Abstract C083: Consumption of lifestyle-associated advanced glycation end products promotes prostate tumor growth by creating a tumor-enhancing stromal microenvironment

Abstract

Our research has demonstrated that advanced glycation end products (AGEs) derived from the diet can directly impact neoplastic growth by creating a tumor-enhancing micro-environment. Most people are unaware of what AGEs are or the damage they can cause, but we are exposed to them every day through the lives we lead and the foods that we eat. The Western diet together with more sedentary habits means that lifestyle-associated AGEs are accumulating in our bodies at a faster rate than ever before. Changes in the AGE equilibrium due to lifestyle cause protein dysfunction, reduced genetic fidelity, and aberrant cell signaling activation which we believe contribute to cancer disparity outcomes. Disparity populations defined by AGE-associated risk factors such as diet, smoking, drinking and physical inactivity often bear a greater cancer burden when compared to the general population (reviewed by the PI, Cancer Research 2015). Lifestyle associated AGEs therefore may represent a unifying biological consequence of the social, demographic and environmental risk factors that contribute to the increased cancer incidence and mortality associated with cancer disparity. An important discovery from our work is that consumption of a diet high in AGEs accelerates prostate tumor growth in syngeneic xenograft prostate cancer (PCa) models as well as disease progression in spontaneous PCa models. Critically, dietary-AGE mediated effects on prostate tumor growth were dependent upon the stromal activation of RAGE. An activated stroma is a critical pathway impacting prostate cancer outcomes in African American men. Our studies show that dietary-AGE alters cytokine profiles, increases the activation of cancer associated fibroblasts (CAFs) and increases immune cell recruitment to the tumor microenvironment. Tumor associated immune cells adopt distinct metabolic patterns which function to maintain the energy requirements needed for cell differentiation and functionality. Pathway analysis of expression data from excised tumors shows that AGE consumption significantly impacts energy metabolism through the aberrant expression of MYC regulated transcriptional targets. Our studies also show that AGEs are highest in African American men with prostate cancer. Dietary-AGE mediated activation of tumor stroma therefore may align with the ancestry specific stromal and immune profiles observed in African American men with prostate cancer. Due to their links with lifestyle, both pharmacological and/or interventional strategies aimed at reducing the AGE accumulation pool may be viewed as universal cancer preventive and/or therapeutic initiatives. This may be an attractive option for populations where lifestyle change is not feasible due to poverty, inability, illness, treatment side effects, time, apathy and depression. Citation Format: Bradley Krisanits, Callen Fry, Lourdes M Nogueira, Reid Schuster, Marvella El Ford, Mark T Hamann, Michaell B Lilly, Mahtabuddin Ahmed, Victoria J Findlay, David P Turner. Consumption of lifestyle-associated advanced glycation end products promotes prostate tumor growth by creating a tumor-enhancing stromal microenvironment [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C083.