Integrins alpha(v)beta3 and alpha(v)beta5 are expressed by endothelium of high-risk neuroblastoma and their inhibition is associated with increased endogenous ceramide.
Integrins alpha(v)beta3 and alpha(v)beta5 are expressed by endothelium of high-risk neuroblastoma and their inhibition is associated with increased endogenous ceramide.
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发表时间：
2000
期刊：
影响因子：
11.2
通讯作者：
A. Erdreich-Epstein;H. Shimada;S. Groshen;M. Liu;L. Metelitsa;K. Kim;M. Stins;R. Seeger;D. D
中科院分区：
文献类型：
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作者：
A. Erdreich-Epstein;H. Shimada;S. Groshen;M. Liu;L. Metelitsa;K. Kim;M. Stins;R. Seeger;D. D
在动物模型中，抑制rgd结合的整合素α (v) β a3和α (v) β 5可阻止内皮细胞锚定并诱导内皮细胞凋亡，从而破坏肿瘤血管生成，抑制肿瘤生长。在这项研究中，我们通过免疫组织化学分析证明，整合素α (v) β 3在高危神经母细胞瘤（IV期和mycn扩增的III期，n = 28）中有61%（平均）的微血管表达，而在低危肿瘤（I期、II期和未mycn扩增的III期，n = 12）中只有18%（平均）的微血管表达。在21例IV期肿瘤中，60%（平均）微血管上发现整合素α (v) β 5。这些数据表明，神经母细胞瘤可能是针对内皮整合素α (v) β 3和α (v) β 5进行抗血管生成治疗的目标。在细胞培养中，与对照肽RADfV（分别为37.5%和8.7%）相比，RGDfV（一种RGD功能阻断环肽）抑制整合素依赖性内皮细胞对玻璃体连接蛋白的锚定，诱导牛脑内皮细胞凋亡（分别为37.5%和8.7%），通过染色质凝聚和核断裂检测。RGDfV而非RADfV治疗可阻止内皮细胞与玻璃体连接蛋白或纤维连接蛋白的附着，与内源性神经酰胺（一种可介导细胞死亡的脂质第二信使）增加高达50%相关。此外，外源性c2 -神经酰胺对牛脑内皮细胞具有细胞毒性，并诱导C-jun n -末端激酶（JNK）的激活，这是一种可以在应激诱导的凋亡途径中激活的MAP激酶。这表明神经酰胺可能在分离诱导的内皮细胞凋亡中起作用，起源于抑制玻璃体连接蛋白与α (v) β 3和α (v) β 5等整合素的结合。这是首次证实整合素α (v) β 3和α (v) β 5在儿童肿瘤微血管内皮中的表达，以及它们的表达与神经母细胞瘤侵袭性的关联。此外，我们的数据首次表明，由于rgd结合整合素的特异性阻断，内皮细胞锚定的抑制增加了内源性神经酰胺，这可能导致内皮细胞死亡。
Inhibition of the RGD-binding integrins, alpha(v)beta3 and alpha(v)beta5, prevents endothelial cell anchorage and induces endothelial apoptosis, which results in disruption of tumor angiogenesis and inhibition of tumor growth in animal models. In this study, we demonstrate by immunohistochemical analysis that integrin alpha(v)beta3 was expressed by 61% (mean) of microvessels in high-risk neuroblastomas (stage IV and MYCN-amplified stage III; n = 28) but only by 18% (mean) of microvessels in low-risk tumors (stages I and II and non-MYCN-amplified stage III; n = 12). Integrin alpha(v)beta5 was found on 60% (mean) of microvessels in 21 Stage IV tumors. These data suggest that neuroblastomas may be targeted for antiangiogenic treatment directed against endothelial integrins alpha(v)beta3 and alpha(v)beta5. In cell culture, inhibition of integrin-dependent endothelial cell anchorage to vitronectin by RGDfV, an RGD function-blocking cyclic peptide, induced apoptosis in bovine brain endothelial cells compared with the control peptide, RADfV (37.5% versus 8.7%, respectively), as detected by chromatin condensation and nuclear fragmentation. Treatment with RGDfV but not with RADfV, which prevented attachment of endothelial cells to vitronectin or fibronectin, was associated with up to a 50% increase in endogenous ceramide, a lipid second messenger that can mediate cell death. Furthermore, exogenous C2-ceramide was cytotoxic to bovine brain endothelial cells and induced activation of C-jun N-terminal kinase (JNK), a MAP kinase that can be activated in stress-induced apoptosis pathways. This suggests that ceramide may function in detachment-induced endothelial cell apoptosis, originating from inhibition of vitronectin binding to integrins such as alpha(v)beta3 and alpha(v)beta5. This is the first report to demonstrate expression of integrins alpha(v)beta3 and alpha(v)beta5 by microvascular endothelium of a childhood tumor and association of their expression with neuroblastoma aggressiveness. Furthermore, our data provide the first suggestion that inhibition of endothelial cell anchorage, resulting from specific blockade of RGD-binding integrins, increases endogenous ceramide, which may contribute to endothelial cell death.