Cause and Effect Relationships Between Glycation and the Ancestry Specific Tumor Stroma

PROJECT SUMMARY/ABSTRACT Whole genome analyses support the tumor stroma as the main site of molecular change that promotes deadly prostate cancer in African American men. However, complimentary basic research studies showing a direct cause-and-effect relationship are lacking. As our bodies use the sugars, we consume for energy they generate waste chemicals known as metabolites. One such group of metabolites is known as advanced glycation end products or AGEs for short. AGE accumulation in our tissues and organs causes their functional decline and accelerates the aging process. AGEs represent intrinsic biological elements within health disparity risk factors that align with the stromal profiles that influence prostate cancer in African American men. This group has previously shown that AGEs are elevated in the circulation and tumors of prostate cancer patients with highest levels being observed in men with African ancestry and in more aggressive tumors. Using diet as a surrogate for health inequity, a key and novel finding from this research is that dietary consumption of AGEs can directly accelerate prostate tumor growth. Dietary-AGE mediated effects on tumor growth were shown to be dependent upon stromal signaling by the transmembrane receptor for AGE (RAGE). AGE-RAGE signaling was associated with an activated stroma similar to that observed in African American men with prostate cancer. This was defined by the increased presence of cancer associated fibroblasts (CAFs) and the downregulation of matrix associated genes. The long-term, objective is to integrate ancestral tumor biology into the multilevel framework of health inequity constructs to inform on cancer disparity outcomes. The study hypothesis is that “increased AGE bioavailability contributes to rapid tumor progression in AA men with PCa cancer”. The study will use a combination of prostate cancer cell lines and unique mouse tumor models to define a direct cause-and-effect relationship between AGEs and ancestry specific crosstalk in the tumor associated stroma. It will also assess if the consumption of AGEs has a positive correlation with prostate cancer risk using data from large human cohort studies. By establishing the mechanistic consequences AGEs found in the food chain on ancestry specific tumor biology, defined strategies to limit their accumulation in at risk populations, such as African American men with prostate cancer, may be viewed as cancer preventive or therapeutic strategies when combined with existing treatment regimens.