Prostate stem cell study examines links of luminal to cancer-initiating cells

A Sweden-based study investigating the characteristics of prostate stem cells in mouse models have identified a stem cell population in the prostate’s luminal cell layer which could later help in targetting and in the development of new therapeutics for prostate cancer (PCa) particularly those tumours which are metastatic or highly resistant to drug treatment.Dr. Jens Ceder, who is based in Lund University and Skåne University Hospital in Malmö, Sweden, presented the study's second-year results during an abstract session at the 22nd Annual Meeting of the EAU Section of Urological Research (ESUR) held over the weekend in Glasgow, UK.

The ongoing study, under the auspices of the EAU Research Foundation Career Development Programme, has completed its initial aim to identify and characterise normal murine candidate prostate stem cells. In Glasgow, Ceder’s presentation titled “Label retaining and stem cell marker expression in the developing and adult prostate identifies basal and luminal stem cell subpopulations,” described the findings of separate basal and luminal stem cell populations in the mouse prostate.

The investigators used a process called label-retention to identify the normal stem cells (SCs) in the mouse prostate gland by using a label called bromodeoxyuridine (BrdU), which is taken up by dividing cells when the prostate is formed. Later, the BrdU label is washed out in rapidly growing transit amplifying cells.

But so-called “slow-cycling” stem cells, however, will retain the label, enabling their identification as label-retaining cells, and their screening for expression of different markers. The study not only identified a candidate slow-cycling label retaining SC population in the basal cell layer, but more importantly it identified a candidate slow-cycling SC population in the luminal cell layer.

Aside from the candidate prostate SCs, the study also identified cell surface receptors and nuclear androgen receptor (AR) expression in the candidate SC populations, a finding that opens up the possibility that AR expressing luminal SCs or stem-like cells could function as cancer-initiating cells in PCa.

That finding supports current scientfic theory which suggests that tumour-intiating cells of prostate cancers originate from adult stem cells, but it has remained controversial whether luminal SC exists in addition to basal SCs.

“Our goal is for the studies to open up for the development of new therapeutics. It is beyond the scope of this study for any kind of clinical investigation at this stage,” said Ceder when asked if he is optimistic of a breakthrough outcome. “But we have indications that some of the markers we have identified will aid in future prognostics of prostate cancer, and that the pathways found downstream of these markers can be targeted, and naturally we intend to investigate this during the coming year.”

With scarce SC markers and experimental assays for functional studies, researchers still faced obstacles in investigating the cancer stem cells (CSC) theory. Ceder’s preliminary data also suggest that one of the candidate SC markers is up-regulated in advanced disease.

“We are working on identifying pathway-proteins that are up-regulated/activated in these cells in prostate cancer, and which may aid in prognosis, and perhaps also in stratifying patients for different treatment, and targets that could be drugable,” according to Ceder.

Although there are many questions that has to be resolved, the researchers have widened their goals as the study enters its second year, adding objectives such as performing in vivo cell lineage tracing of candidate murine SCs and functional assays of isolated human normal and malignant SCs, with the aim to better characterise biomarkers and regulation of human CSCs.

“But translating the results form mouse to human being is perhaps the biggest obstacle since there are differences that should not be ignored. Therefore, human samples are of utmost importance…Moreover, it is extremely important to validate the data in human material, especially so in advanced disease,” added Ceder.

EAU-RF programme

The EAU-Research Foundation Career Development Programme, which is funding the study, exerts efforts to bridge basic and translational research, and also aims to provide a platform for talented researchers to pursue innovative studies.

Aside from its direct support to novel research, the programme also hopes that its pool of researchers are ably supported in developing their career goals. The EAU-RF links up with both medical and academic institutions in identifying promising talents and research work that deserves support. Supporting Ceder’s team are their partners and collaborators at the Radboud University in the Netherlands and the University of York’s YCR Cancer Research United in the UK.