MECHANISMS AND PREVENTION OF SURGERY-INDUCED METASTASIS

超出所提供的空间。转移是癌症相关死亡的最常见原因。长期以来，人们一直怀疑原发肿瘤切除手术通过多种机制促进转移，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物阻断。我们的第二种策略是基于术前低剂量poly-IC或IL-12的免疫刺激。此外，我们发现了一个独特的NK细胞群，边缘肺(MP)-NK细胞。这个群体具有很强的细胞毒性，可以与循环恶性细胞相互作用，并且在裂解同源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起作用，保护循环细胞和MP-NK细胞免受术后抑制，从而防止手术促进MADB106转移。本研究旨在促进我们两种新开发策略的临床应用，以独立和综合的方式，主要围绕两个目标：(i)测试我们的策略及其在两种C57BL/6小鼠（3LL-D122和B16F10.9黑色素瘤）自发转移模型中的综合应用。与我们之前的实验转移研究不同，这些模型还模拟了原发肿瘤转移、休眠转移和微转移的存在，就像在临床环境中一样。（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Aim 1中使用）在阻断这些新指标的术后抑制方面的有效性。测量将包括细胞因子水平及其诱导产生，细胞活化和粘附标志物，MP-NK细胞的细胞和功能特征，以及体内抗恶性功能。从我们的研究中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会减少术后免疫抑制，提高癌症患者的生存率和治愈率。对于普通大众：大手术及其伴随的心理困扰往往会抑制免疫系统的功能。这种抑制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。拟议的研究将制定和测试预防这种免疫抑制及其有害后果的策略。网站性能 ======================================== 节结束 ===========================================

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