Fibroblast growth factor 8 isoform B overexpression in prostate epithelium: a new mouse model for prostatic intraepithelial neoplasia.
Fibroblast growth factor 8 isoform b (FGF8b), a mitogenic and transforming polypeptide, was demonstrated to be naturally up-regulated in prostatic premalignant and malignant lesions in men. We generated four independent lines of transgenic mice with targeted overexpression of FGF8b in the prostatic epithelium using an improved rat probasin promoter, ARR(2)PB. Transgene expression in the prostate tissue was readily demonstrated by reverse transcription-PCR and localized to the prostatic epithelium by in situ hybridization. The histopathology of the prostate tissues was followed in different age groups of the various lines but most extensively in one line (line 3), starting from 1 month of age up to 24 months. Prostatic hyperplasia appeared in the lateral and ventral prostates in some animals as early as 2-3 months and in other lobes between 6 and 16 months. Beginning at 5-7 months, dysplasia, akin to what may be considered low-grade prostatic intraepithelial neoplasia (LGPIN) in humans, was detected. During the first 14 months, 100% of animals exhibited multifocal epithelial hyperplasia; 35% also had areas of LGPIN. This profile changed in subsequent months (15-24 months) to a higher incidence of LGPIN (66%) along with high-grade PIN (HGPIN) lesions (51%). Similar to HGPIN, stromal proliferation and appearance of papillary hyperplasia with atypia displayed a delayed pattern. The affected stroma consisted primarily of the smooth muscle cell component. The incidence of chronic inflammation, mostly involving T cells, was higher in the prostate of the transgenic mice relative to controls; however, the presence of a direct correlation between inflammation and hyperplasia or preneoplastic lesions was not identified. These transgenic mice represent a "natural" animal model for investigating the mechanism of development and progression of prostatic diseases, such as prostatic hyperplasia and preneoplastic lesions.
Song
Zhigang
Z
Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA.
Wu
Xiantuo
X
Powell
William C
WC
Cardiff
Robert D
RD
Cohen
Michael B
MB
Tin
Robert T
RT
Matusik
Robert J
RJ
Miller
Gary J
GJ
Roy-Burman
Pradip
P
D000818:Animals; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000473:pathology; D019076:Transgenes; D014407:Tumor Cells, Cultured
C496457:Fgf8 protein, mouse; D020033:Protein Isoforms; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors