Mori Fumitaka, Oda Nobuyuki, Sakuragi Motomu, Sakakibara Fukumitsu, Kiniwa Mamoru, Miyoshi Kazuhisa
Discovery and Development Laboratory II, Hanno Research Center, Taiho Pharmaceutical Co, Ltd, Hanno-City, Saitama, Japan.
J Urol. 2009 Feb;181(2):890-8. doi: 10.1016/j.juro.2008.10.067. Epub 2008 Dec 17.
Histological observations of clinical benign prostatic hyperplasia specimens show that benign prostatic hyperplasia tissue is mainly composed of stromal components, smooth muscle and fibrous tissue, so-called stromal hyperplasia. However, little is understood regarding the pathogenesis of this stromal hyperplasia due to no suitable stromal hyperplasia model to elucidate the pathology of benign prostatic hyperplasia. We created a novel model of benign prostatic hyperplasia accompanied by clinically relevant stromal hyperplasia.
The urogenital sinus isolated from male rat 20-day embryos was implanted into pubertal male rat ventral prostates. Two to 8 weeks after the operation the implanted urogenital sinus was isolated, weighed and subjected to histochemical analysis. To distinguish between and characterize the epithelial and stromal components we stained for collagen, smooth muscle components, growth factors and proliferating cell nuclear antigen. In addition, to determine whether the implanted urogenital sinus had differentiated into functional prostate we stained for androgen receptor and dorsolateral prostatic secretory protein.
Urogenital sinuses removed from male rat 20-day embryos initially weighed approximately 1 mg. After implantation into host rat ventral prostates they grew in time dependent fashion with no apparent change in the original ventral prostate weight in the host rat. Implanted urogenital sinus weight was more than 100 mg 3 weeks after implantation. Histological observation demonstrated that the ratio of stromal to total area was approximately 70%, which was much higher than that in age matched rat ventral prostates and in a testosterone induced epithelial hyperplasia model (approximately 20% and 15%, respectively). This predominantly stromal tissue composition was maintained up to 8 weeks after implantation. Proliferating cell nuclear antigen staining revealed that the ratio of proliferating cells in stroma was equal to or greater than that in epithelium. In this model the antiandrogen agent chlormadinone acetate (Wako Pure Chemicals Industries, Osaka, Japan) at a dose of 10 mg/kg prevented the increase in implanted urogenital sinus weight (19.1%) but its potency was less than that seen in the testosterone induced epithelial hyperplasia model, that is 93.4% at the 10 mg/kg dose.
We have established a new experimental stromal hyperplasia model corresponding to clinical benign prostatic hyperplasia in terms of the composition of stromal components and functional differentiation of the prostate. Furthermore, the localization and time course of growth factor expression were also similar to those in men with benign prostatic hyperplasia.
临床良性前列腺增生标本的组织学观察表明，良性前列腺增生组织主要由基质成分、平滑肌和纤维组织组成，即所谓的基质增生。然而，由于缺乏合适的基质增生模型来阐明良性前列腺增生的病理机制，对这种基质增生的发病机制了解甚少。我们创建了一种伴有临床相关基质增生的新型良性前列腺增生模型。
从20日龄雄性大鼠胚胎分离的泌尿生殖窦植入青春期雄性大鼠的腹侧前列腺。术后2至8周，分离植入的泌尿生殖窦，称重并进行组织化学分析。为了区分和表征上皮和基质成分，我们对胶原蛋白、平滑肌成分、生长因子和增殖细胞核抗原进行了染色。此外，为了确定植入的泌尿生殖窦是否已分化为功能性前列腺，我们对雄激素受体和背外侧前列腺分泌蛋白进行了染色。
从20日龄雄性大鼠胚胎取出的泌尿生殖窦最初重约1mg。植入宿主大鼠腹侧前列腺后，它们以时间依赖性方式生长，宿主大鼠原腹侧前列腺重量无明显变化。植入后3周，植入的泌尿生殖窦重量超过100mg。组织学观察表明，基质与总面积的比例约为70%，远高于年龄匹配的大鼠腹侧前列腺和睾酮诱导的上皮增生模型中的比例（分别约为20%和15%）。这种主要由基质组织组成的情况在植入后8周内一直保持不变。增殖细胞核抗原染色显示，基质中增殖细胞的比例等于或大于上皮中的比例。在该模型中，剂量为10mg/kg的抗雄激素药物醋酸氯地孕酮（日本大阪和光纯药工业株式会社）可阻止植入的泌尿生殖窦重量增加（19.1%），但其效力低于睾酮诱导的上皮增生模型，即在10mg/kg剂量下为93.4%。
我们建立了一种新的实验性基质增生模型，该模型在基质成分组成和前列腺功能分化方面与临床良性前列腺增生相对应。此外，生长因子表达的定位和时间进程也与良性前列腺增生男性相似。
