New histopathological experimental model for benign prostatic hyperplasia: stromal hyperplasia in rats.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Mori
Fumitaka
F
Discovery and Development Laboratory II, Hanno Research Center, Taiho Pharmaceutical Co, Ltd, Hanno-City, Saitama, Japan.
Oda
Nobuyuki
N
Sakuragi
Motomu
M
Sakakibara
Fukumitsu
F
Kiniwa
Mamoru
M
Miyoshi
Kazuhisa
K
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D011247:Pregnancy; D011270:Pregnancy, Animal; D011336:Probability; D011470:Prostatic Hyperplasia / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains; D012680:Sensitivity and Specificity; D017154:Stromal Cells / Q000473:pathology