Controversies Surrounding Androgen Deprivation for Prostate Cancer

Stephen G. Patterson, MD, Lodovico Balducci, MD, Julio M. Pow-Sang, MD


Cancer Control. 2002;9(4) 

In This Article

Biological Basis of Androgen Independence

Genetic mutations play an important role in the development of androgen-independent prostate cancer (AIPC).[2] Several investigators have offered evidence that androgen ablation provides selective pressure on the androgen signaling pathway for mutation development.[3,4,5,6] Five AIPC mechanisms have been described.[1] The first three mechanisms (hypersensitive, promiscuous, and outlaw pathways) require the presence of the androgen receptor (AR) and its signaling cascade, the fourth mechanism involves the development of a parallel pathway, and the fifth mechanism involves a separate population of cells.

The "hypersensitive" pathway describes increased sensitivity of the AR to very low serum levels of androgen. Three mechanisms may be involved in the hypersensitive pathway: (1) AR amplification, where prostate cancer cells increase the expression of AR,[7,8] (2) increased AR sensitivity, where tumor cells are hypersensitive to the growth promoting effects of dihydrotestosterone (DHT) (investigators reported the concentration of DHT required for growth stimulation was 4 orders of magnitude lower than that required for androgen-dependent prostate cancers),[9] and (3) increased 5-alpha-reductase activity, where enhanced enzyme increases the conversion of testosterone to DHT. AR signaling would continue even in the presence of dramatically reduced serum testosterone.[10]

The "promiscuous" pathway involves acquisition of mutations in the AR protein ultimately proceeding to activation of the androgen-signaling axis with ligands other than testosterone.[11] In vitro work with the LNCaP model has examined the development of mutations in AR.[12] Molecular analysis and experimentation have shown that hormone ligands such as progestins, estrogens, and antiandrogens bind to mutant AR and function as agonists.[12] The promiscuous pathway may help to explain the clinical observation of the "flutamide withdrawal" syndrome, where patients progressing on therapy improve after flutamide is stopped.[13]

The outlaw pathway provides a mechanism where steroid hormone receptors are activated by mechanisms independent of hormonal ligand.[14] Three growth factors -- insulin-like growth factor (IGF-1), keratinocyte growth factor (KGF), and epidermal growth factor (EGF) -- have been shown to activate receptor tyrosine kinases (RTKs).[7] After the RTKs are activated, the AR is phosphorylated by either protein kinase B (AKT) or mitogen-activated protein kinase (MAPK), resulting in a ligand-independent AR.[1] HER-2/neu, a member of the EGF-receptor family of RTKs, deserves special mention. In breast cancer, estrogen independence correlates with HER-2/neu overexpression.[15] It is theorized that HER-2/neu activation indirectly leads to phosphorylation and activation of the estrogen receptor (ER) in the absence of estrogen.[16] Phosphorylation creates an "outlaw ER" in breast cancer cells.[16] Similarly, overexpression of HER-2/neu can activate AR-dependent genes in the absence of AR ligand.[17,18]

Selective pressure during therapy could upregulate a theorized parallel pathway to provide a substitute survival signal. An effective bypass would facilitate proliferation and inhibit apoptosis.[1] The bcl-2 gene is a bypass candidate that can block apoptosis. Bcl-2 is not expressed in the normal, noncancerous prostate cells,[19] but it is present in AIPC.[20]

Finally, Isaacs[21] proposed the existence of a subpopulation of androgen-independent tumor cells that are present prior to initial therapy. Epithelial stem cells in the prostate are believed to be androgen independent and their rates of proliferation and death are not affected by androgen ablation.[22] Theoretically, the androgen-independent stem cells are thought to be "lurking" in the background until after androgen ablation has eliminated all of the androgen-dependent cells. The malignant epithelial stem cells would then be left to proliferate.[1]


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