Tramp

Abstract: To develop a syngeneic transplantable system to study immunotherapeutic approaches for the treatment of prostate cancer, three cell lines were established from a heterogeneous 32 week tumor of the transgenic adenocarcinoma mouse prostate (TRAMP) model. TRAMP is a transgenic line of C57BL/6 mice harboring a construct comprised of the minimal -426/+28 rat probasin promoter driving prostate-specific epithelial expression of the SV40 large T antigen. TRAMP males develop histological prostatic intraepithelial neoplasia by 8-12 weeks of age that progress to adenocarcinoma with distant metastases by 24-30 weeks of age. The three cell lines (TRAMP-C1, TRAMP-C2, and TRAMP-C3) express cytokeratin, E-cadherin, and androgen receptor by immunohistochemical analysis and do not appear to have a mutated p53. Although TRAMP-C1 and TRAMP-C2 are tumorigenic when grafted into syngeneic C57BL/6 hosts, TRAMP-C3 grows readily in vitro but does not form tumors. The T antigen oncoprotein is not expressed by the cell lines in vitro or in vivo. The rationale for establishing multiple cell lines was to isolate cells representing various stages of cellular transformation and progression to androgen-independent metastatic disease that could be manipulated in vitro and, in combination with the TRAMP model, provide a system to investigate therapeutic interventions, such as immunotherapy prior to clinical trials.

Abstract: Background Animal models that closely mimic clinical disease can be exploited to hasten the pace of translational research. To this end, we have defined windows of opportunity in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer as a paradigm for designing pre-clinical trials. Methods The incidence of cancer, metastasis, and distribution of pathology were examined as a function of time in TRAMP mice. The expression of various markers of differentiation were characterized. Results The TRAMP model develops progressive, multifocal, and heterogeneous disease. Each lobe of the prostate progressed at a different rate. Cytokeratin 8, E-cadherin, and androgen receptor (AR) were expressed during cancer progression but levels were reduced or absent in late stage disease. A distinct epithelial to neuroendocrine (ENT) shift was observed to be a stochastic event related to prostate cancer progression in TRAMP. Conclusions This study will serve as the basis for the rational design of pre-clinical studies with genetically engineered mouse models. Prostate 55: 219–237, 2003. © 2003 Wiley-Liss, Inc.

Abstract: We have previously shown that antibodies to CTLA-4, an inhibitory receptor on T cells, can be effective at inducing regression of transplantable murine tumors. In this study, we demonstrate that an effective immune response against primary prostate tumors in transgenic (TRAMP) mice can be elicited using a strategy that combines CTLA-4 blockade and an irradiated tumor cell vaccine. Treatment of TRAMP mice at 14 weeks of age resulted in a significant reduction in tumor incidence (15% versus control, 75%), as assessed 2 months after treatment. Histopathological analysis revealed that treated mice had a lower tumor grade with significant accumulation of inflammatory cells in interductal spaces when treated with anti-CTLA-4 and a granulocyte-macrophage colony-stimulating factor-expressing vaccine. Vaccination of nontransgenic mice with this regimen resulted in marked prostatitis accompanied by destruction of epithelium, indicating that the immune response was, at least in part, directed against normal prostate antigens. These findings demonstrate that this combinatorial treatment can elicit a potent antiprostate response and suggest potential of this approach for treatment of prostate cancer.

Abstract: We previously established the autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) model to facilitate characterization of molecular mechanisms involved in the initiation and progression of prostate cancer. TRAMP mice display high grade prostatic intraepithelial neoplasia or well-differentiated prostate cancer by 10-12 weeks of age. To test the hypothesis that molecular events leading to androgen independence and metastasis can occur early in the natural history of prostate cancer yet remain silent until selective pressures such as androgen deprivation are applied, we have examined the consequences of castration on the initiation and progression to metastatic prostate cancer in TRAMP mice. Cohorts were castrated at 12 weeks of age and sacrificed at 18 (T12/18) or 24 (T12/24) weeks of age, and the development of primary cancer and metastatic disease was compared to noncastrated (T18 and T24) controls. Median T12/18 and T12/24 genitourinary (GU) weight was significantly less than T18 and T24, respectively. In addition, T12/24 GU weight was significantly greater than T12/18. Histological prostate tumors developed in 3 of 7 T12/18 and 8 of 10 T12/24 mice. All tumors that developed in castrated mice were poorly differentiated in contrast to 27% in noncastrated controls. Although castration significantly decreased GU tumor burden, overall progression to poorly differentiated and metastatic disease was not ultimately delayed. These results demonstrate that prostate cancer in the TRAMP model is heterogeneous with respect to androgen dependence as early as 12 weeks of age; therefore, early androgen ablation may have a variable impact on progression in an individual mouse. Further analysis of this prostate cancer model to identify specific molecular mechanisms that determine androgen sensitivity may facilitate future initiation of appropriate individualized hormonal therapy for the management of human prostate cancer.