Development of a Vascularized In-Vitro Model of the Tumor Microenvironment

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DESCRIPTION (provided by applicant): The study of the tumor microenvironment promises to lead to groundbreaking strategies for the therapy of cancer. Unfortunately, progress of this research is impaired by the lack of available models that recapitulate key features of the interaction between tumor cells, stroma, and vasculature in a 3D in-vitro environment. The National Cancer Institute has identified the development of such models as a high priority. The long-term objective of this project is the development of a vascularized in-vitro model of the tumor microenvironment. The basic components of this model are a disposable, perfused microfluidic device with a viewing chamber filled with an extracellular-matrix gel. Tubular channels are created within the gel into which endothelial cells are introduced to form parent vessels. The parent vessels are capable of angiogenic sprouting and the formation of capillary-like networks. The design of the fluidic device allows for direct luminal perfusion of the engineered vessels and sprouts. Cancer cells can be integrated into this model in various ways for studies including metastasis, tumor-angiogenesis, and the screening of cancer therapeutics. In its commercial version, the system will be self-contained, comprising fluidic pumps, reservoirs for growth medium, sensors, and an array of microfluidic devices. Aim 1 will focus on the microfabrication and quality-control testing of a commercially-viable device for an in-vitro tumor microenvironment model. All devices will be characterized for their ability to create perfusable parent vessels and the associated angiogenic sprouts. Aim 2 will establish the utility of the device for the study of extravasation, which is the process of cancer cells breaking through the endothelial lining of the vasculature to form metastases. Extravasation will be measured as the number of cancer cells which break through the vascular sprouts into the extracellular matrix. Two prostate-cancer cell lines of different metastatic potential will be compared to a normal prostate cell line. The successful completion of these studies presents an important step toward the development of a new generation of tumor- microenvironment models that can be standardized and made commercially available to a broad community of researcher in academia and industry. PUBLIC HEALTH RELEVANCE: The study of the organ-specific environment in which tumors grow and spread is crucial for developing new cancer therapeutics. Unfortunately, progress is impaired by the lack of available research tools. We propose the development of a model that mimics the natural tumor environment, including perfused blood vessels and capillaries. We expect our model to become a valuable system in cancer research, commercially available to scientists in academia and industry.