Primary brain tumors are among the most aggressive and fatal human neoplasms, often affecting children and younger adults. The availability of transgenic and gene targeting methods, and the large number of spontaneous and induced mutant mouse strains, have led to the increased use of the mouse as a key animal model system to study cancer. In the past several years, the use of mouse genetics has led to significant progress in understanding the genetic pathways and molecular events involved in the formation and progression of both medulloblastoma and glioma, the most common pediatric and adult brain tumors, respectively. In order to realize the full potential of these genetically engineered mouse models, it is imperative to develop in vivo microscopic imaging approaches, allowing longitudinal analysis of tumor progression and response to novel therapeutic agents. Angiogenesis is thought to be a critical prerequisite for tumor progression, and brain tumor malignancy is intimately related to angiogenesis and vascular density, especially in gliomas. The broad goals of this project are to develop both functional and molecular magnetic resonance micro-imaging (mu MRI) approaches to detect and quantify angiogenesis in mouse brain tumors. We have recently used in utero retrovirus injection to induce medulloblastomas in the postnatal mouse cerebellum. We propose to use a similar retrovirus injection, a measure of angiogenesis to induce gliomas, and will also investigate a transgenic mouse glioma model. We are developing contrast-enhanced perfusion mu MRI techniques to measure cerebral blood volume (CBV) approach in normal mouse brain and brain tumors. A direct, in vivo molecular targeting approach will also be developed to assess angiogenesis. We will generate transgenic mice that overexpress cell surface receptors in neovascular endothelial cells, and image the brains of these mice after intravenous injection of a superparamagnetic MRI contrast agent-tagged ligand. Brain tumors will be induced in these transgenic mice and imaged with mu MRI to quantify vascular density in the developing brain tumors. The functional and molecular mu MRI approaches will be developed during an exploratory, feasibility phase (R21) and later used in careful studies of tumor progression and response to anti-angiogenic therapies in a development phase (R33). The new technologies developed under this project are of critical importance for understanding angiogenesis and brain tumor progression, and will revolutionize tumor biology in genetically accurate mouse models of cancer.
