Abstract
Prostate cancer (PCa) is the most common malignancy in men worldwide, thus developing effective prevention strategies remain a critical challenge. Insulin-like growth factor 1 (IGF-1) is produced mainly in the liver by growth hormone signaling and is necessary for normal physical growth. However, several studies have shown an association between increased levels of circulating IGF-1 and the risk of developing solid malignancies, including PCa. Because the IGF-1 receptor is overexpressed in PCa, IGF-1 can accelerate PCa growth by activating phosphoinositide 3-kinase and mitogen-activated protein kinase, or increasing sex hormone sensitivity. Short-chain fatty acids (SCFAs) are beneficial gut microbial metabolites, mainly because of their anti-inflammatory effects. However, we have demonstrated that gut microbiota-derived SCFAs increase the production of IGF-1 in the liver and prostate. This promotes the progression of PCa by the activation of IGF-1 receptor downstream signaling. In addition, the relative abundance of SCFA-producing bacteria, such as Alistipes, are increased in gut microbiomes of patients with high-grade PCa. IGF-1 production is therefore affected by the gut microbiome, dietary habits, and genetic background, and may play a central role in prostate carcinogenesis. The pro-tumor effects of bacteria and diet-derived metabolites might be potentially countered through dietary regimens and supplements. The specific diets or supplements that are effective are unclear. Further research into the “Gut–IGF-1–Prostate Axis” may help discover optimal diets and nutritional supplements that could be implemented for prevention of PCa.
Highlights
Prostate cancer (PCa) is the most common malignancy in men worldwide and the fifth most common cause of cancer-related death with as many as 360,000 men dying of PCa annually [1]
We have reported that Short-chain fatty acids (SCFAs) metabolized by intestinal bacteria contribute to PCa growth by increasing systemic and prostate local Insulin-like growth factor 1 (IGF-1) productions, and revealed the “gut–prostate axis” involving bacterial metabolites [7]
These results suggest that SCFAs derived from intestinal bacteria promote PCa growth through IGF-1 signaling, butyrate in SCFAs may inhibit cancer cell proliferation as an histone deacetylate (HDAC) inhibitor
Summary
Prostate cancer (PCa) is the most common malignancy in men worldwide and the fifth most common cause of cancer-related death with as many as 360,000 men dying of PCa annually [1]. A positive association was observed between serum IGF-1 level and overall cancer risk in men in the United Kingdom (hazard ratio [HR] = 1.03 per 5-nmol/L increment in IGF-1) and specific cancer risk, such as prostate, melanoma, kidney, and thyroid (HR = 1.09, 1.08, 1.10, and 1.22, respectively) [45] In these cancer types, basic studies have shown an association with IGF-1 signaling [46–48]. Serum IGF-1 levels in 94 men who required prostate biopsy showed no significant difference between positive and negative cancer (26.4 vs 23.7 nmol/ L; P = 0.08) [59] This discrepancy suggests that prostate epithelial cells may be at an increased risk of cancer development or progression only after prolonged exposure to high concentrations of IGF-1. Suppression of IGF-1 signaling is a potential therapeutic approach, because the IGF1R inhibitor in combination with castration inhibited PCa growth in rodent models of bone metastasis and subcutaneous xenografts [61, 62]. As a more potent treatment strategy, a combination of novel IGF1R inhibitors and existing prostate cancer therapies is expected to be effective
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