The role of danger signals in tumor elicited inflammation (TUM5P.934)

Abstract

Abstract Sporadic colorectal cancer (CRC) has traditionally been considered a genetic disease, with inactivation of classic tumor suppressors, such as APC and P53, driving tumorigenesis. Recently, however, it has come to light that inflammation plays a major role in the progression of CRC, and that tumor cells can induce a massive infiltration of immune cells into the tumor. Danger Associated Molecular Patterns (DAMPs) are proteins that are released from dying or stressed cells, which promotes an immune response. While these so called “danger signals” are often up-regulated in cancer, the mechanisms behind their role in tumor progression and inflammation require further exploration. Using a number of mouse models of spontaneous CRC, we are beginning to uncover which inflammatory cues induce danger signals, and which immune cells are the major producers. We have found that S100A8/A9 and HMGB-1 are significantly up-regulated in tumor tissue and mesenteric lymph nodes (MLN) of mice with CRC, compared to adjacent normal colon tissue. Additionally, using FACS to sort individual immune populations within the mouse tissue, intraepithelial monocytes and neutrophils seem to be the major immune cell producers of danger signals. Finally, in a kRas inducible model, to simulate a more aggressive cancer, danger signals are elevated even further in tumor tissue and MLN. Future work will focus on elucidating the precise signaling between immune modulators and danger signals.