Androgen deprivation therapy is an effective treatment for advanced prostate cancer, however a small subset of tumour cells survive therapy and result in disease progression. Identifying whether castrate-resistant, hormone sensitive cells with stem cell features pre-exist in localised prostate cancer, provides a novel but important therapeutic target prior to the onset of progressive castrate-resistant disease.
To determine whether there are tumour cells in localised disease that can persist in the castrate environment, prostate cancer specimens from 12 men with localised disease were xenografted into host mice to establish tumours. The host mice then underwent periods of castration and androgen restoration to identify and characterise residual castrate-resistant tumour cells and their hormone responsiveness. Harvested tumour grafts were analysed by pathology, proliferation/apoptotic index and biomarker expression.
It was found that the histopathology of all 12 tumours mimicked that of the original tumours when maintained in control hosts and when host mice were castrated, these tumours regressed. Four weeks thereafter, the remaining tumour cells were growth quiescent luminal cells, expressing low AR and PSA and variable immuno-positivity for common stem cell markers including Nkx3-1, CD44 and ALDH1 and nanog. These castrate-resistant cells showed regenerative capacity when testosterone was re-administered to castrated hosts, and restoration of normal AR and PSA expression.
In conclusion these findings show common stem-like and regenerative features of castrate resistant, but hormone sensitive, tumour cells in localised prostate cancer. Future studies should aim to further characterise these cells and elucidate the common pathways which can be exploited to therapeutically target them.