ANGIOGENESIS, ENDOTHELIAL SURVIVAL, AND ORAL CANCER

血管生成、内皮细胞存活和口腔癌

• 批准号: 2825515
• 负责人: PETER John POLVERINI
• 金额: $ 28.11万
• 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 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2825515
• 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.

实体瘤的发展严格依赖于新毛细血管的持续向内生长;这一过程称为血管生成。 我们最近发现，血管内皮生长因子（VEGF），一种有效的促血管生成介质，是由各种正常和肿瘤细胞，包括口腔鳞癌，是能够提高内皮细胞（EC）的生存和维持血管生成的上调表达的抗凋亡蛋白Bcl-2。 此外，人真皮微血管EC（HDMEC）基因工程过表达Bcl-2表现出增强的能力，组织成功能性毛细血管和显示延长的生存期在体内的SCID小鼠。 这些结果表明，毛细血管的不受限制的生长，肿瘤血管生成的标志，可能是由于一些促血管生成因子赋予EC的生存优势，从而维持肿瘤血管生成和生长的能力。所提出的工作的假设是，毛细血管的持续生长的特征实体瘤的发展是部分由于一些肿瘤促血管生成因子的能力，以提高EC的生存上调Bcl-2。 这表明了一种机制，即肿瘤促血管生成介质能够破坏细胞凋亡程序，该程序通常用于防止延长的血管生成反应并通过增加EC的存活和维持血管生成来增强肿瘤进展。该提案的具体目标是：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中Bcl-2的长期表达是否有助于肿瘤的生长和进展。 3.定义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减弱肿瘤血管生成的研究。本提案中概述的研究应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，并提出治疗实体瘤（如口腔鳞状细胞癌和其他血管生成依赖性疾病）的新策略。