The metastatic cascade is generally seen as a sequence of steps beginning with tumor cell invasion of lymph or blood vessel, followed by circulation with arrest in the vasculature of distant organs, and finally, extravasation and formation of metastatic loci in the new organ environment. Recent findings suggest that the latter stages of the cascade are more complex because the tumor cells can proliferate at the site of arrest within a vessel and can form vessel-like structures on their own whereas endothelial ceils can be recruited from distant sites. In the first aim we will test the hypothesis of two endothelial cell populations that contribute to tumor infiltrating vessels, a resident pool from the tumor-bearing organ and a precursor pool originating in the bone marrow. An orthotopic human melanoma model in chimeric SCID mice is used to determine the contribution from each pool during tumor progression. Human bone marrow-derived adult progenitor cells that are induced to differentiate to endothelial cells are characterized in a three-dimensional fibroblast-dependent vessel formation model. In the second aim we will determine the biological significance of cross talk between endothelial and melanoma cells focusing on cell surface receptors such as MeI-CAM and alphavbeta3 that are shared between both cells types. By modeling in vitro a 'metastatic focus' containing nests of tumor cells with interspersed micro-capillary networks and fibroblasts we can determine whether and how shared receptors contribute to vessel and focus formation, respectively. We hypothesize that tumor and endothelial cells utilize the same tools for invasion and nest or vessel formation but that the malignant cells are dominating the normal ceils due to genetic alterations leading to constitutively activated signaling pathways. Their functional plasticity allows tumor cells to respond more rapidly and efficiently to environmental challenges such as hypoxia or tissue barriers and we can directly compare the same signaling pathways in normal and malignant cells that contribute to plasticity. These studies should lead to a better understanding of the tumor-specific signatures in pathways associated with invasion and metastasis.
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