荷瘤状态下中性粒细胞的信号途径调控机制研究

Polymorphonuclear leukocytes (PMNs or neutrophils) make up a significant portion of the inflammatory cell infiltrate found in a wide variety of human cancers and murine models. Neutrophils have the potential to suppress tumor growth through their cytotoxicity against tumor cells and cause the damage of vascular endothelium by producing oxidants and releasing proteolytic enzymes. In contrast, however, in recent years studies have begun to emerge showing critical roles of neutrophils in tumorigenesis. There are compelling data that neutrophils have significant protumor actions, and that they are key mediators of tumor angiogenesis..In our recent studies, we found that tumor-derived G-CSF and IL-6 could augment the protumor potential of neutrophils. Our data showed that tumor burden altered the function and response of neutrophils, characterized by increased activation level of STAT3 in neutrophils, and the inefficient activation of PI3K and p38MAPK pathways in neutrophils in response to the stimuli in tumor milieu. Moreover, in vivo expression of G-CSF and IL-6 in absence of tumor showed same effect on neutrophils. STAT3, PI3K, and p38MAPK pathways are crucial signaling pathways which influence the anti- and pro-tumor potential of neutrophils. In this project, we will investigate the mechanisms underlying the modulatory effect of G-CSF and IL-6 on the function of neutrophils, especially on the activation of these signaling pathways. Meanwhile, we will also investigate whether IFN-β, IFN-γ and TNF-α could recover the response of neutrophils based on the modulation of G-CSF and IL-6. .Although there are compelling data indicate a deleterious role of neutrophils in tumor progression, therapeutically targeting this cell type in cancer is fraught with difficulties. Neutrophils are critical mediators of host defense against infection, and depletion of these cells could result in dangerous levels of immunosuppression. Our study will try to elucidate the mechanism underlying the regulation of neutrophil activation. The results may not only be important for the theory of immunoregulation, but also lead to the new strategy of tumor therapy by recovering the anti-tumor function of neutrophils in presence of tumor.

中性粒细胞（PMN）是肿瘤微环境中大量存在的免疫细胞。虽然PMN具有抗肿瘤潜能，但肿瘤微环境中的PMN却不能产生抑瘤效应，反而具有促瘤作用。我们在研究中发现，肿瘤产生的G-CSF和IL-6使骨髓PMN产生促瘤功能。同时观察到，荷瘤状态改变了骨髓PMN的反应特性，使PMN的STAT3激活水平升高，而在受到肿瘤组织间液分子刺激时，PI3K和p38MAPK途径不能有效激活；体内表达G-CSF和IL-6亦产生同样效应。STAT3、PI3K、p38MAPK是影响PMN促瘤与抗瘤潜能的关键信号途径，本项目研究中，将着重探讨G-CSF和IL-6协同调控这些信号途径的相关机制，同时还将研究干扰素和TNF-α恢复PMN反应性的作用。本项目研究可从信号途径激活调控的角度阐明PMN激活的控制机制，不仅具有重要的理论价值，而且可为建立荷瘤状态下有效激活PMN的策略、利用PMN治疗肿瘤的研究提供新的思路和依据。

中性粒细胞（PMN）是肿瘤微环境中大量存在的免疫细胞。虽然PMN具有抗肿瘤潜能，但肿瘤微环境中的PMN却不能产生抑瘤效应，反而具有促瘤作用。我们在研究中发现，肿瘤产生的G-CSF和IL-6使骨髓PMN产生促瘤功能。同时观察到，荷瘤状态改变了骨髓PMN的反应特性，使PMN的STAT3激活水平升高，而在受到肿瘤组织间液分子刺激时，PI3K和p38MAPK途径不能有效激活；体内表达G-CSF和IL-6亦产生同样效应。STAT3、PI3K、p38MAPK是影响PMN促瘤与抗瘤潜能的关键信号途径，本项目研究中，将着重探讨G-CSF和IL-6协同调控这些信号途径的相关机制，同时还将研究干扰素和TNF-α恢复PMN反应性的作用。在完成本项目研究内容的基础上，我们根据研究的新发现还扩展了相关研究内容。主要研究结果包括：（1）荷瘤状态下G-CSF和IL-6协调增强PMN STAT3的激活和表达，而G-CSF通过Lyn和SHIP-1抑制PI3K和p38MAPK途径的激活效应，使PMN功能从抑瘤转变为促瘤。（2）肿瘤微环境中PMN产生的TLR4 配体和H2O2 激活的non-Smad途径可增强TGF-β1促进非侵袭性乳腺癌细胞的转移潜能。（3）14,15-EET诱导PMN浸润和促瘤功能可触发微小休眠转移灶生长。（4）细胞内IL-37b 与Smad3 相互作用抑制多条信号途径和肿瘤细胞转移表型。（5）在正常NK细胞存在条件下，干扰素和TNF-α预激活促瘤潜能的PMN有效抑制肿瘤生长。.本项目研究从信号途径激活调控的角度阐明了PMN功能调控的机制，所获得的结果为PMN从抑瘤功能转变为促瘤功能、在荷瘤状态下逆转PMN朝向抑瘤功能转变的机制研究，以及为肿瘤微小转移灶复发机制研究提供了有价值的实验依据。不仅具有重要的理论价值，而且为利用PMN治疗肿瘤的研究提供了新的思路和依据。为肿瘤的防治提供了有效治疗策略。