Prostate cancer is a particularly heterogeneous tumour, both in appearance and behaviour, resulting in uncertainty about the diagnosis of prostate cancer, but also in determining the prognosis and decisions about treatment.

Many non-surgical prostate cancer therapies are directed against the response to male sex hormones via the androgen-receptor axis, which is active in most cells in >80% of prostate cancer. Any residual cells which do not express androgen receptors survive to form the basis for new androgen-independent tumours. This regime has changed little since the pioneering castration studies of Charles Huggins in the 1940’s. The introduction of PSA screening in the early 1990’s simply served to identify the targets for these therapies at an earlier stage. New diagnostic tools such as blood tests for PCA3 and serum proteomics simply serve to increase the frequency and certainty of prostate cancer diagnosis. While earlier intervention is potentially curative, the presence of extra-prostatic disease indicates an extremely poor prognosis. New paradigms in the treatments of advanced, extraprostatic cancer have centred on novel combinations of conventional therapies and the introduction of microtubule disruptors. Even effective combination therapies, e.g. those recently introduced with Docetaxel, are not guaranteed to improve survival by much more than 20%. Equally, in a relatively slow-growing tumour such as prostate cancer, cells that are not in the cell cycle are often inherently resistant to chemotherapy and radiotherapy which targets replicating cells. It is likely that the most slowly cycling cells of all are the cancer stem cells.

While these practical considerations pose a problem for the urologist and oncologist, heterogeneity also has a distinct role in the origins of the tumour. For example, there are two proposed genetic origins for cancers. The stochastic model predicts that every cell within a tumour is identical and can give rise to new primary tumours. This mechanism forms the basis of most conventional tumour therapies. By contrast, the hierarchical or stem cell model predicts that only a rare subset of cells is tumorigenic. Thus the tumour is heterogeneous in appearance, consisting of both less- and more-differentiated cell types. The degree of heterogeneity depends on the differentiating influences within the tumour mass. According to this mechanism, most tumour cells are unable to initiate tumours.

The tumour stem cell hypothesis is not new. As most tumour types are heterogeneous, comprising cells with different phenotypes and different proliferative and malignant potentials, e.g. in both leukaemia and solid cancers, it was presumed that a small subset of cells was clonogenic in culture and in vivo. This led to the hypothesis that only a rare, phenotypically distinct subset of cells had the capacity to form new tumours, the cancer stem cells. The challenge was to prospectively identify, purify and characterise these unique cells.

Cancer stem cells therefore represent a valuable target for new therapies, since evidence suggests that these cells both maintain and progress the development of tumours, whilst also presenting greater challenge to drug therapy. The fundamental problems for scientists and the drug development industry to date is that the importance of stem cells in the progression of cancer has not, until recently, been understood or properly evaluated. The work of the YCR Cancer Research Unit has resulted in pioneering advances in this field, which it is believed open up valuable new opportunities in cancer therapy for Pro-Cure to exploit.