ANGIOGENESIS, ENDOTHELIAL SURVIVAL, AND ORAL CANCER

血管生成、内皮细胞存活和口腔癌

• 批准号: 6796981
• 负责人: PETER John POLVERINI
• 金额: $ 11.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6796981
• 关键词: BCL2 gene /protein; SCID mouse; angiogenesis; angiogenesis factor; apoptosis; cell growth regulation; human tissue; laboratory rat; neoplasm /cancer blood supply; neoplasm /cancer genetics; oral pharyngeal neoplasm; squamous cell carcinoma; tissue /cell culture; vascular endothelium

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.

实体肿瘤的发展严格依赖于新的毛细血管的持续生长，这一过程被称为血管生成。我们最近发现，血管内皮生长因子(VEGF)是一种强大的促血管生成介质，由包括口腔鳞癌在内的各种正常和肿瘤细胞产生，能够通过上调抗凋亡蛋白Bcl-2的表达来促进内皮细胞(EC)的存活和维持血管生成。此外，通过基因工程过表达Bcl2的人真皮微血管内皮细胞(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。这些结果提示，作为肿瘤血管生成标志的毛细血管不受抑制的生长，可能是由于某些促血管生成因子能够赋予EC生存优势，从而维持肿瘤的血管生成和生长。支持这项工作的假设是，实体肿瘤发展的特征是毛细血管的持续生长，部分原因是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颠覆正常功能的凋亡程序，通过增加EC的存活率和维持血管生成来阻止旷日持久的血管生成反应并促进肿瘤进展。该提案的具体目的是：1.确定在填充肿瘤血管的内皮细胞中是否上调了Bcl-2的表达。2.确定肿瘤血管内皮细胞中Bcl2的持续表达是否参与了肿瘤的生长和发展。3.明确Bcl一2促进内皮细胞存活的机制(S)。4.启动旨在通过诱导内皮细胞凋亡来减少肿瘤血管生成的研究。这项建议中概述的研究将揭示在肿瘤发展过程中导致毛细血管持续生长的重要机制，增加我们对异常血管生成机制的理解，并为口腔鳞癌和其他血管生成依赖型疾病等实体肿瘤的治疗提出新的策略。