EXCEED THE SPACE PROVIDED. Metastases are the most common cause of cancer-related death. Surgery for resection of the primary tumor has long been suspected to promote metastases via several mechanisms, including postoperative immunosuppression. In our recent studies in F344 rats, we uncovered neuroendocrine mediators of postoperative immune suppression, and devised two effective strategies to overcome suppression of NK activity and promotion of MADB106 experimental metastasis caused by surgery. Our first strategy is based on a combined pharmacological blockade of catecholamine and prostaglandins. Our second strategy is based on pre-operative immunostimulation with low-doses of either poly-IC or IL-12. Additionally, we uncovered a unique population of NK cells, marginating pulmonary (MP)-NK cells. This population is highly potent in its cytotoxicity, is strategically located to interact with circulating malignant cells, and is distinct in its ability to lyse syngeneic MADB106 tumor cells. Seemingly, our two strategies act through different cellular mechanisms to protect circulating and MP-NK cells from postoperative suppression, thus preventing promotion of MADB106 metastasis by surgery. The proposed studies are aimed at promoting the clinical applicability of our two newly-developed strategies, independently and in an integrated approach, and are focused around two aims: (i) To test our strategies and their integrated use in two models of spontaneous metastasis in C57BL/6 mice (3LL-D122, and B16F10.9 melanoma). Unlike our previous studies of experimental metastasis, these models also simulate the presence of metastasizing primary tumors, dormant metastases, and micrometastases, as in the clinical setting. (ii) To extend our studies of NK cells to other immune indices relevant to tumor progression, and to test the efficacy of our strategies (employed in Aim 1) in blocking postoperative suppression of these new indices. Measures will include cytokine levels and their induced production, cellular markers of activation and adhesion, cellular and functional characteristics of MP-NK cells, and in vivo anti-malignant functioning. The knowledge gained by our studies will enable clinical trials to examine whether these novel therapeutic approaches will reduce postoperative immunosuppression and increase survival and cure of cancer patients. For the general public: Major surgeries and their accompanied psychological distress often suppress the functioning of the immune system. Such suppression can lead to post-operative outbreak of infections. In some cancer patients, the risk for metastases may increase. The proposed studies will develop and test strategies to prevent such immune suppression and its deleterious consequences. PERFORMANCE SITE ========================================Section End===========================================

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BBBP-2 (01))
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Howcroft, Thomas K
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Tel Aviv University
Tel Aviv
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