Mechanisms of the development of androgen independence in prostate cancer.

The effectiveness of androgen ablation in the management of advanced prostate cancer is of limited duration, with the median length of response being only 18-24 months. The transition of the prostate cancer cell to an androgen independent phenotype is a complex process that involves selection and outgrowth of pre-existing clones of androgen-independent cells (clonal selection) as well as adaptive up-regulation of genes that help the cancer cells survive and grow after androgen ablation (adaptation). These two mechanisms share an important pre-requisite characteristic: prostate cancers are heterogeneous tumours comprised of various subpopulations of cells that respond differently to androgen withdrawal therapy. This tumour heterogeneity may reflect either a multifocal origin, adaptation to environmental stimuli, and/or genetic instability of the initial cancer. This review will reexamine the different mechanisms that enable prostate cancer cells to proliferate in an androgen depleted environment.