New research from multiple institutions has identified distinct molecular and immune mechanisms through which chronic gut inflammation, a characteristic of conditions such as inflammatory bowel disease (IBD), may contribute to an increased risk of colorectal cancer. Two independent studies have elucidated specific pathways, including epigenetic changes and immune cell signaling, that promote tumor development even after inflammatory conditions subside.
Recent findings from researchers at the Broad Institute of MIT and Harvard, and separately from Weill Cornell Medicine investigators, have provided insights into these complex biological processes.
Context: Inflammation and Cancer
The association between chronic inflammation and an increased risk of cancer, particularly in the gastrointestinal tract, is an established area of medical research. However, the precise molecular and cellular mechanisms underpinning this link have been a subject of ongoing investigation.
Epigenetic Memory and AP-1 Transcription Factors
A study conducted by authors from the Broad Institute of MIT and Harvard, with partial funding from the National Institutes of Health (NIH) and other organizations, focused on epigenetic changes in the gut. Researchers simulated chronic colitis in mice and observed specific changes that increased the activity of AP-1 transcription factors, proteins known to guide cellular responses to stress.
- Mechanism Observed: Damage from inflammation was found to alter colonic stem cells. These alterations, identified as an epigenetic change, resulted in increased activity of AP-1 transcription factors.
- Persistence: This epigenetic "memory" persisted in the epigenomes of cells for over 100 days after colitis-inducing chemicals were removed from the animals. A method was developed using an organoid model of colitis, confirming that this AP-1 memory was heritable and passed from colonic stem cells to new cells during division.
- Impact on Tumor Growth: To assess the long-term effect on cancer risk, genes capable of initiating tumor growth were introduced into mice that had either recovered from chronic colitis or were previously healthy. Colorectal tumor growth was observed to be significantly more rapid in the colitis-recovered animals compared to the healthy group.
- Targeted Intervention: Heightened regenerative activities associated with AP-1 were found within tumors of the recovered animals. When AP-1 activity was blocked, the pro-cancer effect of colitis ceased. This suggests that AP-1 transcription factors may be a central component linking chronic gut inflammation to an increased colorectal cancer risk.
If this mechanism operates similarly in humans, tests for these epigenetic memories could potentially inform patients of colorectal cancer risk early. Furthermore, therapeutics targeting post-colitis AP-1 activity may offer a strategy to help slow tumor growth.
This study received support from various grants, including NCI grants 1OT2CA297577 and 3OT2CA297577, Cancer Research UK, the French National Cancer Institute, the Bowelbabe Fund, the National Human Genome Research Institute (NHGRI) through grant UM1HG011986, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) through grant P30DK034854.
Immune Pathway Involving TL1A and Neutrophils
A separate preclinical study by Weill Cornell Medicine investigators, published in Immunity, focused on an immune pathway relevant to inflammatory bowel disease (IBD). IBD, which encompasses conditions such as Crohn's disease and ulcerative colitis, is characterized by chronic gut inflammation and affects an estimated 2.4 to 3.1 million Americans. IBD is associated with a significantly elevated risk of colorectal cancer, often presenting at younger ages and with less favorable outcomes in affected individuals.
- Key Protein Identified: This study investigated TL1A, an inflammatory immune signaling protein previously associated with both IBD and colorectal cancer.
- Immune Cell Cascade: In an animal model, TL1A was found to primarily influence gut immune cells known as ILC3s. When activated by TL1A, these ILC3 cells trigger an increased production of neutrophils, a type of white blood cell, from the bone marrow, followed by their migration to the gut.
- Neutrophil Role in Tumor Promotion: These neutrophils were observed to be reprogrammed in a manner that promotes tumor formation. This process involves the release of highly reactive molecules that may damage DNA in gut-lining cells. The research team also found that gut ILC3s induce a distinct gene activity pattern in neutrophils, including increased expression of genes known to promote tumor initiation and growth. In mouse models of gut cancer, the introduction of such neutrophils was sufficient to promote tumor development.
A similar tumor-promoting signature was observed in colitis-affected gut tissue samples from IBD patients. This signature was reduced in patients receiving an experimental TL1A-blocking treatment. The findings suggest that TL1A, ILC3s, GM-CSF (secreted by ILC3s), and ILC3-summoned neutrophils could be targets for future strategies aimed at treating IBD and preventing associated colorectal tumors.
Outlook
These distinct research findings contribute to a more comprehensive understanding of the mechanisms by which chronic gut inflammation can drive colorectal cancer development. The identified molecular and immune pathways offer potential avenues for developing new strategies for early detection, prevention, and therapeutic intervention in individuals at risk for inflammation-associated colorectal cancer.