Department of Microbiology, Immunology, and Cell Biology
West Virginia University School of Medicine
Gastric cancer is the 5th most common cancer in the world. Most cases of gastric cancer are associated with infection by the bacteria Helicobacter pylori. The infection causes massive gastric inflammation, which damages the stomach, and promotes gastric carcinogenesis. The factors that regulate gastric inflammation and how the inflammatory microenvironment promotes cancer development are unclear. Our goal is to understand how inflammation promotes gastric cancer development to facilitate the discovery of new gastric cancer diagnostics and treatments.
Glucocorticoid Regulation of Gastric Inflammation and Carcinogenesis
Glucocorticoids are steroid hormones produced by the adrenal glands. These hormones function as the brake pedal for the immune system. Within the stomach, glucocorticoids are critical for regulating the intensity of gastric inflammation. We've recently shown that disruption of glucocorticoid signaling quickly leads to spontaneous stomach inflammation. Type 2 innate lymphoid cells (ILC2s) and macrophages are at the forefront of this pathogenic inflammatory response, damaging the stomach and leading to the development of potentially precancerous spasmolytic polypeptide-expressing metaplasia (SPEM). We are currently investigating the role of glucocorticoid signaling in controlling inflammation during Helicobacter pylori infection. We hypothesize that disruption of glucocorticoid signaling during Helicobacter pylori infection leads to a more severe inflammatory response and promotes gastric cancer development.
Sex Hormone Regulation of Gastric Inflammation
Inflammation is regulated differently in males and females. Females typically have a more robust inflammatory response than men. While this provides greater protection from infection, women are more susceptible to autoimmune and chronic inflammatory diseases. Sex can influence inflammation through a host of different mechanisms ranging from lifestyle to sex chromosomes. We have found that androgen's, the male sex hormone, suppress gastric inflammation by regulating ILC2 activation. Interestingly, sex also affects gastric cancer, and cancer rates in men are nearly double rates in women. This relationship between men being protected from inflammation yet being more susceptible to gastric cancer is somewhat confusing. Androgen's may promote an alternative immune response that protects from inflammatory damage at the expense of immune surveillance for cancer. Our lab is currently investigating the important relationship between sex, inflammation, and gastric cancer.
Busada et al. 2021. Gastroenterology
Effects of endocrine disrupting chemicals on gastric cancer susceptibility
Glucocorticoids are master regulators of gastric inflammation. In mice, surgical removal of the adrenal gland (adrenalectomy) triggers spontaneous gastric inflammation and SPEM. Adrenalectomy is a convenient and easy model to study gastric inflammation and metaplasia. However, unlike mice, glucocorticoid deficiency in humans is a potentially fatal condition. This begs the question, how are glucocorticoids disrupted in humans to potentiate gastric carcinogenesis? One potential mechanism is through exposure to endocrine-disrupting compounds (EDCs). A host of EDCs are ubiquitous in our environment. While their impact on estrogen signaling has received the bulk of attention from researchers and the news media, EDC's effects on glucocorticoid signaling remained largely unknown. We are currently studying the impact of various EDCs on glucocorticoid's ability to regulate gastric inflammation.