AGE metabolites: a biomarker linked to cancer disparity?

Abstract

Socioeconomic and environmental influences are established factors promoting cancer disparity, but the contribution of biologic factors is not clear. We report a mechanistic link between carbohydrate-derived metabolites and cancer that may provide a biologic consequence of established factors of cancer disparity. Glycation is the nonenzymatic glycosylation of carbohydrates to macromolecules, which produces reactive metabolites called advanced glycation end products (AGE). A sedentary lifestyle and poor diet all promote disease and the AGE accumulation pool in our bodies and also increase cancer risk. We examined AGE metabolites in clinical specimens of African American and European American patients with prostate cancer and found a higher AGE concentration in these specimens among African American patients when compared with European American patients. Elevated AGE levels corresponded with expression of the receptor for AGE (RAGE or AGER). We show that AGE-mediated increases in cancer-associated processes are dependent upon RAGE. Aberrant AGE accumulation may represent a metabolic susceptibility difference that contributes to cancer disparity.

Figure 1. AGE levels are elevated in prostate cancer

Quantification of circulating AGE (CML) levels, analyzed by ELISA, in serum from prostate cancer patients separated by A. grade (low = Gleason 4-6, high = Gleason 7-9) B. race (African American (AA) and European American (EA)) and C. race and grade. D. IHC staining (10X magnification) of AGE with an antibody raised against CML in tumor tissue (N=8) compared to non-cancer prostate tissue (N=4). Black arrows indicate the benign tissue and white arrows indicate the malignant tissue. Insets show 100 x magnifications. E. Pearson correlation analysis of tumor AGE and serum AGE levels.

Figure 2. AGE levels are highest in the epithelial tissue of high grade African American prostate cancer patients

A. IF staining (10X magnification) of AGE with an antibody raised against CML in tumor tissue (N=8) compared to non-cancer prostate tissue (N=4). B. Quantification of the fluorescent intensity observed in 5 independent microscope fields of European American (EA) and African American (AA) patients with either low grade (LG) or high grade (HG) prostate cancer. C. Higher magnification (40x magnification) of the immunofluorescent staining in the tumor epithelial cells and the stroma.

Figure 3. RAGE levels are elevated in high grade and African American prostate cancer tissue

A. IHC staining (10x magnification) of RAGE in prostate tumor (N=8) compared to non-cancer (N=4) tissue. B. IF staining and quantitation of RAGE expression in tumor tissue (N=8) compared to non-cancer prostate tissue (N=4). C. Pearson correlation analysis of tumor RAGE and tumor AGE levels.