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，但其功效可能会随着时间的推移而减弱，最终可能会促进肿瘤的进展。慢性炎症与许多类型的癌症的发生和发展有关。就其本身而言，癌细胞可以在促进有利于转移的微环境方面发挥积极作用。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，特别是当它们与肿瘤和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。在我们的研究的一个方面，我们已经证明了促炎细胞因子，如TNF，IL-6，IL-1 β和IL-17在器官中的上调，包括肝脏和肺，这些器官通常具有肿瘤转移。这种细胞因子表达的增加伴随着巨噬细胞、嗜中性粒细胞和其他白细胞的显著肿瘤依赖性扩增，特别是在存在转移的那些器官中。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的转移过程中的相对贡献。认识到肥胖是一个全球性的慢性问题，对宿主免疫反应有潜在的深远影响，我们还评估了高脂饮食（HFD）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启动的肝肿瘤，我们对比对照组和HFD喂养小鼠的肿瘤发展。有趣的是，对照组小鼠需要两种癌基因的协同作用（例如失调的AKT和β-连环蛋白），而我们的数据表明，HFD可能作为一种炎症性的打击，提供激活的AKT，并有助于启动肝脏肿瘤与一个单一的癌基因，如单独的β-连环蛋白。除了肿瘤发生率，我们还通过定量腺瘤与癌肿瘤病灶的数量来表征肝脏肿瘤的病理学。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，许多国家的常规做法鼓励频繁和长期使用抗生素。然而，最近的证据表明，宿主微生物组，由大量的共生和寄生细菌主要驻留在肠道，是重要的宿主免疫反应的稳态调节。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，应研究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中描述的癌基因启动的肝肿瘤。我们已经确定了对照组与抗生素治疗的荷瘤小鼠的生存率存在显着差异，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，这些重叠的方法将有望导致免疫方法的发展，这些免疫方法使炎症反应偏离以对抗肿瘤生长。

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.