MICROVESSEL PERMEABILITY AND TUMOR METASTASIS

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DESCRIPTION: (Adapted from the investigator's abstract) This is a first submission of an Academic Research Enhancement Award (AREA) grant from a new investigator aimed at examining the role of microvessel permeability in tumor cell extravasation using an in vivo rat mesentery vessels model. The overall objective of the proposal is to quantify the relationship between microvessel permeability and tumor growth and metastasis in intact microvessels and to test the hypothesis that VEGF induced hyperpermeability is associated with enhanced tumor cell adhesion and extravasation. Four hypotheses will be tested. 1. That VEGF induced hyperpermeability enhances tumor cell adhesion and extravasation, 2. That extravasation requires specific signaling molecules in breast cancer cells, 3. That agents that induce an increase in cAMP in endothelial cells decrease hyperpermeability caused by VEGF and 4. that these agents inhibit tumor cell adhesion and extravasation. The in vivo model used consists of perfused mesenteric microvessels from rat in which permeability is quantitatively determined by injection of fluorescently dyed molecules and monitored by fluorescent video microscopy. Adhesion and extravasation of tumor cells is similarly evaluated by following fluorescently labeled tumor cells. The proposal has 4 specific aims according to the 4 hypotheses proposed. In aim 1, the effect of VEGF on microvessel permeability will be evaluated. In specific aim 2, the effect of VEGF on tumor cell adhesion and extravasation will be determined. In specific aim 3, the effect of 8 bromo-cAMP and agents that increase cAMP such as forskolin or rolipram on VEGF induces hyperpermeability will be examined. In specific aim 4 the effect of these agents on tumor cell extravasation will be studied. It is anticipated that this project will provide a useful tool in the quantitative assessment of tumor microvessel transport and help define a new class of target for chemotherapeutic drug design.