Midtveisevaluering - Astrid Børretzen
Midtveisevaluering for ph.d.-graden ved Universitetet i Bergen for kandidat Astrid Børretzen
Astrid Børretzen er tilknyttet Klinisk institutt 1. Veiledere er Ole Johan Halvorsen, Lars Andreas Akslen og Christian Beisland.
Epithelial-mesenchymal transition, angiogenesis and molecular markers in aggressive prostate cancer
Epithelial-mesenchymal transition (EMT) is a conserved embryonic cellular trans-differentiation programme, seen in development and in pathologic conditions such as wound healing, fibrosis and in aggressive carcinomas. In EMT, the epithelial tumour cells change to a motile, mesenchymal like phenotype, thereby enabling the tumour cells to become invasive and to metastasise. EMT is regulated by transcription factors, including FOXC2, Twist, Slug and Snail. During the last years, there have been increasing focus on the flexibility of the EMT programme. Partial reversal of EMT is important for metastatic colonisation and tumour cells that easily transit between epithelial and mesenchymal phenotypes may be more aggressive.
In the first part of the PhD-project, the expression of FOXC2, Twist, Slug, Snail, HIF-1α, E-cadherin and N-cadherin were examined by immunohistochemistry on tissue microarray sections from 338 radical prostatectomies and on sections from benign prostatic hyperplasias, non-skeletal metastases, skeletal metastases and castration resistant prostate cancer.The EMT-related markers were associated with adverse clinico-pathologic features, angiogenesis, recurrence and cancer specific death. In paper I, a subgroup of intermediate risk carcinomas (Gleason score 7) was used, focusing on FOXC2, against which a small molecule inhibitor has been developed recently. In addition, a hybrid epithelial-mesenchymal phenotype, with co-expression of E- and N-cadherin, was found in the majority of the skeletal metastases and in a substantial part of the castration resistant tumours in our material confirming the existence of these phenotypes in advanced human prostate cancer.
Continuing work will focus on angiogenesis in prostate cancer. Sections from radical prostatectomies are immunohistochemically stained for immature vessel proliferation by Nestin-Ki67. The relationship between microvessel density/vascular proliferation and anatomically corresponding flow data from multiparametric magnetic resonance imaging (mpMRI) will be evaluated.