长特征为增殖增加、凋亡减少以及激活转录因子 NFATc1 的水平升高。这些肿瘤还显示出比对照肿瘤更发达的血管网络，并分泌大量的 VEGF。通过向肿瘤内注射 VEGF 阻断抗体阿瓦斯汀（贝伐单抗）、药理学 P2X7 阻断或体内 P2X7 沉默，可阻断表达 P2X7 的肿瘤的生长和新血管生成。免疫组织化学显示，几种人类癌症中存在强烈的 P2X7 阳性。总之，我们的研究结果提供了直接证据，表明 P2X7 促进体内肿瘤生长。
