Characterization of the anti-angiogenic properties of arresten, an alpha1beta1 integrin-dependent collagen-derived tumor suppressor.
Characterization of the anti-angiogenic properties of arresten, an alpha1beta1 integrin-dependent collagen-derived tumor suppressor.
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DOI：
10.1016/j.yexcr.2008.08.011
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发表时间：
2008-11-01
影响因子：
3.7
通讯作者：
Kalluri R
中科院分区：
文献类型：
--
作者：
Nyberg P;Xie L;Sugimoto H;Colorado P;Sund M;Holthaus K;Sudhakar A;Salo T;Kalluri R
生理和病理的基底膜周转释放生物活性的隐分子。一些胶原来源的片段具有抗血管生成活性。Arresten是IV型胶原α1链的26kda非胶原结构域。在小鼠模型中，它是一种有效的血管生成和肿瘤生长抑制剂，但其抗血管生成机制尚不完全清楚。本研究表明，通过减少bcl -家族、Bcl-2和Bcl-xL抗凋亡分子的数量，阻滞显著增加了体外内皮细胞的凋亡。尽管在体外实验中，arresten的促凋亡作用是内皮细胞特异性的，但在小鼠肿瘤实验中，arresten同时诱导内皮细胞和肿瘤细胞凋亡。肿瘤细胞凋亡可能是由于抑制血管生长进入肿瘤而产生的间接作用。通过缺失诱变，阻滞活性位点被定位在分子的c端。我们之前已经证明，在人脐静脉内皮细胞上，arresten与α1β1整合素结合。然而，微血管内皮细胞（MLECs）在肿瘤血管系统中更为重要。我们在这里表明，arresten也通过α1β1整合素与微血管内皮细胞结合。此外，它对整合素α1缺失的mlec的新生血管形成和生存能力没有影响。在整合素α1缺失小鼠上植入肿瘤后，宿主源性血管内皮中没有整合素α1的表达，因此阻滞对肿瘤生长没有抑制作用。总的来说，这些数据揭示了心脏骤停的抗血管生成机制。
Physiological and pathological turnover of basement membranes liberates biologically active cryptic molecules. Several collagen-derived fragments possess anti-angiogenic activity. Arresten is the 26-kDa non-collagenous domain of type IV collagen α1 chain. It functions as an efficient inhibitor of angiogenesis and tumor growth in mouse models, but its anti-angiogenic mechanism is not completely known. Here we show that arresten significantly increases apoptosis of endothelial cells in vitro by decreasing the amount of anti-apoptotic molecules of the Bcl-family, Bcl-2 and Bcl-xL. Although the pro-apoptotic effect of arresten is endothelial cell specific in vitro, in mouse tumors arresten induced apoptosis both in endothelial and tumor cells. The tumor cell apoptosis is likely an indirect effect due to the inhibition of blood vessel growth into the tumor. The active site of arresten was localized by deletion mutagenesis within the C-terminal half of the molecule. We have previously shown that arresten binds toα1β1 integrin on human umbilical vein endothelial cells. However, the microvascular endothelial cells (MLECs) are more important in the context of tumor vasculature. We show here that arresten binds also to the microvascular endothelial cells via α1β1 integrin. Furthermore, it has no effect on Matrigel neovascularization or the viability of integrin α1 null MLECs. Tumors implanted on integrin α1 deficient mice show no integrin α1 expression in the host-derived vascular endothelium, and thus arresten does not inhibit the tumor growth. Collectively, this data sheds more light into the anti-angiogenic mechanism of arresten.
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DOI：
10.1016/j.bbrc.2004.04.038
发表时间：
2004-05-28
影响因子：
3.1
作者：
He, GA;Luo, JX;Wang, FY
通讯作者：
Wang, FY
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
7.8
作者：
Bix, G;Fu, J;Iozzo, RV
通讯作者：
Iozzo, RV
影响因子：
2.8
作者：
Liu, SG;Tobias, R;Jackowski, E
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Jackowski, E
影响因子：
7.8
作者：
DEFILIPPI, P;VANHINSBERGH, V;TARONE, G
通讯作者：
TARONE, G