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Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
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2005 (Engelska)Ingår i: Prostate, ISSN 0270-4137, Vol. 62, nr 4, s. 394-399Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
2005. Vol. 62, nr 4, s. 394-399
Nyckelord [en]
Aged, Angiopoietin-1/biosynthesis/pharmacology, Angiopoietin-2/*biosynthesis/pharmacology, Gene Expression Profiling, Gene Expression Regulation; Neoplastic, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Neovascularization; Pathologic, Prognosis, Prostatic Neoplasms/blood supply/*pathology
Identifikatorer
URN: urn:nbn:se:umu:diva-14263DOI: 10.1002/pros.20163PubMedID: 15378518OAI: oai:DiVA.org:umu-14263DiVA, id: diva2:153934
Tillgänglig från: 2007-09-14 Skapad: 2007-09-14 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Examining the prostate stroma and vasculature: importance and potential as targets for therapy
Öppna denna publikation i ny flik eller fönster >>Examining the prostate stroma and vasculature: importance and potential as targets for therapy
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Medicinsk biovetenskap, 2008. s. 57
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1158
Nyckelord
Prostate cancer, castration therapy, vasculature, stroma, the angiopoietins, the PDGF-receptors, mast cells
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-1589 (URN)978-91-7264-512-7 (ISBN)
Disputation
2008-03-28, hörsal Betula, Byggnad 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2008-03-18 Skapad: 2008-03-18 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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