The immunoregulatory role of heme in colitis-associated cancer (CAC)

• Applicant: Dr. Philippa Seika
• Subject Area: General and Visceral Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528835020

Colorectal cancer (CRC) is a worldwide health burden with high incidence and mortality, particularly in advanced stages of disease. Colorectal cancer is associated with chronic inflammation such as is seen in inflammatory bowel disease (IBD). Treatment of IBD is symptom driven and aimed at suppressing immune responses but often remains inefficient – resulting in scarring, delayed wound healing, infection and cancers. Chronic inflammation, such as seen in radiation enteritis or IBD, leads to the release of free heme. Overall, while free heme is considered to be pro-inflammatory, it can also have modulatory effects on the inflammatory response. The balance between these pro- and anti-inflammatory effects may depend on various factors, including the concentration and duration of exposure to free heme, as well as the specific context of the inflammatory response. Our investigation is therefore based on the following hypotheses: 1) We believe that damage to colonic epithelial cells caused by free heme, is mediated by G4 secondary structures. We have previously shown that heme coordinates with d(TTGAGG) oligonucleotides to form heme:G4 complexes. G4 structures are found in several regulatory regions of the genome, including oncogene promoters (i.e., Kras, c-myc), telomeres and are linked to genomic stability, tumor initiation and progression. We therefore believe this to be a mechanism by which heme promotes CAC development and progression. Therefore, we will define the pro-ongogenic role of heme:G4 complexes in vitro. 2) Free heme is known to have pro-inflammatory effects and contribute to the pathogenesis of various inflammatory diseases, such as sepsis, acute lung injury, and atherosclerosis. Our data suggest that heme promotes inflammation through control of transcription, DNA replication and modulation of immune cell function. Pro-inflammatory effects of enteral free heme are ameliorated after elimination of the gut microbiome. This suggests that constitution of the gut microbiome contributes to heme induced inflammation. We will explore these mechanisms in colon inflammation using an established model of radiation enteritis and DSS colitis. 3) We have previously shown that labile heme in the TME is pro-ongogenic in a model of prostate cancer. Increased heme levels lead to heme:G4 complexes and senescence of immune cell subsets promoting tumour growth. Free heme can modulate the function of various immune cells, such as neutrophils, macrophages, and dendritic cells, by altering their cytokine production, phagocytic activity, and antigen presentation. Macrophages are important for elimination of free heme; therefore we will focus on macrophage function. Free heme can be eliminated by several other mechanisms including binding to hemopexin (Hx), which is then cleared by the liver, or by heme oxygenase-1 (HO-1), which catalyses heme degradation. We believe that the elimination of free heme is a therapeutic application for prevention of CAC.

• DFG Programme: WBP Position