ANGIOGENESIS, ENDOTHELIAL SURVIVAL, AND ORAL CANCER

实体瘤的发展严格依赖于新生毛细血管的持续长入；这个过程被称为血管生成。我们最近发现血管内皮生长因子（VEGF）是一种有效的促血管生成介质，由多种正常细胞和肿瘤细胞（包括口腔鳞状癌）产生，能够通过上调抗凋亡蛋白Bcl-2的表达来提高内皮细胞（EC）的存活率并维持血管生成。此外，通过基因工程过度表达Bcl-2的人皮肤微血管EC （HDMEC）在SCID小鼠体内表现出更强的组织成功能毛细血管的能力，并显示出更长的存活时间。这些结果表明，作为肿瘤血管生成的标志，毛细血管的无限制生长可能是由于一些促血管生成因子赋予EC生存优势，从而维持肿瘤血管生成和生长的能力。这项研究的假设是，实体瘤发展的特征——毛细血管的持续生长，部分是由于一些肿瘤促血管生成因子通过上调Bcl-2来提高EC的存活率。这提示了一种机制，即肿瘤促血管生成介质能够破坏凋亡程序，而凋亡程序通常通过增加EC的存活和维持血管生成来阻止血管生成反应的延长，并促进肿瘤的进展。该建议的具体目的是：1。确定肿瘤血管内皮细胞中Bcl-2表达是否上调。2. 确定肿瘤血管内皮细胞Bcl-2的长期表达是否有助于肿瘤的生长和进展。3. 明确Bcl-2增强内皮细胞存活的机制。4. 启动旨在通过诱导内皮细胞凋亡来减弱肿瘤血管生成的研究。本提案概述的研究将揭示肿瘤发展过程中持续毛细血管生长机制的重要新见解，增加我们对异常血管生成机制的理解，并为治疗实体肿瘤（如口腔鳞状癌和其他血管生成依赖疾病）提供新的策略。

The development of solid tumors is strictly dependent on the sustained ingrowth of new capillary blood vessels; a process termed angiogenesis. We have recently found that vascular endothelial growth factor (VEGF), a potent proangiogenic mediator that is produced by a variety of normal and tumor cells including oral squamous carcinomas, is able to enhance the survival of endothelial cells (EC) and sustain angiogenesis by upregulating expression of the anti-apoptotic protein Bcl-2. Furthermore, human dermal microvascular EC (HDMEC) genetically engineered to overexpress Bcl-2 exhibit an enhanced ability to organize into functioning capillaries and display prolonged survival in vivo in SCID mice. These results suggest that the unrestrained growth of capillary blood vessels, a hallmark of tumor angiogenesis, may be due to the ability of some proangiogenic factors to confer a survival advantage on EC and thus sustain tumor angiogenesis and growth. The hypothesis underlying the proposed work is that the sustained growth of capillary blood vessels that characterizes solid tumor development is due in part to the ability of some tumor proangiogenic factors to enhance the survival of EC by upregulating Bcl-2. This suggests a mechanism whereby tumor proangiogenic mediators are able to subvert the apoptotic program that normally functions to prevent a protracted angiogenic response and enhance tumor progression by increasing the survival of EC and sustaining angiogenesis. The specific aims of the proposal are to: 1. Determine if Bcl-2 expression is upregulated in endothelial cells that populate tumor vessels. 2. Determine if prolonged expression of Bcl-2 in endothelial cells populating tumor vessels contributes to tumor growth and progression. 3. Define the mechanism(s) by which Bcl-2 enhances endothelial cell survival. 4. Initiate studies designed to attenuate tumor angiogenesis by inducing endothelial cell apoptosis. The studies outlined in this proposal should reveal important new insights into the mechanisms responsible for sustained capillary growth during tumor development, increase our understanding of the mechanism underlying aberrant angiogenesis, and suggest novel strategies for the treatment of solid tumors such as oral squamous carcinoma and other angiogenesis-dependent diseases.