How immune cells promote tissue injury to increase risk of colon cancer

Project: Research project

Project Details


Abstract: Due to exacerbated inflammation and recurring tissue injury, patients with Inflammatory Bowel Disease (IBD) are at higher risk of developing colorectal cancer (CRC). Although, PMN infiltration of the intestinal mucosa is a hallmark of IBD and is often associated with severe injury, the contribution of PMNs to CRC development is not known. Our recent work identified a new mechanism by which PMNs in the inflamed colonic tissue exacerbate inflammation and promote colonic injury. Tissue infiltrating PMNs were found to release microparticles (MPs) transporting regulatory microRNAs to surrounding epithelial cells to promote DNA double strand breaks (DSBs) and potently suppress DSB repair by high fidelity homologous recombination (HR, a major DNA repair pathway in healthy replicating cells). Due to DSB accumulation, resolution of colonic wounds in an animal model was significantly impaired. Importantly, indicating therapeutic relevance, inhibition of PMN activity, by neutralizing miRNAs reduced DSBs and improved wound healing. Our preliminary data further suggested that in the setting of chronic inflammation and recurring epithelial injury, as seen in IBD, PMN-mediated continued suppression of HR can lead to increased DSB repair by error-prone non-homologues end joining (NHEJ), leading to site-specific deletions in the tumor suppressor gene, TP53, rendering it inactive. Loss of TP53 can lead to cellular transformation and carcinogenesis. Thus, we propose that PMNs in an inflammatory condition, such as IBD, may shift the balance of cellular renewal and tissue homeostasis to carcinogenesis, by promoting injury/inflammation-associated inactivation of tumor suppressor genes and cellular transformation. We will use fresh/fixed human tissue specimens and a physiologically relevant murine model of Colitis/Colorectal cancer to define new and more specific therapeutic targets to alleviate symptoms of IBD and prevent IBD-associated CRC.
Effective start/end date7/1/196/30/20


  • Northwestern Memorial Hospital (Agmt 17 Exhibit B.5)