Characterization of the interaction between inflammation and cancer progression

虽然免疫系统最初可能对肿瘤的发展具有保护作用，但随着时间的推移，其有效性可能会减弱，最终可能会促进肿瘤的进展。慢性炎症与多种癌症的发生和发展有关。就癌细胞本身而言，它们可以在促进有利于转移的微环境方面发挥积极作用。本项目的目标是研究炎症在体内调节肿瘤进展、转移和宿主抗肿瘤免疫反应的细胞和分子机制，特别是当它们与肿瘤与器官微环境之间的复杂细胞相互作用以及外部因素(如肥胖和常用药物如抗生素和酒精)有关时。在我们研究的一个方面，我们已经证明了促炎细胞因子，如肿瘤坏死因子、IL-6、IL-1β和IL-17在包括肝和肺在内的经常存在肿瘤转移的器官中上调。这种细胞因子表达的增加伴随着巨噬细胞、中性粒细胞和其他白细胞的急剧膨胀，特别是在那些存在转移的器官中。我们正在进行的研究旨在阐明这些特定的白细胞和细胞因子在转移过程中的相对贡献。认识到肥胖是一个全球性和慢性问题，可能会对宿主免疫反应产生深远影响，我们也在评估喂食高脂饮食(HFD)的小鼠的抗肿瘤反应。使用可移植的转移性肾细胞癌和癌基因引发的肝脏肿瘤，我们对比了对照组和高脂饲料喂养的小鼠的肿瘤发展。有趣的是，尽管对照组小鼠需要两个癌基因的协同作用(例如，失调的AKT和β-连环蛋白)，但我们的数据表明，HFD可能作为一种炎症刺激，提供激活的AKT，并与单一的癌基因协同作用，例如单独的β-连环蛋白，从而促进肝脏肿瘤的发生。除了肿瘤发病率，我们还通过量化腺瘤与癌的肿瘤灶数量来表征肝脏肿瘤的病理特征。该项目的一个重叠方面解决了世界各地长期使用抗生素的新问题。为了控制感染，许多国家的普遍做法鼓励经常和长期使用抗生素。然而，最近的证据表明，宿主微生物群在宿主免疫反应的动态平衡调节中起着重要作用。宿主微生物群由大量共生和共生细菌组成，主要存在于肠道。因此，抗生素的广泛使用可能会对这种体内平衡产生重要影响，应该调查抗生素对慢性炎症和癌症的影响。我们正在利用可移植的肿瘤模型，如转移性肾细胞癌模型，以及项目4中描述的癌基因引发的肝肿瘤。我们发现对照组和抗生素组荷瘤小鼠的存活率存在显著差异，并正在进一步研究这些差异背后的免疫学参数。正在进行的和未来的工作还将调查酒精和肝损伤模型对肝肿瘤进展的影响。通过表征炎症在肿瘤进展中的作用，这些重叠的方法有望导致免疫治疗方法的发展，从而扭曲炎症反应以对抗肿瘤生长。

Although the immune system may initially be protective against tumor development, its efficacy may diminish over time and it may ultimately facilitate tumor progression. Chronic inflammation is associated with the initiation and progression of many types of cancer. For their own part, cancer cells can play an active role in promoting a microenvironment that is favorable for metastasis. The goal of this project is to investigate the cellular and molecular mechanisms by which inflammation regulates tumor progression, metastasis and host anti-tumor immune responses in vivo, particularly as they relate to the complex cellular interactions between the tumor and organ microenvironments as well as external factors such as obesity and commonly used drugs such as antibiotics and alcohol. In one aspect of our research, we have demonstrated the upregulation of pro-inflammatory cytokines, such as TNF, IL-6, IL-1Beta, and IL-17 in organs including the liver and lungs which often harbor tumor metastases. This increase in cytokine expression is accompanied by the dramatic tumor-dependent expansion of macrophages, neutrophils and other leukocytes, specifically in those organs in which metastases are present. Our ongoing research aims to clarify the relative contributions of these specific leukocytes and cytokines to the metastatic process. Recognizing that obesity is a global and chronic problem with the potential for profound effects on the host immune response, we are also evaluating anti-tumor responses in mice fed a high fat diet (HFD). Using both transplantable metastatic renal cell carcinoma and oncogene-initiated liver tumors, we are contrasting tumor development in control and HFD-fed mice. Intriguingly, whereas control mice require the collaboration of two oncogene hits (e.g. dysregulated AKT and Beta-catenin), our data suggest that HFD may serve as an inflammatory hit, provide the activated AKT and contribute to the initiation of liver tumors in collaboration with just a single oncogene, such as beta-catenin alone. In addition to tumor incidence, we are also characterizing the pathology of liver tumors, by quantifying the number of adenoma versus carcinoma tumor foci. An overlapping aspect of this project addresses the emerging problem of long-term antibiotic use around the world. In order to control infections, common practices in many countries encourage the frequent and chronic use of antibiotics. However recent evidence suggests that the host microbiome, consisting of a vast array of symbiotic and commensal bacteria residing primarily in the gut, is important in the homeostatic regulation of host immune responses. The widespread use of antibiotics is therefore likely to have an important effect on this homeostatic balance and the effects of antibiotics on chronic inflammation and cancer should be investigated. We are utilizing transplantable tumor models, such as the metastatic renal cell carcinoma model, as well as the oncogene-initiated liver tumors described in Project 4. We have identified significant differences in the survival of control versus antibiotic treated tumor-bearing mice and are investigating further the immunologic parameters underlying these differences. Ongoing and future work will also investigate the effects of alcohol and liver injury models upon liver tumor progression. By characterizing the role of inflammation upon tumor progression, these overlapping approaches will hopefully lead to the development of immunotherapeutic approaches that skew the inflammatory response to counter tumor growth.