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Androgen-insensitive prostate cancer cells transiently respond to castration treatment when growing in an androgen-dependent prostate environment.
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.
2007 (English)In: The Prostate, ISSN 0270-4137, Vol. 67, no 4, 370-7 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2007. Vol. 67, no 4, 370-7 p.
Keyword [en]
Androgens/*metabolism, Animals, Anoxia/metabolism/pathology, Apoptosis, Cell Division, Epithelial Cells/cytology/metabolism, Male, Neoplasm Transplantation, Orchiectomy, Organ Size, Prostate/blood supply/cytology/metabolism, Prostatic Neoplasms/metabolism/*pathology/*surgery, Rats, Rats; Inbred Strains, Receptors; Androgen/metabolism
Identifiers
URN: urn:nbn:se:umu:diva-6839DOI: 10.1002/pros.20473PubMedID: 17192959OAI: oai:DiVA.org:umu-6839DiVA: diva2:146509
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-12-22Bibliographically approved
In thesis
1. Targeting the prostate tumor microenvironment and vasculature: the role of castration, tumor-associated macrophages and pigment epithelium-derived factor
Open this publication in new window or tab >>Targeting the prostate tumor microenvironment and vasculature: the role of castration, tumor-associated macrophages and pigment epithelium-derived factor
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Mikromiljö och angiogenes i prostatacancer : effekter av kastration, tumör associerade makrofager och Pigment epithelium-derived factor
Abstract [en]

BACKGROUND: Prostate cancer is the most common cancer among Swedish men. For patients with metastatic prostate cancer the standard therapy is castration, a treatment that initially provides symptomatic relief but unfortunately is not curative. New therapeutic targets for advanced prostate cancer are therefore needed.  Prostate cancers are composed of tumor epithelial cells as well as many non-epithelial cells such as cancer associated fibroblasts, blood vessels and inflammatory cells.  Many components of the tumor microenvironment such as tumor associated macrophages and angiogenesis have been shown to stimulate tumor progression. This thesis aims to explore mechanisms by which the local environment influences prostate tumor growth and how such mechanisms could be targeted for treatment.

MATERIALS AND METHODS: We have used animal models of prostate cancer, in vitro cell culture systems and clinical materials from untreated prostate cancer patients with long follow up. Experiments were evaluated with stereological techniques, immunohistochemistry, western blotting, quantitative real-time PCR, PCR arrays and laser micro dissection.

RESULTS: We found that the presence of a tumor induces adaptive changes in the surrounding non-malignant prostate tissue, and that androgen receptor negative prostate tumor cells respond to castration treatment with temporarily reduced growth when surrounded by normal castration-responsive prostate tissue. Further, we show that macrophages are important for prostate tumor growth and angiogenesis in the tumor and in the surrounding non-malignant tissue. In addition, the angiogenesis inhibitor Pigment epithelium-derived factor (PEDF) was found  to be down-regulated in metastatic rat and human prostate tumors. Over-expression of PEDF inhibited experimental prostate tumor growth, angiogenesis and metastatic growth and stimulated macrophage tumor infiltration and lymphangiogenesis. PEDF was found to be down-regulated by the prostate microenvironment and tumor necrosis factor (TNF) α.

CONCLUSIONS: Our studies indicate that not only the nearby tumor microenvironment but also the surrounding non-malignant prostate tissue are important for prostate tumor growth. Both the tumor and the surrounding non-malignant prostate were characterized by increased angiogenesis and inflammatory cell infiltration. Targeting the surrounding prostate tissue with castration, targeting tumor associated macrophages, or targeting the vasculature directly using inhibitors like PEDF were all shown to repress prostate tumor growth and could prove beneficial for patients with advanced prostate cancer.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2009. 57 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1293
Keyword
Prostate cancer, angiogenesis, castration therapy, microenvironment, stroma, tumor-associated macrophages, pigment epithelium-derived factor, PEDF, vasculature
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-30300 (URN)978-91-7264-862-3 (ISBN)
Public defence
2010-01-22, Hörsal Betula, 6M, Norrlands universitetssjukhus, Umeå, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2009-12-22 Created: 2009-12-16 Last updated: 2010-04-20Bibliographically approved

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Halin, SofiaHammarsten, PeterWikström, PernillaBergh, Anders

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