Prostate cancer is increasingly prevalent in our ageing Western Society. Despite recent advances in the detection of early prostate cancer there remains little effective therapy for patients with locally advanced and/or metastatic disease. The goal of existing therapies for prostate cancer has been to eradicate the bulk of cells within a tumour. However, most patients go on to develop androgen-independent disease that remains incurable by current treatment strategies. The major unanswered question remains as to the origin of this resistance: is it the acquisition of drug resistance by the cancer cells as they evolve or is it that existing therapies fail to kill cancer stem cells effectively? Here, we show that we can distinguish the tumour-initiating from the non-tumour-initiating cells based on cell surface marker expression. We have identified and isolated the tumourigenic cells as CD44+2β1hi/CD133+ in a series of patients samples, ranging from well differentiated to metastatic disease, using magnetic cell sorting and rapid adhesion to type I collagen. Approximately 0.1% of cells express this phenotype and are clonogenic in soft agar (33% colony forming efficiency; CFE), unlike their more differentiated progeny (CD44+2β1hi/CD133; transit amplifying population; 1% CFE), CD44+2β1low/CD133; committed basal population; 0% CFE), CD57+/CD44 (secretory luminal population; 0% CFE). In the presence of stroma and androgens, spheroids generated from selected CD44+2β1hi/CD133+ cells are capable of differentiating into prostatic-like acini , depending upon the Gleason grade of the original tumour, but most importantly express markers associated with prostate differentiation, namely androgen receptor, prostatic acid phosphatase and prostate specific antigen expression. Injection of as few as 500 CD44+2β1hi/CD133+ cells directly into the prostates of NOD/SCID mice was sufficient to form multiple tumours in 5/5 mice injected, whereas tumours were only detected after injection of the unselected population when greater than 5x105 cells were injected (5/5 mice formed tumours, but multiple tumours were not observed). Tumours formed in 2/5 mice grafted with CD44+2β1low/CD133 cells , but only if sufficeint cells were grafted (5 x 105 cells). However, multiple tumours were not detected. Tumours were not detected from mice grafted with 5 x 105 CD57+/CD44 cells. In summary, the selected cancer cells displayed stem cell-like properties, in that they were capable of generating new clones containing additional stem cells, as well as regenerating phenotypically mixed populations of non-clonogenic cells present in the original tumours.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]