Date of Award

2021

Embargo Period

3-17-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

David P. Turner

Second Advisor

Victoria J. Findlay

Third Advisor

Michael C. Ostrowski

Fourth Advisor

R. Amanda C. Larue

Fifth Advisor

Michael B. Lilly

Abstract

Interrelated lifestyle factors such as a sedentary habit, obesity and diets consisting of highly processed, high protein and fat containing foods, contribute to the accumulation of reactive metabolites known as advanced glycation end-products (AGEs). AGE pathogenic effects are mediated through modification of protein function, genetic fidelity, stress responses, and aberrant cellular signaling. For the first time, this study examined the effects of dietary AGE consumption on cancer progression in vivo and assessed physical activity (PA) as a potential intervention to reduce dietary AGE mediated effects. Given the links between lifestyle and AGEs, we propose that a diet high in AGEs can accelerate prostate cancer progression and severity which can be negated by regular PA. We found that chronic consumption of AGEs promotes prostate tumor growth and progression in vivo using syngeneic xenograft and spontaneous prostate cancer mouse models. Mechanistically, the stromal function of the transmembrane receptor for AGE (RAGE) was found to be a key substrate and effector of dietary-AGE tumorigenic function. Dietary AGE mediated activation of RAGE promoted a pro-tumorigenic microenvironment through the activation of cancer associated fibroblasts (CAFs) and macrophage polarization. Regular PA intervention by mice inhibited dietary-AGE induced tumor growth and progression. These results identify AGE content in food as a ubiquitous pro-tumorigenic consequence of lifestyle. They serve to focus future studies on the therapeutic potential of reducing AGEs through intervention and pharmacological strategies.

Rights

All rights reserved. Copyright is held by the author.

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