Pathologic progression of autochthonous prostate cancer in the TRAMP model

Abstract

The ability to manipulate gene expression in speci®c cell types at speci®c times utilizing transgenic technology has allowed the development of novel mouse model systems that can mimic human disease. We have previously established the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model for prostate cancer using the rat probasin promoter to direct expression of the SV40 early genes to prostate epithelium. Male TRAMP mice exhibit consistent prostatespeci®c patterns of expression and develop prostatic intraepithelial neoplasia that will become invasive and metastasize primarily to the lymph nodes and lungs. In this paper we report our continued experience with this model and present a standardized histologic grading system to designate low and high grade prostatic intraepithelial neoplasia and well, moderate, and poorly differentiated prostate adenocarcinoma. In addition, we demonstrate the persistence of androgen receptor expression during pathologic progression and characterize heterogeneous cytokeratin expression in localized and metastatic prostate cancer. Finally, we report on our observations that phenotypic variability in tumor and pathologic progression in TRAMP occurs as a function of genetic background.

Early and delayed castrations confer a similar survival advantage in TRAMP mice

“…Similar to most other cancers, prostate carcinogenesis in TRAMP mice involves a multistep progression from precancerous lesions to localized carcinoma, which is followed by metastatic carcinoma, and this progression closely mimics the progression of prostate cancer in humans [11,12]. The transgene is androgen-regulated in TRAMP mice, such that removal of androgens will inhibit the development of androgen-dependent prostate cancer in this mouse model.…”

“…In npg the early-castrated mice, only 2.5% ± 0.2% of tumour cells showed positive staining ( Figure 2C). We adopted an earlier reported grading system [12] for the TRAMP tumours, which was based on their histological patterns. Well-differentiated prostate cancers were observed in the sham-castrated group (Figure 2A) and moderately well-differentiated prostate cancers were observed in the delayed castration group ( Figure 2B), whereas the prostate tumours in the early-castrated group were poorly differentiated ( Figure 2C).…”

“…The SV40 large T antigen effectively abrogates p53 and retinoblastoma tumour suppressor functions and thus acts as an oncoprotein. As a result, TRAMP mice develop spontaneous progressive prostatic tumours from early lesions of prostatic intraepithelial neoplasia (PIN), to locally invasive carcinoma and finally to metastatic disease, which mimics the whole spectrum of human prostatic carcinoma [11][12][13].…”

The impact of bcl-2 expression and bax deficiency on prostate homeostasis in vivo

“…The most extensively studied transgenic model involves the targeting of transgene expression using the probasin promoter (Greenberg et al, 1995;Gingrich et al, 1996Gingrich et al, , 1997. We used the probasin promoter to target expression of a human bcl-2 transgene speci®-cally to the prostate in order to assess its impact on conferring resistance to androgen withdrawal in prostatic glandular epithelial cells in vivo.…”

Androgens and growth factors in prostate cancer: a transgenic perspective

“…7 We have since determined that the phenotype of the TRAMP tumors is a function of the strain and that strain speci®c responses will in¯uence the rate of tumor growth and frequency of distant site metastasis. 8 For this reason we currently cross the C57BL/6 TRAMP mice to non-transgenic FVB/n mice to obtain [C57BL/6 6 FVB] F1 TRAMP males for our studies. For the sake of simplicity I will hereafter refer only to the [C57BL/6 6 FVB] F1 TRAMP males.…”