Paracrine sonic hedgehog signaling contributes significantly to acquired steroidogenesis in the prostate tumor microenvironment. Issue 2 (20th October 2016)

• Record Type: Journal Article
• Authors: Lubik, Amy A.; Nouri, Mannan; Truong, Sarah; Ghaffari, Mazyar; Adomat, Hans H.; Corey, Eva; Cox, Michael E.; Li, Na; Guns, Emma S.; Yenki, Parvin; Pham, Steven; Buttyan, Ralph
• Is Part Of: International journal of cancer. Volume 140:Issue 2(2017:Jan. 15)
• Page Start: 358
• Page End: 369
• Publication Date: 2016-10-20
• Subjects: prostate cancer -- acquired intratumoral steroidogenesis -- paracrine hedgehog signaling -- sonic hedgehog -- androgens -- stroma; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.30450
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? For most men with metastatic prostate cancer, initial tumor‐control benefits of hormone therapy are eventually overcome by the development of castration‐resistant disease. Several mechanisms potentially drive this resistance, including acquired intratumoral androgen synthesis. This study shows that the conversion of benign prostate stromal cells into androgen‐producing cells involves paracrine hedgehog signaling and activation of multiple steroidogenic enzymes. In mice bearing castration‐resistant xenografts, treatment with the hedgehog antagonist TAK‐441 resulted in a significant reduction in prostate tumor androgens. The data suggest that hedgehog antagonists could serve an important role in targeting acquired intratumoral steroidogenic activity in castration‐resistant prostate cancer.