Abstract IA031: AGEing and RAGEing in prostate cancer: Integrating ancestral tumor biology into the multilevel framework of health inequity constructs to inform on cancer disparity outcomes

Abstract

Abstract Black/African American (AA) men have a 70% higher risk of prostate cancer (PCa) and are more than twice as likely to die of their disease as non-Hispanic White men (NHW). While the negative impacts of health inequity on PCa incidence and mortality are undeniable, ancestry specific tumor biology also plays a significant role. The circumstances and environments where individuals are born, live, work, and play, likely cause molecular changes that are synergistic or at least additive in their biological effects when combined with ancestral tumor biology. However, studies that assess how ethnic and racial disparities in health inequity constructs can exacerbate ancestry specific tumor biology are lacking. Through their ability to perpetuate a reactive stroma, this study defines the increased bioavailability of reactive metabolites called advanced glycation end products (AGEs) as a pro-tumorigenic consequence of interrelated health inequity risk factors that influence ancestry specific tumor biology. AGEs are significant because AA communities who often bear the highest cancer burden are more likely to be exposed to health inequity risk factors that greatly increase AGE exposure. For example, AAs communities often have the highest poverty rates, be more sedentary, and are more likely to live in designated food deserts. This promotes the consumption of unhealthy foods that are AGE laden, lead to weight gain, obesity, and increase cancer risk. In mice, chronic AGE consumption caused a rapid progression through prostate intra-epithelial neoplasia (p=0.049), adenocarcinoma (p=0.042) and metastatic disease (p=0.001). Mechanistically, AGEs recapitulated a regulatory program of ‘activated’ stroma similar to that observed in AA prostate tumors. Specifically, increased AGE bioavailability caused receptor for AGE (RAGE) dimerization in resident prostate fibroblasts leading to a regulatory program of immune, metabolic, and oxidative dysregulation and the downregulation of matrix regulatory proteins. Functionally, AGE treated AA-derived fibroblasts were able to increase epithelial cell migratory potential to a much greater extent than NHW-derived fibroblasts irrespective of the ancestral origin of the cocultured epithelial cells. In collaborative epidemiological studies, cancer patients in the highest quartile of past AGE consumption associated with both aggressive disease and increased all-cause mortality. The irreversible nature of AGE adducts, their association with health inequity, and their ability to impact the tumor microenvironment supports the premise that “increased AGE bioavailability contributes to the rapid tumor progression and poor outcomes observed in AA men with PCa”. AGE bioavailability provides an unexploited opportunity to consider how ethnic and racial disparities in health inequity can exacerbate ancestral tumor biology. Multidisciplinary educational, interventional, and pharmacological studies aimed at reducing AGE exposure may be viewed as novel cancer preventive and/or therapeutic initiatives. Citation Format: David P. Turner. AGEing and RAGEing in prostate cancer: Integrating ancestral tumor biology into the multilevel framework of health inequity constructs to inform on cancer disparity outcomes [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA031.