MECHANISMS AND PREVENTION OF SURGERY-INDUCED METASTASIS

超出提供的空间。转移是癌症相关死亡的最常见原因。长期以来，手术切除原发肿瘤一直被怀疑通过几种机制促进转移，包括术后免疫抑制。在我们最近对F344大鼠的研究中，我们发现了术后免疫抑制的神经内分泌介质，并设计了两种有效的策略来克服手术引起的NK活性抑制和促进MADB106实验性转移。我们的第一个策略是基于儿茶酚胺和前列腺素的联合药理阻断。我们的第二个策略是基于术前免疫刺激，使用低剂量的多聚IC或IL-12。此外，我们发现了一种独特的NK细胞群，即分泌肺(MP)-NK细胞。该群体具有高度的细胞毒性，位于与循环中的恶性细胞相互作用的战略位置，并在其裂解同基因的MADB106肿瘤细胞方面具有独特的能力。似乎，我们的两种策略通过不同的细胞机制来保护循环和MP-NK细胞免受术后抑制，从而防止手术促进MADB106转移。拟议的研究旨在促进我们两种新开发的策略的临床适用性，分别是独立的和综合的方法，并围绕两个目标：(I)测试我们的策略及其在C57BL/6小鼠(3LL-D122和B16F10.9黑色素瘤)的两个自发转移模型中的集成使用。与我们以前对实验性转移的研究不同，这些模型还模拟了临床环境中转移的原发肿瘤、隐匿转移和微转移的存在。(Ii)将我们对NK细胞的研究扩展到与肿瘤进展相关的其他免疫指标，并测试我们的策略(在目标1中采用)在阻断这些新指标的术后抑制方面的有效性。措施将包括细胞因子水平及其诱导产生，激活和黏附的细胞标记物，MP-NK细胞的细胞和功能特征，以及体内抗肿瘤功能。通过我们的研究获得的知识将使临床试验能够检验这些新的治疗方法是否将减少术后免疫抑制，并提高癌症患者的存活率和治愈率。对于普通大众：大手术及其伴随的心理痛苦往往会抑制免疫系统的功能。这种抑制可能会导致术后感染的爆发。在一些癌症患者中，转移的风险可能会增加。拟议的研究将开发和测试防止这种免疫抑制及其有害后果的策略。表演网站========================================Section End===========================================

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===========================================