Accumulating evidence suggests that cancer stem/progenitor cells (CSCs) are involved in tumour relapse and therapy resistance in urothelial carcinoma. These cells seem less affected by anti-proliferative therapies (e.g. chemotherapy), since they are largely quiescent, have an increased DNA-damage response, reside in difficult-to-reach, protective cancer stem cell-niches and express ABC-transporters, which can efflux drugs from the cells. Identifying the cell(s) of origin in bladder cancer and its distant metastases may permit the development of more effective treatment and preventive therapies. In this study, aldehyde dehydrogenase (ALDH) activity was used to isolate and compare ALDHhigh and ALDHlow subpopulations of human bladder cancer cells. ALDHhigh cells display strongly elevated clonogenic and migratory potential when compared with the more differentiated ALDHlow subpopulation. Moreover, ALDHhigh cells were capable of self-renewal, whereas the ALDHlow population was not, as determined with a sphere assay. In line with these data, the mRNA expression levels of several bladder CSC markers including NANOG and KRT14 were significantly increased in the ALDHhigh cells. Besides the observed effects in vitro, ALDHhigh cells displayed strongly enhanced tumour take and readily formed skeletal metastases in vivo while ALDHlow do not. In conclusion, our findings suggest that ALDH-based viable cell sorting can be used to identify and characterise tumour-initiating and bone metastasis-initiating cells in human bladder cancer.
Disclosure: The authors declared no competing interests. This work is supported by a grant from the Dutch Cancer Society UL 2011-4930. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.