This application attempts to clarify the mechanistic basis for the association between excessive adiposity and
risk factors for prostate cancer-specific morbidity and mortality in men with clinically localized prostate cancer.
The overall hypothesis is that excess adiposity alters prostatic exposure to nutritional, hormonal, and
immunologic factors influenced by weight status and implicated in prostate cancer progression, and that inter-
individual variation in gland-level exposure to these factors mediates the effects of adiposity on the pathologic
presentation and course of the disease. To test this hypothesis, we will: Aim 1) conduct a prospective 2-year
cohort study of incident cases of clinically localized prostate cancer to measure the association of adiposity
with pathologic tumor features at diagnosis and 2-year risk of biochemical (PSA) failure after radical
prostatectomy; Aim 2) measure fatty acids, insulin-like growth factor (IGF) axis activity, modulators of
inflammation, and sex steroid hormone profiles in prostate tissue and periprostatic fat collected at surgery, and
use mediation model analysis to determine which physiologic variables account for the effects adiposity on
tumor characteristics and risk of biochemical failure; Aim 3) and evaluate the effects of post-treatment changes
in adiposity on 2-year risk of biochemical failure. The cohort will consist of 540 men enrolled in the urology
clinics of four Chicago-area medical centers who are awaiting prostatectomy for clinically localized prostate
cancer. Adiposity will be quantified by anthropometry and dual energy x-ray absorptiometry at diagnosis and
one year after surgery. Pathologic tumor characteristics will be determined by a single pathologist, and
biochemical outcomes will be ascertained using a standard clinical protocol. Potential mediators to be studied
include fatty acids, the IGF-1 receptor signaling pathway, adipose tissue-derived cytokines, eicosanoids
products of arachidonic acid, and metabolites of estrogen and testosterone.
Lifestyle factors that associate with more rapid progression of clinically early-stage prostate cancer are of
increasing concern to health care providers and public health professionals. This research, to be completed
over 5 years, will identify some of the biological reasons why obesity associates with more "aggressive"
prostate cancer at diagnosis and decreases a man's chances for cure with surgery. It will also shed light on
ways to prevent prostate cancer recurrence that may involve new or existing medicines or lifestyle changes.
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