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.
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