Paracrine sonic hedgehog signaling contributes significantly to acquired steroidogenesis in the prostate tumor microenvironment.
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.
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Amy A
AA
Lubik
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Mannan
M
Nouri
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Sarah
S
Truong
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Mazyar
M
Ghaffari
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Hans H
HH
Adomat
Department of Urology, University of Washington, Seattle, WA.
Eva
E
Corey
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Michael E
ME
Cox
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Na
N
Li
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Emma S
ES
Guns
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Parvin
P
Yenki
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Steven
S
Pham
The Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Ralph
R
Buttyan
D000728:Androgens / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002369:Castration / Q000379:methods; D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019899:Paracrine Communication / Q000502:physiology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology*
D000728:Androgens; D053823:Hedgehog Proteins; D011944:Receptors, Androgen; D013739:Testosterone
acquired intratumoral steroidogenesis; androgens; paracrine hedgehog signaling; prostate cancer; sonic hedgehog; stroma