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Targeted expression of maspin in tumor vasculatures induces endothelial cell apoptosis

Oncogene volume 24, pages 2008–2019 (2005)Cite this article

Abstract

Angiogenesis, the formation of new blood vessels, is required for normal tissue development and pathological conditions such as tumorigenesis. Most solid tumors can not grow beyond a few millimeters without the recruitment of neovessels since cancer cells require access to blood vessels for nutrients and to escape the local environment and metastasize to other tissue and organ sites. Targeting tumor vessel endothelium therefore should serve as an effective therapy for cancers. Maspin is a serpin that exhibits antiangiogenic properties. In this report, we show that when maspin overexpression is targeted in vivo to endothelial cells, it actively induces endothelial cell apoptosis. Intravascular administration of adenovirus-maspin to mice bearing mammary tumors disrupts tumor-induced angiogenesis. Interestingly, tumor neovessels become leaky after maspin treatment, whereas normal mature vessels are not affected by maspin treatment. We further demonstrate that maspin directly induces endothelial cell apoptosis in vitro, and this effect is maspin specific. The induction of apoptosis is accompanied by changes in the expression of Bcl-2 family genes and is blocked by caspase inhibitors. In addition, the apoptotic effect is mediated by intracellular maspin and is dependent on the RSL region of maspin. Furthermore, we have shown that transient overexpression of Bcl-2 protected the HUVECs from maspin-mediated apoptosis, and the presence of both maspin and Bax accelerated the apoptosis process. These findings demonstrate that neovascular endothelial cells are highly sensitive to maspin level inside the cells. This property can be used for targeted therapy against tumor angiogenesis and metastasis.

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Acknowledgements

We thank Dr RD Gerard at UT Southwestern Medical School for kindly providing us with the Ad-PAI-1 and Ad-PAI-2, and Dr RJ Youle at NIH for kindly providing us with the Bcl-2-EGFP and Bax-EGFP expression constructs. This study is supported by a NIH Grant CA79736 to MZ.

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  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Zhigang Li, Heidi Y Shi & Ming Zhang

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  1. Zhigang Li
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Correspondence to Ming Zhang.

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Li, Z., Shi, H. & Zhang, M. Targeted expression of maspin in tumor vasculatures induces endothelial cell apoptosis. Oncogene 24, 2008–2019 (2005). https://doi.org/10.1038/sj.onc.1208449

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