992 A PARACRINE HEDGEHOG SIGNALING MICROENVIRONMENT IN ADT-TREATED PROSTATE TUMORS INDUCES STEROIDOGENESIS FROM BENIGN PROSTATE STROMAL CELLS
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Résumé
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 ...
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».