992 A PARACRINE HEDGEHOG SIGNALING MICROENVIRONMENT IN ADT-TREATED PROSTATE TUMORS INDUCES STEROIDOGENESIS FROM BENIGN PROSTATE STROMAL CELLS
Bibliographic record
Abstract
You have accessJournal of UrologyProstate Cancer: Basic Research (V)1 Apr 2013992 A PARACRINE HEDGEHOG SIGNALING MICROENVIRONMENT IN ADT-TREATED PROSTATE TUMORS INDUCES STEROIDOGENESIS FROM BENIGN PROSTATE STROMAL CELLS Amy Lubik, Emma Guns, Hans Adomat, and Ralph Buttyan Amy LubikAmy Lubik Vancouver, Canada More articles by this author , Emma GunsEmma Guns Vancouver, Canada More articles by this author , Hans AdomatHans Adomat Vancouver, Canada More articles by this author , and Ralph ButtyanRalph Buttyan Vancouver, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.574AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Androgen deprivation therapy (ADT) induces the expression and release of Hedgehog ligands (Hhs) from prostate cancer (PCa) cells. Previously we showed that treatment of primary human prostate stromal cells (PrSCs) with an HH agonist (SAG) increased the expression of steroidogenic genes and enabled them to significantly increase production of testosterone (T) when fed with DHEA, an adrenal precursor. We proposed that a paracrine HH microenvironment in ADT-treated PCas contribute to intratumoral steroidogenesis through this process. Here we show that steroidogenic activity of PrSCs is induced by alternate HH agonists and better describe the steroidogenic process leading to androgen production in PrSCs induced by paracrine HH. METHODS Human primary PrSCs (Clonetics) were grown in recommended medium. PrSCs were pre-starved of serum to induce primary cilia formation, then treated with 1 nM Ag1.5 (a HH agonist) for 48 hrs. Expression of steroidogenic genes was measured by quantitative PCR. Outputs of steroids from vehicle- or agonist-treated PrSC cells fed 22 OH-cholesterol were measured by LC/MS/MS. The HH antagonist, KAAD-cyclopamine (100 nM) or an HMGR inhibitor (simvastatin) was used to block the PrSC response to Ag1.5 or to inhibit active Hh release from Sonic Hh producing LNCaP cells. RESULTS Ag1.5 is as effective as 100 nM SAG in inducing expression of steroidogenic genes in PrSCs. Outputs of progesterone, DHEA, androsterone, T, or dihydrotestosterone (DHT) from 22 OH-cholesterol was significantly increased by Ag1.5. The effects of Ag1.5 on the expression of these genes was blocked by KAAD-cyclopamine. The ability of Ag1.5 to induce RDH5 expression and androsterone production show that the DHT output from PrSCs was a consequence of increased classical and backdoor pathway activities. Steroid outputs from HH-induced PrSCs was significantly higher (on a weight-per-weight basis) than production from parental LNCaP or the androgen growth-independent LNCaP-AI cells. Simvastatin reduced the release of active Hhs from LNCaP-Sonic Hh producing cells as measured by the reduced ability of conditioned medium from treated cells to induce steroidogenic genes in PrSCs. CONCLUSIONS Our results further confirm the potential of a paracrine HH signaling microenvironment of ADT-treated prostate tumor to induce steroidogenesis and androgen production from benign PrSCs. Outcomes show that a HH antagonist or cholesterol synthesis inhibitor might block the effects of paracrine HH in an ADT-treated tumor and delay progression to CRPC. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e407 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Amy Lubik Vancouver, Canada More articles by this author Emma Guns Vancouver, Canada More articles by this author Hans Adomat Vancouver, Canada More articles by this author Ralph Buttyan Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".