Increased levels of macrophage-secreted cathepsin S during prostate cancer progression in TRAMP mice and patients.

BACKGROUND: Protein expression during prostate tumour progression in transgenic TRAMP mice was studied, with the aim of identifying proteins associated with tumour progression and castration resistant tumour growth. MATERIALS AND METHODS: Protein expression was compared between normal mouse prostate, primary TRAMP tumours and peripheral metastases in long-term castrated TRAMP mice using 2-dimensional differential in-gel electrophoresis and MALDI TOF/TOF analysis. Results were verified with Western blot analysis and immunohisto-chemistry in the TRAMP model and samples from patients. RESULTS: The active form of cathepsin S (Cat S) was identified as being significantly up-regulated in poorly differentiated TRAMP tumours and in castration-resistant metastases compared to normal mouse prostate and well-differentiated tumours. Increased Cat S levels were also found in high Gleason grade tumour areas in patients. Cat S was primarily expressed by tumour-infiltrating macrophages, as shown by double staining of Cat S and CD68 expressing cells. A significantly higher number of Cat S expressing macrophages was found in castration-resistant than in hormone naïve high grade tumours in patients. No relation was found between Cat S levels and suggested Cat S regulated, matrix-derived fragments of collagen IV or laminin 5 gamma2. CONCLUSION: Macrophage-secreted Cat S levels increase during prostate cancer progression and could be an interesting target for therapy.

PPARalpha and PPARgamma regulation of liver and adipose proteins in obese and dyslipidemic rodents.

Zucker fatty rats and ob/ob mice are both frequently used hyperlipidemic and insulin-resistant spontaneous genetic models of obesity. We used them to study the effect of PPAR agonists on the protein-expression level in liver and white adipose tissue. PPARalpha-agonist treatments of the rats resulted in that 27% of the quantified hepatic proteins were altered; implicating pronounced peroxisome proliferation and increase in capacity for beta-oxidation of fatty acids although no correction of plasma triglycerides were obtained. On treatment with PPARgamma agonists, adipose proteins were regulated to a much larger extent in the rats compared to mice, 18% and 2%, respectively.

Characterization of the autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) as a model to study effects of castration therapy.

BACKGROUND: In order to learn more about short- and long-term effects of castration therapy, relevant model systems for prostate cancer are required. In this study, we examined whether the transgenic adenocarcinoma of the mouse prostate (TRAMP) tumor response to castration in C57BL/6 mice mimics that seen in patients. METHODS: Transgenic animals were examined before and 3 days after castration, at the ages of 17, 24, and 36 weeks. Moreover, 24-weeks old animals were castrated and followed for 6 months. Immunohistochemistry (IHC) and stereology were used to evaluate epithelial cell proliferation and death, blood vessel volume, androgen receptor (AR) expression, and transgenic expression of SV40 large T. RESULTS: Cancer developed preferentially in the dorso-lateral prostate lobe. Tumor burden and incidence of metastases increased with age. The majority of tumors were well differentiated, while poorly differentiated, large tumors and macroscopic metastases developed in 8% of the animals. Well and moderately differentiated tumors responded to castration with cessation of proliferation and induction of apoptosis. Poorly differentiated tumors and metastases did not respond. Castration prevented local tumor growth for at least 6 months in 82% of the cases. Although, 45% of the treated animals developed wide-spread metastatic disease suggesting that castration may enhance growth of distant metastases. CONCLUSIONS: The C57Bl/6 TRAMP tumor in several ways mimics how prostate cancer in patients responds to castration both in the short and long term, but some differences may also exist. This model can preferably be used to elucidate how this treatment works, and to test how it can be improved by additional therapies.