Date of Award

2020

Embargo Period

4-28-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

David P. Turner

Second Advisor

Victoria J. Findley

Third Advisor

Robin Muise-Helmericks

Fourth Advisor

Scott Eblen

Abstract

Advanced glycation end products (AGEs) are sugar-protein adducts that may worsen cancer severity and may contribute to health disparity outcomes among prostate cancer (PCa) patients. AGEs are formed endogenously via a slow, nonenzymic reaction; however, AGEs are also formed in foods as a result of subjecting meats and sugars to high-heat conditions. AGEs are therefore prolific in the Western Pattern Diet (WPD), which has become increasingly common among industrialized nations. Previous work has identified dietary AGE as contributing to MYC-driven PCa progression, and the dependence of this process upon stromal receptor for advanced glycation end products (RAGE). This study therefore examines the changes in function and expression in macrophages -a key stromal population- in relation to this phenomenon. First, it was observed, via immunohistochemistry, that dietary AGE in a MyC-CaP xenograft model altered macrophage tumor infiltration, but not total population. Primary macrophages were isolated from wildtype and RAGE KO mice fed regular diets, and, along with RAW264.7 immortalized macrophage cell line, were subjected to BSA-AGE treatments in vitro. Evaluation of these cell populations found that AGE treatment increased MYC expression at the translational level and, to some degree, the transcriptional level. AGE treatment also increased RAGE protein expression in the immortalized RAW264.7 cells, but in all other cases remained unchanged. Macrophage polarization in response to AGE treatment was probed using qPCR, and using the markers TNF-α, IL-10, iNOS, and Arg1, it was determined that AGE treatment promoted a shift towards the classically activated M1 phenotype, which is typically characterized as being pro-inflammatory and addressing infectious disease. This relates to the nonpathogenic function of RAGE, which is a pattern recognition receptor (PRR) used for the early detection and response to local pathogens and suggests that AGEs pervert this antipathogenic process to the benefit of PCa progression.

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All rights reserved. Copyright is held by the author.

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