ECE2013 Oral Communications Adrenal (6 abstracts)
Pre-clinical model detects castrate-resistant cancer repopulating cells in localised prostate tumours
Gail Risbridger 1 , Roxanne Toivanen 1 , Mark Frydenberg 1 , Declan Murphy 2 , John Pedersen 3 , Andrew Ryan 3 , David Pook 1 , David Berman 4 & Renea Taylor 1
1Monash University, Melbourne, Victoria, Australia; 2Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; 3TissuPath Laboratories, Melbourne, Victoria, Australia; 4Queen’s University, Kingston, Ontario, Canada.
Introduction: Lack of clinically relevant experimental models of human prostate cancer hampers evaluation of novel therapeutic agents. Currently, androgen deprivation therapy is the gold standard treatment for advanced prostate cancer, but inevitably cells survive and repopulate the tumour. Castrate-resistant cells are critical therapeutic targets for more effective treatments but current model systems cannot determine when they arise in disease progression and are unable to recapitulate variable patient response to treatment.
The aim of this study was to develop stromally supported xenografts from multiple patients with early stage-localised disease to investigate the castration response. It was postulated that prior to the development of aggressive/metastatic disease, localised prostate cancer specimens may already harbour castrate-resistant, cancer repopulating cells.
Methods: To test this concept a reproducible and reliable model was used to establish 12 patient localised prostate cancers in vivo. Using these 12 engrafted tumours, response to short and long term castration, as well as androgen restoration was examined. Tumour grafts were analysed using pathology, proliferation/apoptotic indices and biomarker expression.
Results: Histopathology of all 12 engrafted tumours mimicked that of the original tumours and when host mice were castrated, the tumours regressed showing significant changes in proliferation and apoptosis. Four weeks thereafter, a population of growth quiescent luminal cells, expressing low AR and PSA remained, which expressed variable immuno-positivity for common stem cell markers Nkx3-1, CD44, ALDH1 and NANOG. These castrate-resistant cells showed regenerative capacity when testosterone was re-administered to castrated hosts, and restoration of normal AR and PSA expression.
Conclusions: Stem-like castrate-resistant (but hormone sensitive) tumour cells were detected in localised prostate cancer specimens from which tumours regenerate; thus proving the need to further characterise these cells and elucidate common pathways to therapeutically target them.
Volume 32
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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