Invasion and metastasis of tumor cells (collectively termed malignancy) represent the most dangerous and least understood aspects of cancer. It is clear that alterations m cell adhesion must play significant roles in several of the steps leading to invasion and metastasis. Given progress in understanding the molecular basis of cell adhesion and its consequences for cell behavior and the pending availability of a complete list of mammalian genes, the time is ripe to investigate exactly which genes affecting cell adhesion are altered in their expression in the course of metastasis and how such changes contribute to invasion and metastasis. Using DNA microarrays several such genes have recently been identified and this application is for support to continue and extend in breadth and in depth this analysis. The project will develop cDNA arrays specifically designed to analyze alterations in the expression of genes contributing to cell adhesion and its consequences. The metastasis of human tumor cells will be studied in mouse models. Alterations in gene expression in the tumors and in the surrounding stroma can be distinguished using oligonucleotide arrays. Gene expression in the tumor cells and during the stromal response will be analyzed and the functional consequences of expression of individual genes for the processes involved in metastasis will be analyzed both in vivo and in vitro. The project will also use mice lacking specific adhesion receptors (selectins, beta3 integrins) to probe the significance of those receptors in the metastasis of human tumor cells and to investigate the possibility that tumor-platelet, tumor-leukocyte or tumor-endothelium interactions mediated by these receptors contribute to metastasis. Evaluation of the functions of cell adhesion proteins and the consequences of their misexpression in metastatic cells will lead to new leads for therapeutic interventions against metastasis.
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