Osteoblasts Generate Testosterone From DHEA and Activate Androgen Signaling in Prostate Cancer Cells

Abstract

Bone metastasis is a complication of prostate cancer in up to 90% of men afflicted with advanced disease. Therapies that reduce androgen exposure remain at the forefront of treatment. However, most prostate cancers transition to a state whereby reducing testicular androgen action becomes ineffective. A common mechanism of this transition is intratumoral production of testosterone (T) using the adrenal androgen precursor dehydroepiandrosterone (DHEA) through enzymatic conversion by 3β‐ and 17β‐hydroxysteroid dehydrogenases (3βHSD and 17βHSD). Given the ability of prostate cancer to form blastic metastases in bone, we hypothesized that osteoblasts might be a source of androgen synthesis. RNA expression analyses of murine osteoblasts and human bone confirmed that at least one 3βHSD and 17βHSD enzyme isoform was expressed, suggesting that osteoblasts are capable of generating androgens from adrenal DHEA. Murine osteoblasts were treated with 100 nM and 1 μM DHEA or vehicle control. Conditioned media from these osteoblasts were assayed for intermediate and active androgens by liquid chromatography–tandem mass spectrometry. As DHEA was consumed, the androgen intermediates androstenediol and androstenedione were generated and subsequently converted to T. Conditioned media of DHEA‐treated osteoblasts increased androgen receptor (AR) signaling, prostate‐specific antigen (PSA) production, and cell numbers of the androgen‐sensitive prostate cancer cell lines C4‐2B and LNCaP. DHEA did not induce AR signaling in osteoblasts despite AR expression in this cell type. We describe an unreported function of osteoblasts as a source of T that is especially relevant during androgen‐responsive metastatic prostate cancer invasion into bone. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis

“…Most mCRPC remains androgen‐dependent via various mechanisms that increase AR signaling despite castrate levels of circulating testosterone following ADT 59 . One such mechanism is tumoral uptake and intracellular conversion of adrenal androgens 60 . The adrenal gland itself is a unique environment due to the local secretion of adrenal androgens by the zona reticularis of the adrenal cortex which are not subject to decreased adrenal androgens following castration, making it a more hospitable environment for tumor colonization 61 .…”

“…59 One such mechanism is tumoral uptake and intracellular conversion of adrenal androgens. 60 The adrenal gland itself is a unique environment due to the local secretion of adrenal androgens by the zona reticularis of the adrenal cortex which are not subject to decreased adrenal androgens following castration, making it a more hospitable environment for tumor colonization. 61 Similarly, tumor DHEA and androstenedione have been shown to be within or above the normal limits in the adrenal glands of CRPC patients receiving ADT.…”

Local Effects of Steroid Hormones within the Bone Microenvironment

“…Recent evidence indicated that osteoblasts not only respond to steroid hormones but can also synthetize testosterone from DHEA under pathological conditions during the development of prostate cancer bone metastases [106]. Intratumoral production of the adrenal androgen precursor DHEA allowed bone-forming osteoblasts to convert and secrete androgens to drive the development of osteosclerotic skeletal lesions [106]. Both human and murine osteoblasts were found to express Hsd3b2 and Cyp17a1 enzymes, suggesting that osteoblasts are capable of generating testosterone from DHEA [106].…”

“…Intratumoral production of the adrenal androgen precursor DHEA allowed bone-forming osteoblasts to convert and secrete androgens to drive the development of osteosclerotic skeletal lesions [106]. Both human and murine osteoblasts were found to express Hsd3b2 and Cyp17a1 enzymes, suggesting that osteoblasts are capable of generating testosterone from DHEA [106]. In another publication authors also suggested a role for osteoblasts in promoting castration-resistant prostate cancer development by altering intratumoral steroidogenesis [107].…”

“…Recent evidence indicated that osteoblasts and osteoclasts can also respond to steroid hormones produced by extranglandular steroidogenesis within the bone microenvironment. We and others demonstrated that pregnenolone and its derivates secreted by osteotropic tumor cells and osteoblasts are able to stimulate androgen production and osteoclast development and function [106][107][108][109][110][111]. Therefore, understanding the cellular and molecular effects of steroid hormones in the skeletal system is expected to facilitate the development of new therapies for the treatment of bone disease.…”