Increased transcriptional and metabolic capacity for lipid metabolism in the peripheral zone of the prostate may underpin its increased susceptibility to cancer

Abstract

The human prostate gland comprises three distinct anatomical glandular zones, namely the peripheral, central and transitional zones. Although prostate cancer can arise throughout the prostate, it is more frequent in the peripheral zone. In contrast, hyperplasia occurs most frequently in the transitional zone. In this paper, we test the hypothesis that peripheral and transitional zones have distinct metabolic adaptations that may underlie their different inherent predispositions to cancer and hyperplasia. In order to do this, we undertook RNA sequencing and high-throughput metabolic analyses of non-cancerous tissue from the peripheral and transitional zones of patients undergoing prostatectomy. Integrated analysis of RNAseq and metabolomic data revealed that transcription of genes involved in lipid biosynthesis is higher in the peripheral zone, which was mirrored by an increase in fatty acid metabolites, such as lysolipids. The peripheral zone also exhibited increased fatty acid catabolic activity and contained higher level of neurotransmitters. Such increased capacity for de novo lipogenesis and fatty acid oxidation, which is characteristic of prostate cancer, can potentially provide a permissive growth environment within the peripheral zone for cancer growth and also transmit a metabolic growth advantage to newly emerging clones themselves. This lipo-rich priming may explain the observed susceptibility of the peripheral zone to oncogenesis.

Accumulation of Dietary S‐Methyl Cysteine Sulfoxide in Human Prostate Tissue

“…Access to tissue and subsequent analyses were undertaken under ethical approval granted from the Faculty of Medicine and Health Sciences Research Ethics Committee of the University of East Anglia (FMHS 20122014–37). The prostate gland was removed from the abdominal cavity immediately after resection and rapidly biopsied after extraction to avoid ischemic artifacts using a standard core biopsy instrument, as previously described . The extracted whole prostatectomy specimen was placed on a surgical table, the apex and base of the gland were identified, and the prostate cut transversely (axial section) half way along the gland.…”

The impact of transcription on metabolism in prostate and breast cancers

“…Several key enzymes involved in the lipid biosynthetic pathway are frequently upregulated in PCa. Kadhi et al made an interesting observation that the peripheral zone of prostate are naturally endowed with a higher capacity for de novo lipogenesis and fatty acid oxidation, which makes it susceptible to oncogenesis and explains the frequent occurrence of cancer in this zone (Al Kadhi et al 2017). the lipogenic switch in PCa cells.…”

Molecular Characterization of Prostate Cancer with Associated Gleason Score Using Mass Spectrometry Imaging

“…There is a growing body of literature suggesting that metabolic changes occur in prostate cancer development and could be used as a measure of disease aggression and grade (12)(13)(14)(15)(16)(17)(18). Metabolic reprogramming is a hallmark of prostate cancer (11).…”

“…Metabolic reprogramming is a hallmark of prostate cancer (11). Changes in genetic regulators of lipid metabolism result in upregulation of de novo lipid biosynthesis and fatty acid b-oxidation (12). Such changes are thought to facilitate tumor development by helping to meet the energy demand for increased cell proliferation and growth.…”

“…The carnitine cycle regulates fatty acid mitochondrial import and export, and several components of the carnitine system are upregulated in prostate cancer and ensure mitochondrial fatty acid supply (20). It has been suggested that an increased capacity for de novo lipid synthesis and fatty acid oxidation provides a permissive growth environment within the peripheral zone of the prostate, within which approximately 70% of prostate cancers occur (12,21). Spatially resolved measurement of metabolomic signatures from prostate tissue could therefore enable a better understanding of how these processes occur in situ, how tumor cells interact with surrounding apparently nonneoplastic tissue, and how differences in molecular content of different regions of tissue might support tumor proliferation.…”