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Home » How Neutrophils Drive DNA Damage Linked to Cancer
Disease Discoveries

How Neutrophils Drive DNA Damage Linked to Cancer

By Anna WilliamsJan 15, 2019
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Ronen Sumagin, PhD, assistant professor of Pathology, was the senior author of the study published in the Journal of Clinical Investigation.

In a study published in the Journal of Clinical Investigation, Northwestern Medicine scientists have demonstrated how innate immune cells in inflamed tissue induce accumulation of DNA damage that promotes the development of cancer.

The findings for the first time directly link immune cell-induced inflammation and cancer, and may explain why patients with inflammatory bowel diseases (IBD) are at an increased risk for colorectal cancer. The study also points to potential new targets for treatment.

Ronen Sumagin, PhD, assistant professor of Pathology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, was the senior author of the study.

Veronika Butin-Israeli, PhD, research assistant professor of Pathology, was the first author.

IBD, which includes Crohn’s disease and ulcerative colitis, are characterized by chronic inflammation of the gastrointestinal tract. Patients with IBD are also at a significantly higher risk of developing colorectal cancers.

Veronika Butin-Israeli, PhD, research assistant professor of Pathology, was the first author of the study.

Neutrophils, a type of immune cell, are the “first responders” recruited to inflamed tissue and are important for protecting the body against invading pathogens. However, they can also be detrimental, and the infiltration of neutrophils is a key feature of the tissue damage seen in IBD.

Still, how neutrophils contribute to IBD pathology — and to IBD-linked colorectal cancer development — had previously not been well defined.

In the current study, Sumagin’s laboratory discovered that neutrophils in an inflamed area — such as the colon — release microparticles that carry pro-inflammatory microRNAs to surrounding epithelial cells. These microRNAs downregulate expression of key proteins involved in DNA repair, leading to the accumulation of “double-strand breaks,” a specific type of DNA damage.

The scientists found that this accumulation of double-strand breaks impairs colonic healing and causes genomic instability, which can lead to cancer.

Based on these findings, the scientists also designed molecules to inhibit the microRNAs released by neutrophils. In an animal model, those molecules led to significant improvement in tissue recovery and a decrease in the accumulation of DNA breaks.

As such, the approach could be incorporated into future therapies to potentially resolve recurring inflammation in IBD, improve tissue healing and prevent cancer development, the scientists said.

“Our work not only showed how neutrophils during inflammation can affect genome stability, but also determined how we can treat and prevent this hazardous effect of inflammation — without compromising neutrophils’ capacity to defend us against pathogenic bacteria,” Butin-Israeli said.

In ongoing research, the team is investigating whether neutrophil-derived microRNAs could also be used in the clinic as prognostic markers for IBD patients’ risk of developing colorectal cancer. They are also working to define how neutrophils inactivate key tumor suppressor genes.

The study was also co-authored by Robert Goldman, PhD, the Stephen Walter Ranson Professor of Cell Biology and chair of Cell and Molecular Biology; Stephen Hanauer, MD, the Clifford Joseph Barborka Professor of Medicine in the Division of Gastroenterology and Hepatology; Stephen Adam, ’86 PhD, associate professor of Cell and Molecular Biology; Triet Bui, a doctoral student; Hannah Wiesolek; Lorraine Mascarenhas; Joseph Lee; Lindsey Mehl and scientists from the Mayo Clinic.

The study was supported by grants from the National Institutes of Health (NIH) DK101675, Digestive Health Foundation, Chicago and by the Robert H. Lurie Comprehensive Cancer Center (Eisenberg Scholar grant).

Cancer Genetics Pathology Research
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