New Immune-Mediated Protective Mechanism Against Colon Cancer Discovered

How stem cells in our colon (large intestine) protect against cancer has been studied for many years. In January 2019, Nature published a study discovering a mechanism preventing intestinal stem cells in the colon from becoming cancerous. It may improve understanding of many inflammatory diseases and cancers.

Our intestines are where the outside and inside worlds meet. Intestinal wall cells encounter bacteria, nutrients, and digestive products from outside. This direct contact is vital. Certain essential nutrients and beneficial bacteria (gut, microbiome) are necessary for health. Sometimes, however, contact is harmful: foreign substances can cause serious genetic changes in intestinal epithelial (inner lining) cells. This DNA damage, if it occurs in intestinal epithelial stem cells , causes cancer development.

Stem Cells Have Highly Developed DNA Repair Capacity to Prevent Cancer

When DNA damage is severe, apoptosis (programmed cell death) eliminates damaged cells. Until now, stem cells were thought to trigger this repair mechanism. The new study discovered that the immune system effectively carries out DNA repair in damaged stem cells and prevents colon cancer.

• What You Need to Know About Colon and Rectal Cancer

In mouse models, researchers observed that the primary immune system recognizes genotoxic compounds in the colon and activates protection. Some foods naturally contain compounds called glucosinolates, which may damage our cells. When primary immune cells detect them, they secrete interleukin 22 , a molecule enabling epithelial stem cells to anticipate DNA repair and repair rapidly, preventing cancer. Mice with this system blocked rapidly developed colon cancer.

What Does This Discovery Mean for Us?

• Our bodies were discovered to have developed protective systems against colon cancer. Once again, the immune system proved more complex than assumed.
• The immune system simultaneously controls healthy growth and organ function.
• The next stage plans to examine relationships between food, intestinal flora, the intestinal wall, and immunity.

ADVANCED INFORMATION: Graphical Summary of the Study

IL-22-mediated protection model for epithelial stem cells against genotoxic (gene-damaging) stress. These cells in the intestinal barrier constantly face various insults, including threats to genomic integrity from dietary or bacterial genotoxins. Stem-cell genomic integrity requires a DDR (DNA Damage Response) pathway limiting genetic code damage and preventing cancer. Study data describe a homeostatic regulatory loop in which AhR receptor detects food-derived genotoxins acting as AhR ligands, assessing the degree of “genotoxic danger.” AhR signaling in immune ILC3 and γδ T cells controls IL-22 production. In intestinal epithelial stem cells, IL-22 signals in turn control DDR components. In particular, ATM, a PI3-kinase-like molecule and important upstream DDR transducer, is upregulated by IL-22 signaling in stem cells. Following genotoxic stress, ATM controls downstream DDR events including p53 activation and expression of DDR effectors p21 and PUMA, controlling DNA repair and apoptosis, respectively. Disrupting this pathway in mice genetically lacking IL-22, IL-22 receptor, or AhR led to impaired DDR against various forms of genotoxic stress.

In conclusion, when IL-22 signaling or production is disrupted in mouse intestinal epithelial stem cells, mutations causing uncontrolled proliferation accumulate, resulting in accelerated cancer development.