Pinsky M S, Song W, Dong Z, Warner K, Zeitlin B, Karl E, Hall D E, Nör J E
Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, 48109, USA.
J Dent Res. 2006 May;85(5):436-41. doi: 10.1177/154405910608500508.
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.
口腔肿瘤是高度血管化的恶性肿瘤。研究表明，破坏新生血管网络可限制肿瘤细胞获取营养和氧气，从而抑制肿瘤进展。在此，我们评估了在新生血管内皮细胞中表达的人工死亡开关（iCaspase-9）的激活对口腔肿瘤进展的影响。我们使用可生物降解支架，将稳定表达iCaspase-9的人真皮微血管内皮细胞（HDMEC-iCasp9）与表达荧光素酶的口腔癌细胞（OSCC3-luc或UM-SCC-17B-luc）共同植入免疫缺陷小鼠体内。或者，将未转导的HDMEC与口腔癌细胞共同植入，并局部注射转录靶向腺病毒（Ad-VEGFR2-iCasp-9），以便将iCaspase-9传递至新生血管内皮细胞。体内生物发光显示，当肿瘤相关微血管中的iCaspase-9被激活时，肿瘤进展受到抑制，免疫组化显示微血管密度降低。我们得出结论，在新生血管内皮细胞中激活iCaspase-9足以抑制异种移植口腔肿瘤的进展。
