Macrophages (M?s) play a key role in tumorigenesis; they are a major player in the inflammatory response and produce a host of growth factors as well as inflammatory cytokines and chemokines that contribute to cellular transformation, promotion, apoptosis, proliferation, invasion, angiogenesis, and metastasis. While it is well established that M?s are primary contributors to protumoral processes, there has been little mechanistic investigation of their specific role in colorectal cancer (CRC). Emerging evidence links gut microbiota to the development and progression of CRC. The tumor-promoting effects of the microbiota in CRC are caused, at least in part, by altered host-microbial interactions. Host-derived immune and inflammatory responses are important driving forces that shape microbial community composition. Recent research identifies the microbiota as a target of inflammation. In fact, inflammation has been reported to favor cancer-promoting biota that may promote cancer progression. M?s are primary mediators of inflammatory processes; however, their influence on cancer promoting-biota has not yet been investigated. The long-term goal is to uncover the mechanisms linking M?s to CRC. The objective of this F31 is to determine the interaction between M?s and gut microbiota in CRC. My central hypothesis is that changes in gut microbiota are driven by M?-mediated inflammatory processes and lead to enhanced progression of CRC. This hypothesis will be tested by pursuing two specific aims: 1) Determine the role of M?s in inflammation, the gut microbiota profile, and colon tumorigenesis; and 2) Determine whether M?s can influence gut microbiota to promote CRC.
In aim 1, I will test the hypothesis that M?s play a role in CRC and that this is associated with inflammation and an altered gut microbiota profile. I will examine the association between macrophages, inflammation, gut microbiota and CRC. Further, I will deplete macrophages at various stages of CRC to determine their role in colon tissue inflammation, the gut microbiota profile and tumorigenesis. Finally, I will use adoptive transfer techniques to test the role of M? phenotype in colon tissue inflammation, gut microbiota, and colon tumorigenesis. In the second aim, I will test the hypothesis that M?-induced changes in the gut microbiota profile can promote CRC. I will transfer gut microbes from M? depleted mice (or intact mice) to antibiotic treated M? intact mice to specifically test the influence of a M?-induced alteration of gut microbiota on metabolites, oxidative stress, DNA damage, and CRC progression. Secondly, using antibiotics I will deplete gut microflora from mice that will receive M?s (or vehicle) to further confirm the role of M?-induced alterations in gut microbiota on CRC. The proposed investigation is significant as it will uncover a mechanism that promotes CRC. Specifically, I will gain an understanding of the role of M?s in the regulation of gut microbiota in CRC. This will allow for the development of approaches that will identify individuals at risk for CRC (i.e. analysis of fecal samples) and then to mitigate that risk with approaches to restore a more healthy microbial profile in the gut.
Emerging evidence links gut microbiota to the development and progression of colorectal cancer. The tumor- promoting effects of the microbiota in colorectal cancer are caused, at least in part, by altered host-microbial interactions; however, the interaction between macrophages and gut microbiota has not yet been investigated. The overall goal of my proposed study is to determine the interaction between macrophages and gut microbiota in colorectal cancer.
