Characterization of the interaction between inflammation and cancer progression

尽管免疫系统最初可能对肿瘤的发展具有保护作用，但其功效可能随着时间的推移而减弱，最终可能促进肿瘤的发展。慢性炎症与许多类型癌症的发生和发展有关。就癌细胞本身而言，可以在促进有利于转移的微环境中发挥积极作用。该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，特别是它们与肿瘤和器官微环境之间复杂的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。在我们研究的一个方面，我们已经证明了促炎细胞因子，如TNF、IL-6、il -1 β和IL-17在包括肝和肺在内的经常有肿瘤转移的器官中的上调。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肿瘤依赖性扩增，特别是在存在转移的器官中。我们正在进行的研究旨在阐明这些特定白细胞和细胞因子对转移过程的相对贡献。认识到肥胖是一个全球性的慢性问题，可能对宿主免疫反应产生深远的影响，我们也在评估高脂肪饮食（HFD）小鼠的抗肿瘤反应。我们使用可移植的转移性肾细胞癌和癌基因引发的肝肿瘤，对比对照小鼠和饲喂hfd小鼠的肿瘤发展情况。有趣的是，对照小鼠需要两种致癌基因的协同作用（如失调的AKT和β -catenin），而我们的数据表明，HFD可能仅与单一致癌基因（如β -catenin）协同作用，提供活化的AKT并促进肝脏肿瘤的启动。除了肿瘤发病率外，我们还通过量化腺瘤与癌灶的数量来描述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，许多国家的常见做法鼓励经常和长期使用抗生素。然而，最近的证据表明，宿主微生物群由大量主要存在于肠道中的共生和共生细菌组成，在宿主免疫反应的稳态调节中起重要作用。因此，抗生素的广泛使用可能对这种体内平衡产生重要影响，抗生素对慢性炎症和癌症的影响应该进行研究。我们正在使用可移植的肿瘤模型，如转移性肾细胞癌模型，以及项目4中描述的癌基因启动的肝脏肿瘤。我们已经发现对照组与抗生素治疗的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研究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.