Tumor Neovascularization by a Non-angiogenic Mechanism: Plasticity-based Contributions by Brain Stem Cells.
Every year, 2,040 people in California are afflicted by brain cancer. Glioblastoma multiforme, the most prevalent and aggressive form of brain cancer in adult, is believed to stimulate the formation of new blood vessels which are required for this cancer to progress to malignancy and metastasize to other tissues. New blood vessels are believed to be generated by angiogenesis, the process whereby pre-existing blood vessels form new vascular branches that supply oxygen- and nutrient-deprived tissue. Angiogenesis has classically been proposed to be the predominant mechanism of vascular remodeling in adults, putatively linking angiogenesis to the development of solid tumors, ischemia, autoimmune disorders and Alzheimer disease. Our research focuses on neural stem cells that were originally proposed to differentiate to only neuronal cell types. Unexpectedly, we have found that these stem cells can be diverted away from neural lineages and instead be induced to become blood vessels. Thus, neural stem cells are more flexible or "plastic" than previously believed, expanding the importance of the adult neural stem cell in maintaining the cellular composition and function of brain. Our goal is to test the potential of brain stem cells to promote tumor growth of by forming blood vessels. We will also develop methods to arrest the generation of blood vessels by these stem cells so as to block the tumor growth and expansion. The discovery and continued study of neural stem cell-mediated blood vessel formation could define the neural stem cell as a relevant target of vascular therapy.
Gliomas, the most prevalent brain cancer in adult 4, are dependent upon the circulatory system to acquire growth-promoting nutrients and to metastasize to breast, lung, colon and skin. Despite the latest therapies directed against the vasculature of grade IV gliomas, an 85% recurrence rate persists 1, as does the dismal median survival of <1.5 years 4 (2). The latest therapies failed, eliciting significant side effects because they target factors common to normal and cancer blood vessel formation. We have obtained evidence that a distinct, brain stem cell-mediated pathway supplies gliomas, but not healthy brain tissue, with blood vessels. The ultimate goal of our research effort is to develop novel therapies which acutely target this stem cell to specifically block the formation and maintenance of brain tumor capillaries.