EETs调控PMN促进肿瘤转移潜伏病灶发展的相关机制研究

Tumor cells could metastasize from primary tumor to target organ, where the disseminated tumor cells slowly developed into latent micrometastatic lesions due to the restriction of target organ microenvironment. The alteration of target organ microenvironment might be a key element for the development of latent micrometastasis and the metastatic recurrence of tumor. So far the elements modulating target organ microenvironment have not been well understood, which hindered the study on the prevention of metastatic recurrence of tumor. In our recent studies, we found that extra-cellular signals could induce the metastatic phenotype of non-metastatic tumor cells. After disseminating into target organ, the extra-cellular signal-induced metastatic tumor cells could only slowly develop into micrometastatic lesions due to lower proliferation at metastatic sites. Eventually, these tumor cells only formed latent micrometastatic lesions in target organ. Intriguingly, epoxyeicosatrienoic acids (EETs) could promote the development of latent metastatic lesions. EETs could alter the microenvironment of metastatic lesions by promoting the infiltration of neutrophils (PMN) into the metastatic lesions, and modulating the function of neutrophils. The modulatory effect of EETs on PMN was crucial for the development of metastatic lesions. In this project, we will further investigate the mechanisms underlying the modulation of chemotaxis and tumor-promoting function of neutrophils by EETs. Meanwhile, we will investigate whether interferons might antagonize or reverse the modulatory effect of EETs on the function of PMN. The dormant/latent micrometastases are responsible for the recurrence of tumor and even the death of patients. It has been difficult to prevent the metastatic recurrence of tumor due to the poor understanding of the mechanisms underlying the modulation of target organ microenvironment. Our study will try to elucidate the mechanisms underlying the modulatory effect of EETs on target organ microenvironment based on the modulation of neutrophils. The results may not only be important for the theory of tumor metastasis and metastatic recurrence, but also lead to the new strategy of tumor therapy by preventing the metastatic recurrence.

从原发肿瘤部位播散转移的肿瘤细胞常常在转移靶器官组织微环境的制约下形成微小潜伏病灶，而转移部位微环境的改变则是促进潜伏病灶发展、导致肿瘤复发的关键。迄今对转移部位微环境的调控因素了解甚少，成为防治肿瘤转移复发研究的障碍。我们在研究中发现，由细胞外信号诱导产生转移能力的肿瘤细胞侵袭进入靶组织后，只能形成休眠的潜伏病灶，而环氧二十碳三烯酸（EETs）可改变潜伏病灶的微环境而促进其发展。EETs促进中性粒细胞（PMN）浸润肿瘤潜伏病灶部位，并改变了PMN的功能，通过PMN促进肿瘤潜伏转移病灶的发展。本项目研究中，将深入研究EETs调控PMN趋化浸润及其促瘤功能的相关机制，同时还将研究干扰素能否拮抗或逆转EETs对PMN功能的调控。从PMN调控的角度阐明EETs调控肿瘤转移部位微环境的相关机制，不仅具有重要的理论价值，而且可为阻遏肿瘤转移病灶的发展、防止肿瘤转移复发的研究提供新的思路和依据。

从原发肿瘤部位播散转移的肿瘤细胞常常在转移靶器官组织微环境的制约下形成微小潜伏病灶，而转移部位微环境的改变则是促进潜伏病灶发展、导致肿瘤复发的关键。迄今对转移部位微环境的调控因素了解甚少，成为防治肿瘤转移复发研究的障碍。我们在研究中发现，由细胞外信号诱导产生转移能力的肿瘤细胞侵袭进入靶组织后，只能形成休眠的潜伏病灶，而环氧二十碳三烯酸（EETs）可改变潜伏病灶的微环境而促进其发展。EETs促进中性粒细胞（PMN）浸润肿瘤潜伏病灶部位，并改变了PMN的功能，通过PMN促进肿瘤潜伏转移病灶的发展。. 本项目主要研究EETs调控PMN趋化浸润及其促瘤功能的相关机制，同时还研究干扰素能否拮抗或逆转EETs对PMN功能的调控。在完成本项目研究内容的基础上，我们还扩展了相关研究内容。主要研究结果包括：① EETs通过促进PMN促血管生成能力而促进转移潜伏病灶的发展；② EETs通过激活STAT3和JNK信号途径而上调hIL-8/mCXCL15在肿瘤细胞中的表达。同时，STAT3和JNK途径上调miR-155的表达，从而抑制SHIP1和DET1而形成正反馈调控，促进JNK的持续激活；③ EET对PMN的CXCR1和CXCR2没有明显的表达调控作用和激活作用，促进hIL-8/mCXCL15表达是EET体内促瘤的关键机制；④ EET通过促进PMN的STAT3途径激活而促进PMN功能从抑瘤向促瘤转变；⑤ IFN-γ拮抗EETs调控PMN的作用；⑥ 循环肿瘤细胞通过调控PMN的促瘤功能而促进肿瘤转移病灶的形成和发展；⑦ IL-37b抑制肿瘤细胞的侵袭转移能力。. 本项目研究从体内微环境因素对肿瘤细胞和中性粒细胞的调控作用等方面阐明微环境对肿瘤转移病灶发生和发展的影响及相关机制，研究结果不仅具有重要的理论价值，而且可为阻遏肿瘤转移病灶的发展、防止肿瘤转移复发的研究提供新的思路和依据。