Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice
Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice
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DOI：
10.1038/sj.jid.5700413
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发表时间：
2006-10-01
影响因子：
6.5
通讯作者：
Arbiser, Jack L.
中科院分区：
文献类型：
--
作者：
Perry, Betsy N.;Govindarajan, Baskaran;Arbiser, Jack L.
婴儿期血管瘤是儿童期最常见的肿瘤。虽然血管瘤是血管生成的经典例子，但导致血管瘤的血管生成因素还不完全清楚。在此之前，我们证明了恶性内皮性肿瘤是在涉及血管内皮生长因子及其主要有丝分裂受体血管内皮生长因子受体2的自分泌环的环境下发生的。婴儿期的血管瘤与恶性内皮瘤的不同之处在于它们通常会消退，或者可以通过药物手段诱导消退，这表明血管瘤的血管生成与恶性肿瘤的血管生成有根本的不同。在这里，我们展示了婴儿人类血管瘤中内皮Tie-2受体的组成性激活，并使用血管瘤的小鼠模型，bEnd.3细胞；我们证明bEnd.3血管瘤在体内既产生血管生成素-2(Ang-2)，又产生其受体Tie-2。我们还证明，用可溶的Tie-2受体抑制Tie-2信号转导可以减少体内血管瘤的生长。阻断Tie-2的效果表明，体内生长可能需要Tie-2激活或Ang-2。为了解决这个问题，我们使用了Tie-2缺陷的bEnd.3血管瘤细胞，令人惊讶的是，它完全熟练地在体内生长。我们实验室和其他实验室之前的研究表明，产生活性氧的NOx酶参与了血管生成开关，因此我们研究了NOx抑制剂在体外对Ang-2产生的影响和对体内bEnd肿瘤生长的影响。然后，我们使用新的NOx酶抑制剂从药物上抑制Ang-2的产生，并发现这种治疗几乎消除了体内bEnd.3血管瘤的生长。靶向Ang-2产生的信号转导阻断可能对体内人类血管瘤的治疗有用。
Hemangioma of infancy is the most common neoplasm of childhood. While hemangiomas are classic examples of angiogenesis, the angiogenic factors responsible for hemangiomas are not fully understood. Previously, we demonstrated that malignant endothelial tumors arise in the setting of autocrine loops involving vascular endothelial growth factor (VEGF) and its major mitogenic receptor vascular endothelial growth factor receptor 2. Hemangiomas of infancy differ from malignant endothelial tumors in that they usually regress, or can be induced to regress by pharmacologic means, suggesting that angiogenesis in hemangiomas differs fundamentally from that of malignant endothelial tumors. Here, we demonstrate constitutive activation of the endothelial tie-2 receptor in human hemangioma of infancy and, using a murine model of hemangioma, bEnd.3 cells; we show that bEnd.3 hemangiomas produce both angiopoietin-2 (ang-2) and its receptor, tie-2, in vivo. We also demonstrate that inhibition of tie-2 signaling with a soluble tie-2 receptor decreases bEnd.3 hemangioma growth in vivo. The efficacy of tie-2 blockade suggests that either tie-2 activation or ang-2 may be required for in vivo growth. To address this issue, we used tie-2-deficient bEnd.3 hemangioma cells, which, surprisingly, were fully proficient in in vivo growth. Previous studies from our laboratory and others have implicated reactive oxygen-generating nox enzymes in the angiogenic switch, so we examined the effect of nox inhibitors on ang-2 production in vitro and on bEnd.3 tumor growth in vivo. We then inhibited ang-2 production pharmacologically using novel inhibitors of nox enzymes and found that this treatment nearly abolished bEnd.3 hemangioma growth in vivo. Signal-transduction blockade targeting ang-2 production may be useful in the treatment of human hemangiomas in vivo.