Figure 1. Androgen-Dependent and Androgen-Independent Progression of Prostate Cancer.
During androgen-dependent progression, prostate-cancer cells depend primarily on the androgen receptor for growth and survival. When the androgen receptor is inactive, it is bound to heat-shock proteins in the cytoplasm of prostate cells. The androgen dihydrotestosterone binds to the androgen receptor, dissociating it from heat-shock proteins. The dihydrotestosterone-bound androgen receptor translocates into the nucleus, dimerizes, and binds to the androgen-response elements, thereby activating genes involved in cell growth. During androgen-independent progression, prostate cancer relies on various cellular pathways, some involving the androgen receptor and others bypassing it. In the former type of pathway, a mutated androgen receptor may be activated by various ligands.
In addition, deregulated growth factors and cytokines can activate the androgen receptor, usually with the help of androgen-receptor coactivators. The androgen re-ceptor may be amplified and therefore may be activated by reduced levels of dihydrotestosterone. In the pathways that bypass the androgen receptor, the loss of PTEN reverses the inhibition of the phosphatidylinositol 3-kinase (PI3-K)–Akt pathway, permitting activated Akt to phos-phorylate Bad. This activation results in the release of Bcl-2, which eventually leads to cell survival. In addition, androgen-independent cells may overexpress Bcl-2. Prostate-cancer cells may develop neuroendocrine-like behavior. Neuroendocrine cells secrete neuropeptides that in-duce the growth of adjacent cells, and thus prostate cancer may survive therapeutic interventions.
Image reprinted with permission from the New England Journal of Medicine 351;15 October 7, 2004.