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.
