title: Activation of iCaspase-9 in neovessels inhibits oral tumor progression.
abstract: 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.
authors.affiliation: Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, 48109, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Pinsky
authors.forename: W
authors.initials: W
authors.lastname: Song
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.forename: K
authors.initials: K
authors.lastname: Warner
authors.forename: B
authors.initials: B
authors.lastname: Zeitlin
authors.forename: E
authors.initials: E
authors.lastname: Karl
authors.forename: D E
authors.initials: DE
authors.lastname: Hall
authors.forename: J E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D053453:Caspase 9; D020169:Caspases / Q000494:pharmacology* / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D008156:Luciferases; D008163:Luminescent Measurements; D051379:Mice; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*
chemical_list: D008156:Luciferases; C506433:CASP9 protein, human; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases