化学物致癌过程中无菌性炎症分子网络的形成与调控

The environmental pollution has drastically increased the incidence of chemical carcinogenesis in China over the last few years. The sterile inflammation as one of the major driving factors becomes a top priority for cancer research. It is still not clear how the sterile inflammation is initiated, maintained and whether it can be down-regulated during the chemical carcinogenesis. Previous works in this laboratory showed that the pro-inflammatory properties of several cytokines, such as TNFα and IL-4, depended on the same IFNγ-STAT-1 signaling pathway and the effect of inflammation on tumor development could be altered by local microenvironment. A given cytokine, such as IFNγ, could either inhibit or promote tumor development in different tissues depending on the functions of S100A4+ cells. Therefore, it is very important to further explore the mechanism how the inflammation network forms and its dynamic changes during tumor development. The study will deepen our understanding on the relationship between sterile inflammation and cancer and help us to find key regulators for the control of chemical carcinogenesis. . In this project, we will use common polycyclic aromatic hydrocarbons to induce sterile inflammation and cancers in a variety of knockout mice deficient of different cytokine receptors; find out how the sterile inflammatory network forms and whether it can be resolved by different means of genomics and bioinformatics with paying a special attention on the function and regulation of S100A4; screen novel molecular targets and natural drugs to control the sterile inflammation on the basis of experimental and clinical observations. This project will attribute significantly to the early diagnosis and prevention of inflammation-associated cancers.

环境污染加剧使化学物致癌率不断攀升。致癌物引发的无菌性炎症是肿瘤发生的重要原因，但其启动机制，分子网络形成，是否可控等诸多问题尚不明了。本组前期工作表明：许多促炎症因子如TNFα和IL-4等的效应依赖于IFNγ-STAT-1信号通路，后者活化既能促进也可抑制肿瘤发生，后果受微环境中S100A4+细胞之功能影响。鉴于各因子间复杂的相互作用，单一信号通路研究不足以揭示炎症与肿瘤发生规律，系统分析炎症部位以S100A4等为节点的分子网络动态，有助于了解无菌性炎症的发展规律，控制化学物致癌过程。. 本课题拟利用本组具备的多种炎症因子受体缺陷或转基因动物模型，通过蛋白组学和生物信息学方法，研究环境中常见的多环芳香烃类化合物致癌过程；以S100A4等分子为节点的无菌性炎症网络的形成、发展和消退机制；结合临床观察筛选并验证可用于网络调控的分子靶标，为推动炎症相关肿瘤的早期诊断和预防做出贡献。

S100A4具有双面效应。在MCA诱导的肿瘤中，皮肤S100A4+成纤维细胞通过分泌胶原包裹致癌物这一“异物反应”发挥免疫监视作用，而在CCl4诱导的小鼠肝脏纤维化模型中，发现肝脏组织中的S100A4+细胞主要是巨噬细胞，它们能将S100A4以分泌蛋白的形式释放到组织局部，体外实验结果显示，S100A4通过c-myb通路上调α-平滑肌肌动蛋白激活肝脏星形细胞，促进肝纤维化的形成。体内中和S100A4或选择性消除分泌S100A4的细胞，能缓解纤维化的发生发展。肝硬化病人的血清和组织中S100A4有显著升高的趋势。IFNγ的效应也具有两面性。在抑制肿瘤方面：1）IFNγ抑制间质成纤维细胞，阻断血管新生。在MCA诱发纤维肉瘤的过程中，缺乏IFNγ将提高肿瘤的发生率。2）IFNγ抑制内皮细胞生长。IFNγ可直接抑制肿瘤血管出芽新生以及血管内血液的有效灌注，从而抑制肿瘤的生长。这一效果是通过下调内皮细胞表面Dll4分子的表达实现的。3）IFNγ可能发挥免疫监视作用。对DMBA/TPA化学致癌物诱导皮肤黑色素细胞形成和转移过程进行研究，发现中和内源性IFNγ或使其受体缺陷能促使黑色素细胞从皮肤向淋巴结发生转移。IFNγ也可以发挥促进肿瘤生长的作用。在DMBA/TPA致癌模型中，乳突瘤自发消退的过程中伴随着IFNγ在肿瘤局部表达下降。相应地，中和内源性IFNγ或使其受体缺陷能促使乳突瘤加快消退但并不影响肿瘤的恶变。检测发现，中和IFNγ引起肿瘤中炎症水平下降的同时，LXA4的合成却显著提高。阻断LXA4的效应通路能够削弱IFNγ中和抗体促进乳突瘤消退的作用，而给IFNγ信号通路完全的小鼠注射LXA4则能促进乳突瘤消退。这些结果首次证明了内源性IFNγ能够通过下调肿瘤中LXA4的合成，抑制肿瘤消退。IFNγ抑制原位肿瘤生长的同时，却促进肿瘤转移。在IFNγR基因缺陷小鼠的基础上，已经成功构建了VEGF-IFNγR转基因小鼠，它是在VEGF启动子控制下表达IFNγ受体的小鼠。该受体主要表达在成纤维细胞上。IFNγ在血管新生过程中作用于VEGF+的细胞上能够有效抑制原位肿瘤的生长，但是，促进肿瘤发生肺脏和肝脏转移。这可能是由于IFNγ作用于VEGF+的细胞上降低血管周细胞的覆盖率从而引起血管系统紊乱造成的。