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Androgen controlled regulatory systems in prostate cancer: potential new therapeutic targets and prognostic markers
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

BACKGROUND: Prostate cancer is by far the most common cancer among Swedish men. Some patients have an aggressive lethal disease, but the majority of affected men have long expected survival. Unfortunately, the diagnostic tools available are insufficient in predicting disease aggressiveness. Novel prognostic markers are therefore urgently needed. Furthermore, metastatic prostate cancer is generally treated with castration, but the long-term effects are insufficient. Additional studies are therefore needed to explore how the effects of this therapy can be enhanced. Prostate growth and regression is beside testosterone controlled by locally produced regulators. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are two of the major regulators in the normal prostate and in prostate tumours.

MATERIALS AND METHODS: VEGF and EGFR were explored in the prostate, by treating rats with either anti-VEGF or anti-EGFR treatment during castration and testosterone-stimulated prostate growth. Rats with implanted androgen-independent prostate tumours were treated with an inhibitor of both VEGF receptor-2 (VEGFR-2) and EGFR. Stereological techniques, immunohistochemistry, western blotting and quantitative real-time PCR were used to evaluate these experiments. Furthermore, prostate tissue from untreated prostate cancer patients was used to retrospectively explore the expression of phosphorylated-EGFR (pEGFR) in relation to outcome.

RESULTS: Anti-VEGF treatment during testosterone-stimulated prostate growth, inhibited vascular and prostate growth. Anti-EGFR treatment during castration and testosterone-stimulated prostate growth resulted in enhanced castration effects and inhibited prostate growth. Anti-vascular treatment of androgen-independent prostate cancer with an inhibitor of VEGFR-2 and EGFR, that targets the normal and tumour vasculature, enhanced the effects of castration. Low immunoreactivity for pEGFR in prostate epithelial cells, both in the tumour and also in the surrounding non-malignant tissue, was associated with good prognosis.

