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A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model.
Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Radiation Sciences. Umeå University, Faculty of Medicine, Radiation Sciences, Diagnostic Radiology.
Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
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2007 (English)In: The Prostate, ISSN 0270-4137, Vol. 67, no 15, 1664-1676 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration-induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma. METHODS: Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies. RESULTS: In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF-Rbeta were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF-Rbeta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone. CONCLUSIONS: The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced.

Place, publisher, year, edition, pages
2007. Vol. 67, no 15, 1664-1676 p.
URN: urn:nbn:se:umu:diva-22159DOI: 10.1002/pros.20657PubMedID: 17854058OAI: diva2:212921
Available from: 2009-04-24 Created: 2009-04-24 Last updated: 2009-10-12
In thesis
1. Examining the prostate stroma and vasculature: importance and potential as targets for therapy
Open this publication in new window or tab >>Examining the prostate stroma and vasculature: importance and potential as targets for therapy
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Recent studies in cancer research have focused on the reciprocal interaction between cancer cells and their microenvironment. Tumour growth is angiogenesis dependent and the rate of angiogenesis correlates with a poor prognosis in many different cancers. We have shown that the rate of angiogenesis correlates with prognosis in Prostate Cancer (PC). We have also observed that the vasculature is involved during the involution of the prostate in rodents subsequent to hormonal ablation. Patients with metastatic PC are subjected to hormonal ablation therapy – a therapy unfortunately not curative. Our ambition is therefore to find means to enhance the effects of castration therapy of prostate tumours, possibly by a simultaneous inhibition of angiogenesis and of growth factors populating the tumour stroma. The angiopoietins are a family of growth factors that regulate angiogenesis by direct effects on endothelial cells in a context dependent manner. The purpose of this thesis was therefore to examine the role of the angiopoietins and the stroma in general in PC and to explore their potential as novel targets.

Materials and Methods. We have had at our disposal access to clinical materials in the form of paraffin embedded samples from untreated PC patients with a long follow up. We have also used animal tumour models and in vitro cell culture systems followed by immunohistochemistry, in situ hybridization, western blotting, laser micro dissection, and quantitative real-time PCR for evaluation of the experiments.

Results. In paper I, we found a significant correlation between high levels of angiopoietin 2 (Ang 2) and high vascular density, histological grade, metastases and poor prognosis in PC patients. In the second paper we found that the receptor for the angiopoietins, Tie 2, and the ligand Ang 1 mediated the decrease in vascular stability observed after castration treatment. This was not observed in prostate tumours subsequent to hormonal ablation (paper III), nor was there a decrease of other growth factor receptors. In summary (paper III), we found that a combined inhibition of the tumour stroma in terms of an inhibition of the PDGF-Rs by the use of Imatinib, and the vasculature in terms of a perturbed Tie 2 signalling, inhibited tumour growth. Finally, in paper IV, we found that Imatinib inhibited the castration induced influx of mast cells after castration therapy. The mast cells expressed high levels of FGF 2 and epiregulin, and inhibition of mast cell function inhibited tumour growth, by inhibiting angiogenesis.

Conclusions. We have observed that the tumour stroma is of particular importance for tumour growth in PC. Targeting the tumour microenvironment, and in particular by a simultaneous inhibition of the vasculature and stroma, could prove beneficial for patients with advanced PC.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2008. 57 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1158
Prostate cancer, castration therapy, vasculature, stroma, the angiopoietins, the PDGF-receptors, mast cells
National Category
Cell and Molecular Biology
urn:nbn:se:umu:diva-1589 (URN)978-91-7264-512-7 (ISBN)
Public defence
2008-03-28, hörsal Betula, Byggnad 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Available from: 2008-03-18 Created: 2008-03-18 Last updated: 2010-01-18Bibliographically approved

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