Abstract
Considerable levels of testosterone and dihydrotestosterone (DHT) are found in prostate cancer (PCa) tissue after androgen deprivation therapy. Treatment of surviving cancer-initiating cells and the ability to metabolize steroids from precursors may be the keystones for the appearance of recurrent tumors. To study this hypothesis, we assessed the expression of several steroidogenic enzymes and stem cell markers in clinical PCa samples and cell cultures during androgen depletion. Gene expression profiles were determined by microarray or qRT-PCR. In addition, we measured cell viability and analyzed stem cell marker expression in DuCaP cells by immunocytochemistry. Seventy patient samples from different stages of PCa, and the PCa cell line DuCaP were included in this study. The androgen receptor (AR) and enzymes (AKR1C3, HSD17B2, HSD17B3, UGT2B15 and UGT2B17 ) that are involved in the metabolism of adrenal steroids were upregulated in castration resistant prostate cancer (CRPC). In vitro, some DuCaP cells survived androgen depletion, and eventually gave rise to a culture adapted to these conditions. During and after this transition, most of the steroidogenic enzymes were upregulated. These cells also are enriched with stem/progenitor cell markers cytokeratin 5 (CK5) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, putative stem/progenitor cell markers CK5, c-Kit, nestin, CD44, c-met, ALDH1A1, α2-integrin, CD133, ABCG2, CXCR4 and POU5F1 were upregulated in clinical CRPC. The upregulation of steroidogenic enzymes and stem cell markers in recurrent tumors suggests that cancer initiating cells can expand by adaptation to their T/DHT deprived environment. Therapies targeting the metabolism of adrenal steroids by the tumor may prove effective in preventing tumor regrowth.
Highlights
As in normal prostate, the survival and growth of prostate cancer (PCa) cells is driven by androgens
The mRNA expression of genes involved in steroid metabolism (Figure 1) and androgen signaling in patient samples of LG, HG, met and castration resistant prostate cancer (CRPC) were studied by microarray analysis
Most of the statistically significant differences in gene expression appeared in CRPC (Table 2)
Summary
The survival and growth of prostate cancer (PCa) cells is driven by androgens. The presence of cancer-initiating cells that are independent from androgens for their self-renewal, as well as the ability of PCa tissue to synthesize testosterone (T) and dihydrotestosterone (DHT) has been postulated (reviewed in 3). Surgical and pharmacological androgen deprivation therapy aims to lower the amount of circulating testosterone. Several studies have confirmed that there are still sufficient amounts of T and DHT in the prostatic tissue to activate AR and its target genes that drive cancer cell survival and proliferation [4,5,6,7,8] even in the presence of the currently approved antiandrogens. Castration has little effect on the levels of adrenal androgens dehydroepiandrosterone (DHEA), its sulfate (DHEA-S) and androstenedione, by reducing them only 40% to 50% [4,7]
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