Metastases are tumor colonies that develop in distant, often multiple organ sites by dissemination from malignant primary tumors. Although the most frequent organ sites of distant metastases are the first organs encountered by blood-borne tumor cells, many cancers display unique organ colonization patterns that do not fit simple, anatomical-mechanical trapping theories of tumor cell dissemination and, thus, metastasize to distant sites which are unrelated to the initial organ entered by blood-borne malignant cells. Numerous studies on the preferential metastasis of cancers appear to indicate that implantation, invasion, survival, and growth at secondary sites depend upon a number of tumor cell and host characteristics that provide the proper stromal and cellular environment for metastasis formation (Paget's sead-and-soil hypothesis of metastatic spread). In this proposal, we postulate that metastatic patterns are determined by the specific interaction of blood-borne tumors with vascular endothelium, and that these interactions are similar in nature to those governing the homing of lymphocytes to parental lympoid tissues. The molecular mechanisms involved in the specific attachment of tumor cell to vascular endothelium are studied in a novel in vitro assay system. This system takes advantage of the finding that endothelial cells of large vessel origin (aorta, umbilical vein), when grown on the extracellular matrix of an organ, can be modulated to acquire an organ-specific phenotype. Preliminary data show that cancer cells selected in vivo for metastasis to a specific organ site, attach in significantly higher numbers to endothelial cell monolayers grown on the extracellular matrix of that organ. The endothelial cell """"""""homing"""""""" receptor is isolated from monolayer cultures, characterized for lectin-binding affinity, and purified by lectin-affinity and high pressure gel permation chromatography. A monoclonal antibody generated against such molecules will be employed in the further purification of the """"""""homing"""""""" receptor, which in turn, will be used in the characterization of molecules on tumor cell surfaces, that are responsible for the specific attachment to endothelial cells of the metastatic organ site. The uncovering of these mechanisms may allow us to eventually design and develop new approaches for interfering with this process and specifically targeting agents to organ sites at predictable risk for metastatic involvement.
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