Change search
ReferencesLink to record
Permanent link

Direct link
Castration rapidly decreases local insulin-like growth factor-1 levels and inhibits its effects in the ventral prostate in mice.
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
2006 (English)In: The Prostate, ISSN 0270-4137, Vol. 66, no 16, 1687-1697 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2006. Vol. 66, no 16, 1687-1697 p.
Keyword [en]
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
URN: urn:nbn:se:umu:diva-15361DOI: 10.1002/pros.20368PubMedID: 16998818OAI: diva2:155033
Available from: 2008-01-11 Created: 2008-01-11 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

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Ohlson, NinaBergh, AndersWikström, Pernilla
By organisation
In the same journal
The Prostate

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 57 hits
ReferencesLink to record
Permanent link

Direct link