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Activation of iCaspase-9 in Neovessels Inhibits Oral Tumor Progression

¹ Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences, and Endodontics, and
² Department of Oral and Maxillofacial Surgery, University of Michigan School of Dentistry, 1011 N. University, Rm. 2309, Ann Arbor, MI 48109-1078, USA; and
³ Center for Molecular Imaging, Department of Radiology, University of Michigan School of Medicine, Ann Arbor

Correspondence: ^* corresponding author, jenor{at}umich.edu

Tumors of the oral cavity are highly vascularized malignancies. Disruption of neovascular networks was shown to limit the access of nutrients and oxygen to tumor cells and inhibit tumor progression. Here, we evaluated the effect of the activation of an artificial death switch (iCaspase-9) expressed in neovascular endothelial cells on the progression of oral tumors. We used biodegradable scaffolds to co-implant human dermal microvascular endothelial cells stably expressing iCaspase-9 (HDMEC-iCasp9) with oral cancer cells expressing luciferase (OSCC3-luc or UM-SCC-17B-luc) in immunodeficient mice. Alternatively, untransduced HDMEC were co-implanted with oral cancer cells, and a transcriptionaly targeted adenovirus (Ad-VEGFR2-iCasp-9) was injected locally to deliver iCaspase-9 to neovascular endothelial cells. In vivo bioluminescence demonstrated that tumor progression was inhibited, and immunohistochemistry showed that microvessel density was decreased, when iCaspase-9 was activated in tumor-associated microvessels. We conclude that activation of iCaspase-9 in neovascular endothelial cells is sufficient to inhibit the progression of xenografted oral tumors.

Key Words: angiogenesis • neovascularization • apoptosis • suicide gene • bioluminescence

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