Initial gains have been made in the on-going study of identifying and characterising normal and cancer prostate stem cells (SCs), a three-year project of the EAU-Research Foundation (EAU-RF) with a Sweden-based research team that aims to identify new therapeutic biomarkers.
“We are investigating and characterising normal prostate epithelial SCs by various pulse-chase experiments and in connection with the identification of protein and reporter genes in label-retaining SCs, and by in vivo cell lineage tracing experiments,” said Dr. Jens Ceder of the Lund University, Division of Urological Research at the Skåne University Hospital in Malmö (SE).
Ceder is leading the team which has been granted support under the EAU-Research Foundation (EAU-RF) Career Development Programme, and in collaboration with researchers based in Radboud University Nijmegen in the Netherlands, and the University of York’s YCR Cancer Research Unit in the UK.
Although many prostate cancer patients with metastatic disease initially respond to hormone castration therapy, investigators say most patients develop fatal castration-resistant prostate tumours. Moreover, experts believe that there is increasing evidence suggesting that resistance of cancer stem cells (CSCs) to conventional therapies may account for the inability to cure prostate cancer (PCa).
Cancer stem cells
Ceder explained that although suspected or putative CSCs have been isolated from PCa patients, it remains unclear whether the CSC population is derived from normal prostate stem cells, or if normal mature cells later acquire SC characteristics during the malignant process.
“It is also not known if the isolated basal CSC population constitute or only contain a subpopulation of CSCs, or if also a luminal CSC population can be found in prostate cancer patients,” explained Ceder. Thus, Ceder and his team will be examining if potential SC and so-called ‘niche molecules’ can inhibit human prostate CSC self-renewal, survival, daughter cell proliferation or if it modulates cell differentiation.
“Many questions remain unresolved. It is therefore crucial to better identify and characterise normal prostate SCs and CSCs, and explore the mechanisms of cancer growth and progression,” according to Ceder, adding that with scarce SC markers and experimental assays for functional studies, researchers faced difficulty in probing the CSC theory.
“We also aim to investigate downstream mechanisms and potential biomarkers in responders,” Ceder said as he noted that the study’s findings may help in the prognosis of PCa and in the development of new treatment strategies and the selection of eligible patients.
Among the team’s main objectives are to identify and characterise normal murine candidate SCs, to perform functional in vitro assays and in vivo cell lineage tracing of candidate murine SCs, and to identify and characterise human CSCs and biomarkers.
Using animal (mouse) models, Ceder said the prostate label-retaining SC project will be completed by year 2 (2014), but since the team also collected cells from other organs, they will also work on murine candidate SCs for other urological organs.
The team, which originally planned for mouse prostate, have also expanded its agenda to include human samples of developing prostate.“We intend to investigate if nestin (a neuroepithelial SC marker) is expressed at these early stage, and the manuscript will be completed in year 2,” said Ceder.
Regarding characterising human CSCs and biomarkers, Ceder said the team can now reliably detect c-kit and cytokeratin-7 expression in formalin-fixed routine material obtained from Lund University.
The team has also participated in international conferences, notably the 2013 Annual EAU Congress in Milan, made an oral presentation during the Prostate Cancer Translational Research in Europe meeting held in June last year and in the 21st ESUR Meeting held in collaboration with the German group DGU last September.
Ceder and his colleagues also published last year in the British Journal of Cancer its report titled “miR-205 negatively regulates the androgen receptor and is associated with adverse outcome of prostate cancer patients.” Another peer-reviewed article on how repressor element (RE)-1 silencing transcription factor (REST) mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer, is still in press.
He reiterated that with the research team’s goal they generated new data which identifies both basal and luminal epithelial SC candidates. The hope is that the team would also eventually identify new prognostic and therapeutic markers that can be used in phase 2 clinical trials involving castrate-resistant PCa patients.
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