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Early effects of castration therapy in non-malignant and malignant prostate tissue
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Medicinsk biovetenskap , 2005. , s. 49
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 992
Nyckelord [en]
Prostate cancer, human biopsies, androgen ablation, stroma, epithelium, micro-dissection, PSA, IGF-1, IGF-R1, AR
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-645ISBN: 91-7305-967-6 (tryckt)OAI: oai:DiVA.org:umu-645DiVA, id: diva2:144115
Disputation
2005-12-16, E04, 6E, NUS, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2005-11-22 Skapad: 2005-11-22 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Delarbeten
1. Cell proliferation and apoptosis in prostate tumors and adjacent non-malignant prostate tissue in patients at different time-points after castration treatment.
Öppna denna publikation i ny flik eller fönster >>Cell proliferation and apoptosis in prostate tumors and adjacent non-malignant prostate tissue in patients at different time-points after castration treatment.
2005 (Engelska)Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 62, nr 4, s. 307-315Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
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
Identifikatorer
urn:nbn:se:umu:diva-14264 (URN)10.1002/pros.20139 (DOI)15389788 (PubMedID)
Tillgänglig från: 2007-09-14 Skapad: 2007-09-14 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
2. The magnitude of early castration-induced primary tumour regression in prostate cancer does not predict clinical outcome
Öppna denna publikation i ny flik eller fönster >>The magnitude of early castration-induced primary tumour regression in prostate cancer does not predict clinical outcome
Visa övriga...
2006 (Engelska)Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 49, nr 4, s. 675-683Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

INTRODUCTION: This study was designed to test whether early castration-induced short-term cellular changes in primary prostate tumours could predict clinical outcome in advanced disease. PATIENTS AND METHODS: Biopsies from 83 patients obtained before and within two weeks after surgical castration were investigated. Tumour epithelial cell apoptosis, proliferation, and prostate specific antigen (PSA) levels were quantified using immunohistochemistry, laser capture micro-dissection, and real time RT-PCR. Cellular effects were related to changes in serum PSA levels and clinical outcome. RESULTS: Decreased proliferation and PSA mRNA levels, and increased apoptosis were observed in most tumours. These early cellular responses were not correlated to each other and did not predict serum PSA response or cancer-specific survival. A nadir PSA level below 1 ng/ml predicted a longer cancer-specific survival after castration therapy. CONCLUSION: Castration therapy causes primary tumour regression in most patients with advanced prostate cancer, but these primary tumour effects are not predictive for systemic disease control. Studies of early changes in metastases during hormonal therapy will probably give more predictive information for clinical outcome than further studies in primary tumours.

Nyckelord
Aged, Aged; 80 and over, Androgen Antagonists/*therapeutic use, Apoptosis, Biopsy, Chi-Square Distribution, Combined Modality Therapy, Disease Progression, Flutamide/*therapeutic use, Humans, Immunohistochemistry, Male, Neoplasm Staging, Orchiectomy, Prostate-Specific Antigen/blood, Prostatic Neoplasms/blood/*pathology/*therapy, Reverse Transcriptase Polymerase Chain Reaction, Statistics; Nonparametric, Treatment Outcome
Nationell ämneskategori
Cancer och onkologi Urologi och njurmedicin
Identifikatorer
urn:nbn:se:umu:diva-16282 (URN)10.1016/j.eururo.2005.10.024 (DOI)16387414 (PubMedID)
Tillgänglig från: 2007-09-04 Skapad: 2007-09-04 Senast uppdaterad: 2019-04-17Bibliografiskt granskad
3. Castration rapidly decreases local insulin-like growth factor-1 levels and inhibits its effects in the ventral prostate in mice.
Öppna denna publikation i ny flik eller fönster >>Castration rapidly decreases local insulin-like growth factor-1 levels and inhibits its effects in the ventral prostate in mice.
2006 (Engelska)Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, nr 16, s. 1687-1697Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: The mechanisms by which castration induces prostate involution are largely unknown. METHODS: Early responses to castration in mouse ventral prostate (VP) were explored by quantitative microscopy, cDNA array expression, quantitative RT-PCR, and Western blot analysis. As several changes occurred in the insulin-like growth factor (IGF) system this was studied in more detail. Laser micro-dissection was used to localize sites of IGF-1 and IGF-1 receptor (IGF-R1) production. IGF-1 protein levels and IGF-R1 mediated signaling via insulin regulated substrate 1 and 2 (IRS-1 and 2) were examined. IGF-1 was injected into the VP in intact, and castrated mice and effects studied 1 day later. RESULTS: IGF-1 and IGF binding protein 2 (IGFBP-2) mRNA were rapidly reduced whereas IGFBP-3 and IGF-R1 mRNA were increased after castration. IGF-1 was principally produced in the stromal compartment, while IGF-R1 was produced in both epithelial and stromal cells. IGF-1 and IRS-1 protein levels were decreased 1 and 3 days after castration, respectively, while IRS-2 was unchanged. Inactivating phosphorylation of IRS-1 at serine 307 was increased 1 day after castration, and activating phosphorylation at tyrosine 612 was decreased 2 days later. These changes were accompanied by decreased cell proliferation and increased cell death in the glandular and vascular compartment. Local injection of IGF-1 increased vascular density and epithelial cell proliferation in intact mice, but had no effect in castrated animals. CONCLUSION: Decreased IGF-1 levels and action may mediate some of the key features of castration-induced prostate involution.

Nyckelord
Animals, Cell Growth Processes/drug effects/physiology, Epithelial Cells/metabolism, Insulin-Like Growth Factor Binding Protein 2/biosynthesis/genetics/metabolism, Insulin-Like Growth Factor Binding Protein 3/biosynthesis/genetics/metabolism, Insulin-Like Growth Factor I/biosynthesis/genetics/*metabolism/pharmacology, Male, Mice, Oligonucleotide Array Sequence Analysis, Orchiectomy, Phosphoproteins/metabolism, Prostate/blood supply/cytology/drug effects/*physiology, RNA; Messenger/biosynthesis/genetics, Stromal Cells/metabolism
Identifikatorer
urn:nbn:se:umu:diva-15361 (URN)10.1002/pros.20368 (DOI)16998818 (PubMedID)
Tillgänglig från: 2008-01-11 Skapad: 2008-01-11 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
4. Reduction of local IGF-1 synthesis is of importance for castration-induced regression of normal and malignant human prostate tissue
Öppna denna publikation i ny flik eller fönster >>Reduction of local IGF-1 synthesis is of importance for castration-induced regression of normal and malignant human prostate tissue
Manuskript (Övrigt vetenskapligt)
Identifikatorer
urn:nbn:se:umu:diva-4856 (URN)
Tillgänglig från: 2005-11-22 Skapad: 2005-11-22 Senast uppdaterad: 2010-01-13Bibliografiskt granskad

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