Angiostatic activity of the antitumor cytokine interleukin-21
Angiostatic activity of the antitumor cytokine interleukin-21
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DOI：
10.1182/blood-2007-09-113878
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发表时间：
2008-12-15
期刊：
影响因子：
20.3
通讯作者：
Griffioen, Arjan W.
中科院分区：
文献类型：
--
作者：
Castermans, Karolien;Tabruyn, Sebastien P.;Griffioen, Arjan W.
白细胞介素-21 （IL-21）是最近发现的一种免疫调节细胞因子。在动物模型中，它已被确定为几种癌症类型的非常有效的免疫治疗剂，临床研究正在进行中。IL-21属于I型细胞因子家族，该家族的其他成员，即IL-2、IL-15和IL-4，已被证明对血管内皮细胞（ECs）发挥活性。我们推测IL-21除了诱导抗肿瘤免疫应答外，还能抑制肿瘤血管生成。体外实验显示，IL-21处理后，活化的ECs增殖和出芽减少。我们发现IL-21受体在血管内皮细胞上表达。此外，鸡胚绒毛膜尿囊膜和小鼠肿瘤的体内研究表明，IL-21处理会扰乱血管结构，并对血管生长产生负面影响。我们的结果也证实了先前提出的IL-2在体外和体内的血管抑制潜能。IL-21的血管抑制作用通过血管生成相关基因表达的减少得到证实。有趣的是，IL-21处理ECs导致Stat3磷酸化降低。我们的研究表明，IL-21是一种非常强大的抗肿瘤化合物，它结合了诱导有效的抗肿瘤免疫反应和抑制肿瘤血管生成。（血液。2008;112:4940-4947）
Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis. (Blood. 2008;112: 4940-4947)