Cellular mechanisms of hormonal carcinogenesis in the prostate gland of the noble rat
submitted by Mr Tam Ngai Chung, Neville
for the degree of Doctor of Philosophy
at the University of Hong Kong in May, 2000.
Despite extensive research, the precise mechanism of prostate carcinogenesis remains poorly defined yet. The present study aims to investigate the mechanism of prostate carcinogenesis using the animal model based on the induction by a combination . of testosterone (T) and 17~-estradiol (E2) in the Noble rat. We focused on the expression profiles of steroid receptors, peptide growth factors and their cognate receptors as well as the differentiation status of both epithelial and smooth muscle components of the prostate gland during hormonal carcinogenesis.
Utilizing the modified regimen, we have established a highly successful animal model for prostate carcinogenesis, with 100% (24/24) of rats developed prostate tumors by a prolonged treatment ofT + E2 (> 10 months). Prostate carcinogenesis in our current model followed a multi-step pattern, with dysplasia (a putative precursor of prostate cancer) developed as early as 2 months, carcinoma in situ at 4 months and fully developed carcinomas (microscopic) at 7 months.
Our results have demonstrated significant changes in the steroid receptor status of the prostate gland during hormonal carcinogenesis. Both androgen receptor (AR) and estrogen receptor-~ appeared to be steadily expressed in different stages of prostate cancer progression, suggesting their permissive roles in honnonal carcinogenesis. A more heterogeneous pattern of ER-a expression has been observed in premalignant and neoplastic lesions while various anomalous ER-a isoforrns appeared to be differentially
expressed in different stages of prostate carcinogenesis. Progesterone receptor (PR) was overexpressed in the nuclei of dysplastic and cancerous epithelium. Our immunoblot analyses have revealed striking changes in the profile of PR isoforms in dysplastic and tumor tissues as compared with the nonnal control. It is hypothesized that alterations in steroid receptor status may mediate honnonal induction of prostate cancer in the current Noble rat model.
We have also demonstrated dysregulations in multiple growth factor networks comprising vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), transfonning growth factor-~ (TGF-I3), fibroblast growth factor-l (FGF-I) and FGF-7. Co-expression of VEGF, HGF and their specific receptors (VEGF receptors: flt-l and flk-l and HGF receptor: c-met) in dysplastic and cancer cells suggests that an autocrine mechanism may be involved in the promotion of prostate carcinogenesis. Primary prostate tumors were shown to preferentially overexpress both flt-l precursor and mature flk-I, while metastatic tumors overexpressed flt-l precursor only. Additionally, we have also demonstrated the differential expression of unusual high-molecular-weight isoforms of c-met receptor in various stages of prostate carcinogenesis. There was an elevation of TGF-~l in the prostate with a concurrent down-regulation of TGF-~ receptors during hormonal carcinogenesis. On the other hand, FGF-I was overexpressed in stromal cells in the proximity of epithelial dysplasia, while FGF-7 was overexpressed in both epithelial and stromal components of dysplasia and tumor. The aberrant expression of peptide growth factors and their receptors may play a key role in the sex hormoneinduced prostate carcinogenesis.
Our immunohistochemical, ultrastructural and secretory protein analyses have provided direct evidence of the loss of differentiation in both epithelial and smooth muscle cells during hormonal carcinogenesis. Smooth muscle differentiation markers
were preferentially lost in smooth muscle cells associated with dysplasia and carcinoma. Changes in the structural integrity of smooth muscle layers were also observed and the amount of smooth muscle was markedly reduced in prostate tumors. Dysplastic and tumor cells exhibited nuclear abnormality and a notably loss of secretory organelles, indicating their dedifferentiated phenotype. The loss of a secretory protein marker (e.g., probasin) in hormone-treated LP further reaffirm the dedifferentiation of glandular epithelium following hormone induction. Overall, our results lend support to the hypothesis that a loss of differentiation in both epithelium and smooth muscle may be critically involved in the sex hormone-induced prostate carcinogenesis.
School:The University of Hong Kong
School Location:China - Hong Kong SAR
Source Type:Master's Thesis
Keywords:carcinogenesis prostate cancer cells rats
Date of Publication:01/01/2000