CONCLUSIONS: Anti-vascular treatment, with an inhibitor of VEGFR-2 and EGFR, in combination with castration could be an effective way to treat androgen-insensitive prostate tumours. VEGF and EGFR signalling are necessary components in testosterone-stimulated prostate growth. Phosphorylation of EGFR could be a useful prognostic marker for prostate cancer patients. Tumours may affect the surrounding non-malignant tissue and pEGFR immunoreactivity in the morphologically normal prostate tissue can be used to retrieve prognostic information.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2008. , 56 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1230
Keyword [en]
prostate cancer, angiogenesis, human biopsy, androgen ablation, castration, prognostic marker, prognostic factor, growth control, VEGF, vascular endothelial growth factor, EGFR, epidermal growth factor receptor, pEGFR, phosphorylated EGFR, phosphorylated epidermal growth factor receptor
National Category
Pathobiology
Identifiers
URN: urn:nbn:se:umu:diva-1930ISBN: 978-91-7264-698-8 (print)OAI: oai:DiVA.org:umu-1930DiVA: diva2:142472
Public defence
2008-12-10, Hörsal Betula, 6M, Norrlands universitetssjukhus, 901 85 Umeå, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2008-11-24 Created: 2008-11-24 Last updated: 2010-03-24Bibliographically approved
List of papers
1. Neutralizing VEGF bioactivity with a soluble chimeric VEGF-receptor protein flt(1-3)IgG inhibits testosterone-stimulated prostate growth in castrated mice.
Open this publication in new window or tab >>Neutralizing VEGF bioactivity with a soluble chimeric VEGF-receptor protein flt(1-3)IgG inhibits testosterone-stimulated prostate growth in castrated mice.
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2004 (English)In: Prostate, ISSN 0270-4137, Vol. 58, no 1, 57-65 p.Article in journal (Refereed) Published
Keyword
Animals, Apoptosis/drug effects/physiology, Bromodeoxyuridine/metabolism, Castration, Cell Division/drug effects, Endothelial Cells/cytology/drug effects/metabolism, Immunoglobulin G/pharmacology, Immunohistochemistry, Male, Mice, Mice; Inbred C57BL, Neovascularization; Physiologic/physiology, Organ Size/drug effects, Prostate/blood supply/cytology/*drug effects/metabolism, Receptors; Androgen/metabolism, Recombinant Fusion Proteins/metabolism/pharmacology, Testosterone/antagonists & inhibitors/metabolism/*pharmacology, Vascular Endothelial Growth Factor A/*antagonists & inhibitors/metabolism, Vascular Endothelial Growth Factor Receptor-1/*administration & dosage
Identifiers
urn:nbn:se:umu:diva-14217 (URN)10.1002/pros.10312 (DOI)14673953 (PubMedID)
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2010-04-20Bibliographically approved
2. Inhibition of the epidermal growth factor receptor enhances castration-induced prostate involution and reduces testosterone-stimulated prostate growth in adult rats.
Open this publication in new window or tab >>Inhibition of the epidermal growth factor receptor enhances castration-induced prostate involution and reduces testosterone-stimulated prostate growth in adult rats.
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2007 (English)In: Prostate, ISSN 0270-4137, Vol. 67, no 6, 573-581 p.Article in journal (Refereed) Published
Keyword
angiogenesis, gefitinib, EGF-receptor, castration, stereology, ventral prostate
Identifiers
urn:nbn:se:umu:diva-12244 (URN)doi:10.1002/pros.20529 (DOI)17252557 (PubMedID)
Available from: 2008-01-15 Created: 2008-01-15 Last updated: 2011-01-11Bibliographically approved
3. Inhibitory effects of castration in an orthotopic model of androgen-independent prostate cancer can be mimicked and enhanced by angiogenesis inhibition.
Open this publication in new window or tab >>Inhibitory effects of castration in an orthotopic model of androgen-independent prostate cancer can be mimicked and enhanced by angiogenesis inhibition.
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2006 (English)In: Clinical Cancer Research, ISSN 1078-0432, Vol. 12, no 24, 7431-7436 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-16392 (URN)doi:10.1158/1078-0432.ccr-06-1895 (DOI)17189416 (PubMedID)
Available from: 2008-01-10 Created: 2008-01-10 Last updated: 2010-04-20Bibliographically approved
4. Low levels of phosphorylated epidermal growth factor receptor in nonmalignant and malignant prostate tissue predict favorable outcome in prostate cancer patients.
Open this publication in new window or tab >>Low levels of phosphorylated epidermal growth factor receptor in nonmalignant and malignant prostate tissue predict favorable outcome in prostate cancer patients.
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2010 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 4, 1245-1255 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To explore if the expression of phosphorylated epidermal growth factor receptor (pEGFR) in nonmalignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients. EXPERIMENTAL DESIGN: We used formalin-fixed tissues obtained through the transurethral resection of the prostate from 259 patients diagnosed with prostate cancer after the transurethral resection of the prostate, and patients were then followed with watchful waiting. Tissue microarrays of nonmalignant and malignant prostate tissue were stained with an antibody against pEGFR. The staining pattern was scored and related to clinicopathologic parameters and to outcome. RESULTS: Low phosphorylation of EGFR in prostate epithelial cells, both in the tumor and surprisingly also in the surrounding nonmalignant tissue, was associated with significantly longer cancer-specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were added together with pEGFR to a Cox regression model. Tumor epithelial pEGFR immunoreactivity was significantly correlated to tumor cell proliferation, tumor vascular density, and nonmalignant epithelial pEGFR immunoreactivity. Patients with metastases had significantly higher immunoreactivity for tumor and nonmalignant epithelial pEGFR compared with patients without metastases. CONCLUSIONS: Low pEGFR immunoreactivity is associated with the favorable prognosis in prostate cancer patients and may provide information about which patients with Gleason score 6 and 7 tumors that will survive their disease even without treatment. Changes in the nonmalignant tissue adjacent to prostate tumors give prognostic information.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-32701 (URN)10.1158/1078-0432.CCR-09-0103 (DOI)000278545200018 ()20145160 (PubMedID)
Available from: 2010-03-22 Created: 2010-03-22 Last updated: 2017-12-12Bibliographically approved

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