Notice of Special Interest: Mechanisms Driving Obesity and Prostate Cancer Risk

Notice Number: NOT-CA-24-056

Deadline: October 5, 2024


The purpose of this NOSI is to promote studies examining the mechanisms by which obesity drives aggressive prostate cancer (PCa) risk. About 80% of overall PCa is non-aggressive. The biologic mechanisms driving both overall and aggressive PCa are uncertain. The identification of differences in the mechanisms driving aggressive vs. overall (mostly non-aggressive) disease are critical to optimizing clinical care among men who develop the disease. PCa has an outsized impact on African Americans who are more likely to develop aggressive disease and twice as likely to die from the disease compared to other racial and ethnic groups.


Among hormonally driven cancers, multiple studies document an association between obesity and the risk of both postmenopausal breast and endometrial cancer, and substantive (> 5% total body weight) weight loss lowers the risk of these cancers. On the other hand, the bulk of evidence links obesity with a lower overall PCa risk but a greater risk of high grade, more aggressive disease compared to that of men of normal weight. Most men have low or intermediate risk disease, with only about one in five having high risk disease. Reasons to explain the divergent effects of obesity on overall PCa incidence vs. the aggressive nature of the disease are likely multifactoral, including 1) the hemodilutional effect of obesity on circulating levels of PSA, resulting in a delayed PCa diagnosis; 2) difficulty palpating the prostate gland in obese men on digital rectal exam; and 3) molecular mechanisms driving disease development. The focus of this NOSI is on the mechanisms that drive overall (primarily composed of non-aggressive disease) vs. aggressive PCa risk.

Potential Mechanisms Impacting Obesity’s Influence on PCa Risk

The molecular mechanisms linking obesity to overall and aggressive PCa are not clearly delineated.

  • Estrogens and androgens. Estrogens (E) drive the development of both postmenopausal breast and endometrial cancer, while androgens linked to PCa are precursor hormones which can be converted by aromatase to estrogens. E levels are higher in obese than normal weight men. Preclinical studies suggest that E may play a role in promoting PCa development and progression. Obesity is associated with low testosterone (T) levels, and lower T levels have been associated with increased risk of aggressive prostate cancer.
  • VAT. The assessment of obesity in determining its role in PCa risk has generally been based on body mass index (BMI), which does not control for extra muscle mass among body builders or loss of muscle in the elderly. The two primary storage sites for adipose tissue (AT) are around the abdominal viscera (VAT) and subcutaneously (SAT). VAT is more abundant in men (10-20% of total) than women (5-8% of total). VAT releases more in?ammatory and growth factors compared with SAT, and VAT content has been linked to aggressive PCa, especially in black men.
  • Insulin resistance and insulin-like growth factor (IGF)-1. Obesity increases insulin resistance and IGF-1. Diet-induced hyperinsulinemia accelerates tumor growth in different PCa xenograft models. Higher serum C-peptide, a surrogate of insulin levels, have been associated with increased PCa-specific mortality, and metformin, which lowers insulin levels, appears to reduce PCa risk in men with type 2 diabetes. High levels of IGF-I and insulin have been positively linked to PCa risk and mortality.
  • Chronic inflammation. Obesity increases chronic inflammation, in part through the production of inflammatory cytokines (adipokines) such as TNF- , IL-6, IL-8 and MCP-1 which are produced in adipocytes. Adipokine production is increased in obese individuals, and the expression of individual cytokines that influence cancer risk differs among obese and normal weight individuals. Periprostatic adipose tissue (PPAT) provides locally secreted growth factors and adipokines. There is preliminary evidence, for example, that PPAT-derived IL-6 levels are directly associated with elevated Gleason grade, suggesting a paracrine role for PPAT in modulating PCa aggressiveness.

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