Paracrine sonic hedgehog signaling contributes significantly to acquired steroidogenesis in the prostate tumor microenvironment

Abstract

Despite the substantial benefit of androgen deprivation therapy (ADT) for metastatic prostate cancer, patients often progress to castration-resistant disease (CRPC) that is more difficult to treat. CRPC is associated with renewed androgen receptor activity in tumor cells and restoration of tumor androgen levels through acquired intratumoral steroidogenesis (AIS). Although prostate cancer (PCa) cells have been shown to have steroidogenic capability in vitro, we previously found that benign prostate stromal cells (PrSCs) can also synthesize testosterone (T) from an adrenal precursor, DHEA, when stimulated with a hedgehog (Hh) pathway agonist, SAG. Here, we show exposure of PrSCs to a different Smoothened (Smo) agonist, Ag1.5, or to conditioned medium from sonic hedgehog overexpressing LNCaP cells induces steroidogenic enzyme expression in PrSCs and significantly increases production of T and its precursor steroids in a Smo-dependent manner from 22-OH-cholesterol substrate. Hh agonist-/ligand-treated PrSCs produced androgens at a rate similar to or greater than that of PCa cell lines. Likewise, primary bone marrow stromal cells became more steroidogenic and produced T under the influence of Smo agonist. Treatment of mice bearing LNCaP xenografts with a Smo antagonist, TAK-441, delayed the onset of CRPC after castration and substantially reduced androgen levels in residual tumors. These outcomes support the idea that stromal cells in ADT-treated primary or metastatic prostate tumors can contribute to AIS as a consequence of a paracrine Hh signaling microenvironment. As such, Smo antagonists may be useful for targeting prostate tumor stromal cell-derived AIS and delaying the onset of CRPC after ADT.

Silencing of the transcriptional factor ZEB1 alters the steroidogenic pathway, and increases the concentration of testosterone and DHT in DU145 cells

“…Notably, the relevance of increased concentration of androgens in cells with ZEB1 knockdown may be associated with activation of AR during EMT (6). Therefore, an increase in the expression of steroidogenic enzymes has been suggested as a mechanism underlying resistance to ADT (22,23). According to the present results, it may be hypothesized that an increase in androgen synthesis could lead to an increase in the activation of AR due to its increased availability.…”

Hedgehog Signaling for Urogenital Organogenesis and Prostate Cancer: An Implication for the Epithelial–Mesenchyme Interaction (EMI)

“…Of note, it has also been suggested that paracrine type Shh signaling is involved in the local steroidogenesis in PCa [47]. Although it is generally believed that local steroidogenesis occurs within the tumor, there have been several reports stating that the stroma is also capable of steroidogenesis [47,48,115].…”

Aberrant activation of the Hedgehog signaling pathway in granulosa cells from patients with polycystic ovary syndrome

“…Hh signaling regulates cell fate determination, proliferation, and differentiation (King et al, 2008). Moreover, over-activation of Hh signaling is associated with the tumorigenesis (Hirotsu et al, 2010;Galimberti et al, 2012;Lubik et al, 2017;Rennert et al, 2017). In mammals, the Hh pathway consists of three Hh ligands, indian (IHH), desert (DHH), and sonic (SHH); the membrane receptor patched (PTCH) 1 and 2; and the transmembrane signal transducer protein smoothened (SMO) (Wijgerde et al, 2005).…”