Abstract B067: Investigating the implications of AGE-RAGE overexpression in cancer-associated fibroblasts

Abstract Background: Prostate cancer is the second leading cause of cancer-related mortality in men. Recent investigations by the Turner group have implicated advanced glycation end products (AGEs) in prostate tumor progression through their interaction with the receptor for AGEs (RAGE). AGE-RAGE signaling promotes inflammation, cell proliferation, migration, and activation of cancer-associated fibroblasts (CAFs) within the tumor microenvironment, thereby supporting tumor growth. Additionally, our lab has shown that African American prostate cancer serum and tissue exhibit higher AGE levels than Caucasian serum and tissue samples. This disparity may stem from diets high in sugars, fats, and processed foods - key sources of AGEs. These findings link AGE biology to social drivers of health and disparities in prostate cancer outcomes. Aims: This study examines how AGE-RAGE signaling influences CAF activation and tumor cell behavior, specifically whether AGE treatment of fibroblasts enhances the migration of tumor epithelial cells. We hypothesize that AGE treatment increases fibroblast-driven migration via RAGE, supporting the connection between AGE accumulation and cancer aggressiveness. Methods: Prostate cancer tissue samples (DPT18) were enzymatically processed to establish matched epithelial and fibroblast cell lines. These lines were characterized through histopathological analysis via H&E staining and sulforhodamine B proliferation assays. Functional CAF activation was evaluated via transwell migration assays with matched primary fibroblast and epithelial cell lines, with or without AGE treatment. Statistical analysis was conducted using two-way ANOVA in GraphPad Prism. Results: Histopathology confirmed a Gleason grade 3 for DPT 18. The patient-matched fibroblasts proliferated faster than epithelial cells (doubling times: 1.39–1.42 vs. 2.20–2.57 days at seeding cell densities of 3125 and 6250). AGE treatment of fibroblasts significantly increased epithelial cell migration compared to untreated fibroblasts. Conversely, direct AGE treatment on epithelial cells did not produce a significant change in migration. These results suggest that AGE exposure enhances the pro-migratory capacity of CAFs, likely via AGE-RAGE signaling pathways. Conclusions: Our findings show that AGEs promote prostate cancer tumorigenicity by activating CAFs. The pro-migratory effect observed in fibroblasts, rather than epithelial cells, may be driven by AGE-RAGE signaling. Considering that elevated AGE levels are increased when social drivers are compromised, these results could explain, at least in part, observed disparities in prostate cancer outcomes. Therefore, targeting AGE-RAGE signaling warrants further research as a strategy to reduce cancer aggressiveness and address health disparities. Citation Format: Krithika A. Senthil, Tuong Vi V. Nguyen, David P. Turner. Investigating the implications of AGE-RAGE overexpression in cancer-associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B067.