Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation, and metastasis
Menée sur des modèles murins, cette étude met en évidence le rôle joué par les récepteurs des androgènes du micro-environnement tumoral dans la progression d'un cancer de la prostate
It has been postulated that prostatic carcinogenesis is androgen dependent and that androgens mediate their effects primarily through epithelial cells however, definitive proof of androgen hormone action in prostate cancer progression is lacking. Here we demonstrate through genetic loss of function experiments that prostate cancer (PRCA)-progression is androgen dependent and that androgen dependency occurs via prostatic stromal AR but not epithelial AR. Utilizing tissue recombination models of prostatic carcinogenesis, loss of AR function was evaluated by surgical castration or genetic deletion. Loss of AR function prevented prostatic carcinogenesis, malignant transformation, and metastasis. Tissue specific evaluation of androgen hormone action demonstrated that epithelial AR was not necessary for PRCA-progression, whereas stromal AR was essential for PRCA-progression, malignant transformation, and metastasis. Stromal AR was not necessary for prostatic maintenance suggesting that the lack of cancer progression due to stromal AR deletion was not related to altered prostatic homeostasis. Gene expression analysis identified numerous androgen regulated stromal factors. Four candidate stromal AR regulated genes were secreted growth factors: fibroblast growth factors-2, -7, -10, and HGF which were significantly affected by androgens and anti-androgens in stromal cells grown in vitro. These data support the concept that androgens are necessary for PRCA-progression and that the androgen regulated stromal microenvironment is essential to carcinogenesis, malignant transformation, metastasis, and may serve as a potential target in the prevention of prostate cancer.
http://carcin.oxfordjournals.org/content/early/2012/04/25/carcin.bgs153.abstract 2012