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University of Illinois researchers have identified a link between high levels of neighborhood violence and lung cancer progression that may partially explain disparities in lung cancer outcomes between Black men and White men.

Writing in Cancer Research Communications, study co-lead Zeynep Madak-Erdogan, a food science and human nutrition professor at the University of Illinois Urbana-Champaign, and colleagues say their findings “suggest that the type of chronic stress triggered by residing in high-violence neighborhoods significantly alters cortisol metabolism and [glucocorticoid] binding within the tumor microenvironment, ultimately driving an increase in pathways associated with tumor aggressiveness.”

The authors explain that although Black men have lower rates and intensity of smoking than White men and tend to start smoking at an older age, they experience a higher incidence of lung cancer.

This racial disparity in lung cancer is particularly pronounced in Chicago, a highly segregated urban city, where neighborhood conditions, particularly social stress, may play a role in lung tumorigenesis. Chronic stress exposure has been shown to be associated with increased levels of the glucocorticoid hormone cortisol and other biophysical changes that lead to an increased risk for cancer development and progression.

Cortisol and other steroid hormones bind to receptors that regulate gene activity. Glucocorticoids and their receptors are involved in a variety of key functions, Madak-Erdogan said. They help regulate fetal and newborn lung tissue development, and play a role in metabolism, homeostasis, inflammation and immune function in this tissue.

Previous work by study co-lead  Sage Kim, PhD, from the University of Illinois Chicago School of Public Health, has shown that Black men residing in neighborhoods with higher rates of violent crime have significantly higher levels of hair cortisol, while another study found a link between neighborhood violence and lung cancer in Chicago.

To further investigate these findings, Madak-Erdogan and team used spatial transcriptomics and chromatin analysis to examine the relationship between neighborhood violence, gene expression, and glucocorticoid receptor binding in healthy and tumor cells taken from 15 patients with lung cancer (60% men, 67% Black, mean age 62 years) from Chicago.

They found that gene-expression patterns and glucocorticoid receptor binding to DNA differed between healthy and tumor tissues, and by patients’ zip codes. Overall, glucocorticoid receptor binding was highest in people who lived in high-violence areas. But within the tumor tissues, those living in high-crime zip codes had lower glucocorticoid receptor binding. They also had lower levels of glucocorticoid receptor-regulated genes in the tumor tissues.

The analyses also revealed that, within tumors, the glucocorticoid receptors were activating genes for enzymes that degrade cortisol, which led to lower cortisol levels, and thus lower glucocorticoid receptor binding, in the tumors than in normal lung tissue. The lower cortisol levels were likely influencing the overall behavior of the receptors in the lung cancer tumors, Madak-Erdogan explained.

“In terms of the genes the receptors regulated in the tumors of individuals living in high-violence areas, they were genes related to inflammation, higher proliferation, higher growth-factor signaling, all of which will lead to the worst outcomes for lung cancer,” she said. “While we didn’t prove a direct relationship in this study, our findings suggest that glucocorticoids and glucocorticoid receptors are a main driver of adverse tumor outcomes in patients living with chronically high levels of environmental stress.”

The researchers also checked whether gene expression profiles were associated with other neighborhood characteristics such as race/ethnicity composition and overall violence. Madak-Erdogan told Inside Precision Medicine that, surprisingly, “the only factor that correlated with the lung cancer gene expression was the neighborhood violence. So, what we are studying is independent of the racial/ethnic background of individuals and seems to be associated with the violent crime in the neighborhood.”

She added that the findings could potentially guide policy changes to lung cancer screening guidelines.

“An increased understanding of the link between exposure to neighborhood violent crime, glucocorticoid signaling, and lung tumorigenesis could lead to improved screening criteria for people living in high-stress environments, and consequently reduce racial disparities in lung cancer,” the authors write.

Madak-Erdogan also suggested that “targeting stress signaling in cancer cells might improve disease outcomes for individuals living in high-crime neighborhoods.”

The team is now hoping to extend their analysis to other U.S. cities where similar disparities in neighborhood crime rates exist.

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