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Inhibition of the epidermal growth factor receptor enhances castration-induced prostate involution and reduces testosterone-stimulated prostate growth in adult rats.
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, Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
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2007 (English)In: Prostate, ISSN 0270-4137, Vol. 67, no 6, 573-581 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2007. Vol. 67, no 6, 573-581 p.
Keyword [en]
angiogenesis, gefitinib, EGF-receptor, castration, stereology, ventral prostate
Identifiers
URN: urn:nbn:se:umu:diva-12244DOI: doi:10.1002/pros.20529PubMedID: 17252557OAI: oai:DiVA.org:umu-12244DiVA: diva2:151915
Available from: 2008-01-15 Created: 2008-01-15 Last updated: 2011-01-11Bibliographically approved
In thesis
1. Androgen controlled regulatory systems in prostate cancer: potential new therapeutic targets and prognostic markers
Open this publication in new window or tab >>Androgen controlled regulatory systems in prostate cancer: potential new therapeutic targets and prognostic markers
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
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:nbn:se:umu:diva-1930 (URN)978-91-7264-698-8 (ISBN)
Public defence
2008-12-10, Hörsal Betula, 6M, Norrlands universitetssjukhus, 901 85 Umeå, Umeå, 13:00 (English)
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Available from: 2008-11-24 Created: 2008-11-24 Last updated: 2010-03-24Bibliographically approved

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