Role of the complement C3a receptor on immune and non immune intestinal barrier functions and microbiota in colorectal cancer development

点击翻译按钮获取中文摘要

While it was initially believed that only a minority of CRC are driven by inflammation, studies showing that treatment with anti-inflammatory medications may prevent or delay the development of CRC in hereditary and sporadic cases, clearly identify inflammation as a key driver in the development and progression of all types of CRC. Yet, it is still unclear what are the mechanisms that in the complex intestinal environment contribute to the activation of the inflammatory pathways that initiate CRC. The intestine holds a delicate balance between host protection and control of excessive inflammation, and we posit that a dysregulated communication between the epithelial and the immune component of the intestinal barrier may link a sub-acute state of inflammation and CRC initiation. The complement system is emerging as an important player in the gastrointestinal tract. Specifically, the complement anaphylatoxin C3a and its receptor, C3aR, regulate the immune and epithelial compartments in the intestine and exert antibacterial properties. By mining publicly available datasets, we found that C3aR is down-regulated in patients with CRC and the fact that this down-regulation occurs already in stage 1 tumors, suggests that it may be an early event during CRC development. By crossing C3aR-/- mice with the APCMin/+ mice, that carry a mutation in the apc gene, similarly to the majority of human CRC, we showed that C3aR is protective in CRC. Indeed, while in APCMin/+ mice tumors mostly developed in the small intestine, in APCMin/+/C3aR-/- mice tumorigenesis dramatically shifted almost exclusively to the colon. We also found intestinal barrier dysfunction and microbial dysbiosis in mice lacking C3aR, suggesting that C3aR may be a novel gatekeeper in intestinal homeostasis. However, it is currently unknown how C3aR contributes to CRC development. We hypothesize that loss of C3aR causes intestinal barrier dysfunction by affecting the communication between epithelial and immune cells. This then leads to development of microbiota-driven inflammatory immune responses that promote the development of CRC. To test this hypothesis we propose: 1) to investigate how loss of C3aR affects the epithelial component of the intestinal barrier and the communication with the immune cells; 2) To investigate the contribution of C3aR on immune, non immune cell types, and microbiota to CRC development; 3) To investigate the C3aR status in human pre-invasive lesions and CRC. Bone marrow chimera in combination with single cell high dimensional analysis of immune infiltrates using mass cytometry and REAPseq will determine the contribution of C3aR on immune and non immune cells to colon inflammation and CRC development and progression. We will assess how C3aR down-regulation affects human CRC and survival by using human specimens from our well characterized patient cohorts. As loss of C3aR represents an early event during CRC, identifying the mechanisms linking loss of C3aR to the development of CRC will not only further our understanding of CRC but is highly significant for the prevention of CRC.