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      Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer.

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          Abstract

          Although systemic androgen deprivation prolongs life in advanced prostate cancer, remissions are temporary because patients almost uniformly progress to a state of a castration-resistant prostate cancer (CRPC) as indicated by recurring PSA. This complex process of progression does not seem to be stochastic as the timing and phenotype are highly predictable, including the observation that most androgen-regulated genes are reactivated despite castrate levels of serum androgens. Recent evidence indicates that intraprostatic levels of androgens remain moderately high following systemic androgen deprivation therapy, whereas the androgen receptor (AR) remains functional, and silencing the AR expression following castration suppresses tumor growth and blocks the expression of genes known to be regulated by androgens. From these observations, we hypothesized that CRPC progression is not independent of androgen-driven activity and that androgens may be synthesized de novo in CRPC tumors leading to AR activation. Using the LNCaP xenograft model, we showed that tumor androgens increase during CRPC progression in correlation to PSA up-regulation. We show here that all enzymes necessary for androgen synthesis are expressed in prostate cancer tumors and some seem to be up-regulated during CRPC progression. Using an ex vivo radiotracing assays coupled to high-performance liquid chromatography-radiometric/mass spectrometry detection, we show that tumor explants isolated from CRPC progression are capable of de novo conversion of [(14)C]acetic acid to dihydrotestosterone and uptake of [(3)H]progesterone allows detection of the production of six other steroids upstream of dihydrotestosterone. This evidence suggests that de novo androgen synthesis may be a driving mechanism leading to CRPC progression following castration.

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          Author and article information

          Journal
          Cancer Res
          Cancer research
          American Association for Cancer Research (AACR)
          1538-7445
          0008-5472
          Aug 01 2008
          : 68
          : 15
          Affiliations
          [1 ] Department of Urologic Sciences, University of British Columbia, The Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada.
          Article
          68/15/6407
          10.1158/0008-5472.CAN-07-5997
          18676866
          42b204b9-1d69-4991-9cbf-f70a313e2783
          History

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