Abstract
Our previous presurgical weight loss trial among 40 prostate cancer patients found that rapid (but not slow) weight loss resulted in increased tumor Ki67 and Cathepsin L (CTSL) gene expression. In follow-up analyses, we strove to better understand these unexpected findings. A correlative study was undertaken by performing additional analyses [free fatty acids (FFAs), plasma CTSL, and inflammatory cytokines] on remaining pre-post intervention sera and exploring associations with extant data on tumor Ki67, body composition, physical activity (PA), and fecal microbiota. Positive associations were observed between changes in % body fat and FFAs (ρ = 0.428, p = 0.026), insulin (ρ = 0.432, p = 0.019), and Interleukin-6 (ρ = 0.411, p = 0.041). Change in Ki67 was inversely associated with change in lean mass (ρ = −0.912, p = 0.001) and change in insulin (ρ = −0.650, p = 0.042). Change in insulin was also associated with CTSL (ρ = −0.643, p = 0.024) and FFAs (ρ = −0.700, p = 0.016). Relative abundance of Bifidobacterium was associated with CTSL (ρ = 0.627, p = 0.039) and FFAs (ρ = 0.691, p = 0.019); Firmicutes was positively associated with change in PA (ρ = 0.830, p = 0.003). Contrary to hypotheses, FFAs decreased with systemic fat loss. Moreover, although glucose metabolism improved, it was inversely associated with Ki67 and CTSL. Lean mass loss was highly correlated with increased Ki67. The relationships between prostate tumor Ki67 and CTSL and weight loss associated changes in FFAs, lean mass, and fecal microbiota warrant further investigation.
Highlights
Prostate cancer (PCa) is the most common non-cutaneous malignancy and the second most common cause of cancer-related mortality among men in the United States [1]
We reported gene expression data, finding that Cathepsin L (CTSL) a protease involved in tumor development and metastasis [10, 11], was upregulated in tumor specimens of men in the weight loss group
Rapid weight loss did not result in increased free fatty acids (FFAs), possibly due to potential relative weight stabilization at the time of prostatectomy [20]
Summary
Prostate cancer (PCa) is the most common non-cutaneous malignancy and the second most common cause of cancer-related mortality among men in the United States [1]. We recently published findings from a randomized controlled trial that explored effects of a weight loss intervention in newly diagnosed PCa patients electing radical prostatectomy as primary treatment [5, 6]. We hypothesized that men randomized to the weight loss arm would demonstrate decreased tumor proliferation as assessed by Ki67, a widely accepted biomarker used for pharmacological studies, as it responds to changes in diet and nutritional status [7, 8]. Tumor proliferation increased, rather than decreased with weight loss, and was higher in the intervention group compared to controls at the time of surgery [6]. Corroborating our findings, Henning et al [9] later reported results of a similar trial in which men assigned to weight loss manifested a trend toward higher tumor Ki67 compared to controls
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