CHEMOKINE TUMOR INTERACTIONS AND IDENTIFICATION OF CHEMOKINE ANTAGONISTS

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Our studies of the interactions of chemokines with epithelial tumor cells show that some tumor cells produce chemokines, while some express receptors for chemokines and are chemoattracted by them. Moreover, some tumor cell types are stimulated to proliferate by chemokines. Furthermore some organs produce chemotactic factors that attract metastatic T cell tumor variants. Purification studies have implicated several chemokines namely RANTES and JE/MCP1 as possible contributors to the metastatic spread of these tumor cells. In addition, a metastatic tumor variant produces factor(s) promoting their own mobility. We plan to further identify these tumor cell attractants and motility promoters and to establish whether they are playing a role in the metastatic process. Several of the chemokines (e.g., MCP-1 and IL-8) have been reported to enhance tumor immune responses. Since dendritic cells (DC), the most effective antigen presenting cell (APC), contribute to tumor immunity, we just completed a study of the effects of chemokines on DC. A number of the C-C chemokines (e.g., MCP-1, MCP-2, MCP-3, MIP1alpha and RANTES) are chemotactic for human DC, suggesting that they may contribute to the mobilization of these potent APC. We plan to exploit these observations by studying the immune response to murine tumors transfected with the most potent chemoattractants of DC. Studies also have been initiated to develop mutated variants and peptide analogues of chemokines and their receptors. These experiments have only generated weak antagonists to date. The possibility that some anti-inflammatory plant extracts may contain natural inhibitors of proinflammatory chemoattractants is also being evaluated. Some components in extracts of Aloe contain inhibitors of chemokines. Most recently we have initiated studies to establish whether HIV-1 envelope proteins interfere with chemokines. In fact, gp120 can competitively inhibit the binding of MIP1alpha and RANTES to human monocytes. Further purification and characterization studies are needed to identify the responsible molecular entities.