TGFβ1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment?

Abstract

The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGFβ1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGFβ1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGFβ1 produced time- and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGFβ1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3β hydroxysteroid dehydrogenase (HSD), and down-regulation of 17βHSD5, and 17βHSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens.

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

“…This may be attributed to the well‐documented secretion of ECM remodeling enzymes and chemotactic factors by activated fibroblasts 5. In contrast, the increase in proliferation of AR + but not AR − cell lines upon exposure to CM from activated but not nonactivated fibroblasts suggest potential crosstalk with epithelial AR, a hypothesis consistent with reports that TGFβ1‐activated stromal cells differentially express several androgen‐metabolizing enzymes 38. Notably, proliferation of the AR ‐ DU145 cells was equally stimulated by the conditioned media of both nonactivated and activated fibroblasts and thus plausibly by the same stromal‐derived factor(s).…”

“…5 In contrast, the increase in proliferation of AR 1 but not AR 2 cell lines upon exposure to CM from activated but not nonactivated fibroblasts suggest potential crosstalk with epithelial AR, a hypothesis consistent with reports that TGFb1-activated stromal cells differentially express several androgen-metabolizing enzymes. 38 Notably, proliferation of the AR -DU145 cells was equally stimulated by the conditioned media of both nonactivated and activated fibroblasts and thus plausibly by the same stromal-derived factor(s). These observations reflect the complex heterogeneity of clinical PCa and are the subject of ongoing studies.…”

In touch with your feminine side: how oestrogen metabolism impacts prostate cancer

“…Interestingly, inflammation associated with tumours modulates the expression of 17β-HSD-2 and 17β-HSD-5 (and also 3β-HSD). Treatment of prostate cancer stromal cell lines PrSC with TGFβ1 showed a marked downregulation in mRNA expression of 17β-HSD-2 and 17β-HSD-5 in a dose-dependent manner (Piao et al 2013). The counterintuitive action of TGFβ1 again demonstrates how little is understood about oestrogenic pathways in prostate cancer.…”

Sex steroids in the tumor microenvironment and prostate cancer progression

“…Steroidogenesis is higher in metastatic lesions, and this may also be stimulated by osteoclasts or extravesicle transport of CYP17 (Locke et al 2009, Jernberg et al 2013, Hagberg Thulin et al 2016. Reactive, inflamed prostatic stroma may also increase the synthesis of steroidogenic enzymes, which may in turn facilitate intratumoral androgen synthesis from circulating DHEA (Piao et al 2013). …”