The ability of tumors to develop a blood supply is critical to their capacity for sustained growth and their spread to distant organs. This process of new vessel development, termed angiogenesis, is the result of a complex series of interactions between the tumor and the host. The endothelial cell is the main focus of this process, however, there are a number of other cell types that play a critical role.? ? Our laboratory is focused on understanding the process of tumor angiogenesis with the goal of developing therapies which target the tumor vasculature. To achieve this goal we have embarked on several lines of investigation. These include: 1. the development and validation of in vitro and in vivo model systems for studying tumor-blood vessel-host interactions, 2. the use of gene expression profiling to better elucidate the changes in endothelial cell function in the tumor environment, 3. the study of gene therapy techniques to more efficently deliver anti-angiogenic agents to target tumor tissue, and 4. the translation of these findings to clinical protocols which apply these novel anti-angiogenic therapies to the treatment of patients with cancer.? ? With respect to our model systems, we have developed and continue to utilize a variety of in vitro and in vivo assay systems. Cell proliferation and migration assays help us to understand the direct effects of agents on endothelial cell function. Ex-vivo rat aortic as well as human saphenous vein (developed in our laboratory in collaboration with William Figg) ring assays allow us to examine the process of neovessel formation in a controlled setting. A variety of in vivo assays such as the CAM assay, subcutanoeus matrigel and corneal micropocket assays help us to study the contribution of other host cells to the process of angiogenesis. We also rely on a variety of mouse tumor models including transplantable and spontaneously occurring transgenic models of cancer. Our laboratory has also developed imaging systems using MRI, PET and Fluorescent imaging to stduy changes in tumor blood flow in response to ant-angiogenic therapies.? ? Using cDNA microarray technology, we have begun to identify specific pathways involved in the response of endothelium to tumor derived factors as well as exogenously administered antiangiogenic agents. We have devised strategies to study the endothelial cell specifically in a variety of tissue ranging from normal to neoplastic. Using the techniques of laser capture microdissection (LCM), expression microdissection and RNA amplification we have successfully studied endothelial cells isolated from responding and non-responding tumor tissue after exposure to anti-angiogenic agents. Utilizing this approach, we hope to identify novel targets for therapy.? ? As a result of our use of the aforementioned models, we have studied gene therapy techniques as a means to deliver anti-angiogenic agents in vivo. The potential pharmacokinetic, biotechnological, and economic drawbacks of chronic delivery of recombinant anti-angiogenic proteins have led investigators to address the feasibility of delivering antiangiogenic agents by means of gene therapy. Two general strategies for the antiangiogenic gene therapy of cancer have been proposed: tumor-directed gene therapy and systemic gene therapy. Traditionally, the goal of cancer gene therapy has been to select gene delivery vectors which selectively target tumor tissue with transgenes that produce toxic gene products, enhance tumor immunogenicity, or specifically increase the tumor's susceptibility to chemotherapeutics, radiation, or biologic agents. Along these lines, others have advocated tumor-directed antiangiogenic gene therapy to increase local concentrations of antiangiogenic agents within the tumor, in order to achieve an antitumor effect without the risk of systemic toxicity.
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