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Cell proliferation and apoptosis in prostate tumors and adjacent non-malignant prostate tissue in patients at different time-points after castration treatment.
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
2005 (English)In: The Prostate, ISSN 0270-4137, Vol. 62, no 4, 307-315 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Androgen ablation is the standard treatment for advanced prostate cancer but the short-term cellular effects are largely unknown. METHODS: Sextant prostate biopsies were taken from 77 prostate cancer patients before and 1-10 days after castration treatment. Apoptosis, cell proliferation, and morphology were studied in malignant and non-malignant tissue, using stereological and immunohistochemical methods. RESULTS: Epithelial cell proliferation was significantly decreased both in non-malignant and malignant epithelium already 1 day after therapy. It remained low until day 7, but increased thereafter in the remaining non-malignant epithelial cells and in some tumors. Epithelial cell apoptosis was significantly increased during the first week and then returned to basal levels. The maximal apoptotic indexes, seven- and two-times the intact levels in the non-malignant and malignant glands, respectively, were found at days 3-4 or even earlier in the tumors. Signs of tumor shrinkage such as glandular collapse and decreased tumor cell size were observed from day 3 in most tumors. DISCUSSION: The present study shows that the magnitude and kinetics of the response to castration in the normal human prostate is very similar to the response previously described in rodents. We also demonstrate that most human prostate tumors rapidly respond to castration indicating the need for further evaluation of when and how to best monitor the effects of hormone ablation therapy in prostate cancer patients. (c) 2004 Wiley-Liss, Inc.

Place, publisher, year, edition, pages
2005. Vol. 62, no 4, 307-315 p.
Keyword [en]
Aged, Aged; 80 and over, Androgen Antagonists/therapeutic use, Apoptosis, Biopsy, Castration, Cell Proliferation, Humans, Kinetics, Male, Middle Aged, Prostate/*cytology/drug effects, Prostatic Neoplasms/*drug therapy/*physiopathology
URN: urn:nbn:se:umu:diva-14264DOI: 10.1002/pros.20139PubMedID: 15389788OAI: diva2:153935
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2009-11-26Bibliographically approved
In thesis
1. Early effects of castration therapy in non-malignant and malignant prostate tissue
Open this publication in new window or tab >>Early effects of castration therapy in non-malignant and malignant prostate tissue
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Early Effects of Castration Therapy in Non-malignant and Malignant Prostate Tissue

BACKGROUND. Androgen ablation, the standard treatment for advanced prostate cancer, results in increased apoptosis, decreased cell proliferation and subsequent involution of the prostate gland. The mechanisms behind these responses are largely unknown, but effects in the prostatic epithelium are believed to be mediated by primary changes in the stroma. The purpose of this thesis was to investigate short-term cellular effects of castration-induced prostate tissue involution in mice and humans.

METHODS. Prostate tissue factors affected by castration were investigated using cDNA-arrays, micro-dissection, RT-PCR, immunohistochemistry and Western blot analysis. The effects of local insulin-like growth factor-1 (IGF-1) administration were investigated in intact and castrated mice. Non-malignant and malignant epithelial and stromal cells were micro-dissected from human prostate biopsies taken before and within two weeks after castration treatment from patients with advanced prostate cancer. These tissue compartments were analyzed by RT-PCR and/or immunohistochemistry for IGF-1, IGF-1 receptor, androgen receptor (AR) and prostate specific antigen (PSA) expression. Treatment-induced changes in these factors were related to apoptosis and proliferation as well as to clinical data and cancer specific survival.

RESULTS. Similar to our observations in mouse ventral prostate (VP), non-malignant and malignant human prostate tissues responded with increased epithelial cell apoptosis and decreased proliferation after androgen withdrawal. Also, the PSA mRNA levels were reduced within the first days after therapy both in non-malignant and malignant human prostate epithelial cells. However, neither of these changes was related to subsequent nadir serum PSA or to survival. Locally injected IGF-1 increased epithelial cell proliferation and vascular volume in intact but not in castrated mice. IGF-1 was found to be mostly, but not exclusively, expressed in the stroma, and it decreased rapidly after castration in both humans and mice. This decrease was, however, largely absent in prostate tumor stroma, and tumor stroma cells showed lower pre-treatment levels of AR than stroma surrounding normal epithelial glands. Furthermore, decreased levels of IGF-1 mRNA in the non-malignant and tumor stroma cells, and in tumor epithelial cells in response to castration, were associated with high levels of apoptosis in epithelial cells after therapy.

CONCLUSIONS. In the prostate, IGF-1 may be an important mediator of stroma-epithelial cell interaction that is involved in castration-induced epithelial and vascular involution. Moreover, reduced AR in the tumor stroma may play an important role in prostate cancer progression towards androgen-independency, resulting in inadequate IGF-1 reduction and apoptosis induction in response to castration. Most primary tumors initially respond to castration with markedly decreased PSA synthesis and cell proliferation, and moderately increased apoptosis. Death due to metastatic disease is, however, still common, despite primary tumor regression. This may suggest that tumor cells in metastases respond differently to treatment than primary tumor cells, probably influenced by a different and possibly androgen-independent stroma. Further studies should test the hypothesis that the effect of castration therapy can be enhanced by simultaneous blocking of IGF-1 signaling.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2005. 49 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 992
Prostate cancer, human biopsies, androgen ablation, stroma, epithelium, micro-dissection, PSA, IGF-1, IGF-R1, AR
National Category
Cell and Molecular Biology
urn:nbn:se:umu:diva-645 (URN)91-7305-967-6 (ISBN)
Public defence
2005-12-16, E04, 6E, NUS, Umeå, 13:00 (English)
Available from: 2005-11-22 Created: 2005-11-22 Last updated: 2009-12-08Bibliographically approved

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