(G-274) Quantitatively Assessing the RAGE/AGE Axis in Prostate Cancer

Introduction:: Dietary advanced glycation end-products (AGEs) and their transmembrane receptor (RAGE) have been found to have higher expression in prostate cancer and the activation of RAGE plays a significant role in initiating and developing inflammatory responses which, if the serum levels of AGEs are high, can develop into chronic inflammation. Compelling evidence demonstrates that chronic inflammation in the tumor microenvironment creates a tumor-promoting climate favoring cancer initiation, proliferation, and survival. In this context, RAGE and dietary AGEs emerge as functional elements that, through autocrine and paracrine mechanisms, continuously fuel an inflammatory milieu in the tumor microenvironment contributing to anti-tumor immunity, angiogenesis, invasion, and metastatic potential. The complex tumor biology of the RAGE/AGE axis in cancer uniquely positions molecular imaging with RAGE-targeted probes to contribute significantly to cancer evaluation and the assessment of anti-cancer therapeutic interventions. This study aimed to develop and utilize an imaging and histological strategy for quantitatively assessing the RAGE/AGE axis in prostate cancer as well as attempt to modulate it through pharmacological intervention.


Materials and Methods:: Mice were first divided into two separate groups, one of which was provided a standard powdered AIN-93G diet and the other was provided the same diet after a baking process to generate AGEs. These animals were provided these low- and high-AGE diets for four weeks before LNCaP prostate cancer xenografts were implanted on the hind portion of both of their flanks. The diet groups continued to be provided low- and high-AGE diets until tumors were detected, after which a pharmaceutical inhibitor of AGEs, alagebrium chloride, was administered daily to half of each group. Animals then underwent serial non-invasive PET-CT imaging of metabolism through the use of FDG, angiogenesis through a radiotracer targeting α_vβ3 integrin, and RAGE expression through a RAGE-antagonistic peptide radiotracer. Blood was collected post-mortem to determine levels of AGE in both the low- and high-AGE diet groups. Tumors were also collected post-mortem for both AGE analysis as well as for use in histology targeted at RAGE expression, neuroendocrine differentiation, androgen receptor levels, other markers of progression or aggression, and histological grading of each tumor.


Results, Conclusions, and Discussions:: While tumors were present in most animals, there was a clear difference in bilateral tumor development. Low-AGE animals were significantly more likely to develop only a single tumor whereas high-AGE animals were significantly more likely to develop tumors on both flanks. Tumor weights had no significant difference between low- and high-AGE diet groups. For PET-CT imaging, there was decreased FDG uptake over time in both groups but the diet groups were not significantly different, angiogenesis was comparable in both groups and RAGE expression decreased over time but remained consistently higher in the high-AGE diet group. The decrease in uptake of the radiotracers over time can be explained by necrosing tumor tissue in the center of the tumors. Tumors and blood have been collected and sent for both AGE analysis and histology staining for RAGE. A second cohort of animals is currently underway.


Preliminary data appears to support the hypothesis that there is a link between low- and high-AGE diets to RAGE activation and expression in tumor tissue. The data also shows that tumor physiology is not markedly changed between low- and high-AGE diets, however, this may be skewed as the tumors have variable sizes of the necrotic region, further analysis is being performed. The blood and tumor levels of AGEs, histology, and alagebrium chloride treatment data is forthcoming as the current cohort is being performed and analysis is ongoing.




Acknowledgements (Optional): :

References (Optional): :