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Mechanisms of Androgen-Refractory Prostate Cancer
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     Prostate cancer is the second-leading cause of cancer-related death among men and the seventh most common cause of death in the United States overall. Most prostate cancers are androgen-dependent, meaning that they respond to androgen-ablation therapy. However, these tumors eventually become androgen-independent and grow despite androgen ablation. When prostate cancer is localized in the prostate, the treatment of choice is prostatectomy or irradiation. However, when the tumor relapses or is already metastatic at diagnosis, therapy is problematic. Androgen ablation has been the main option for unconfined disease for more than 50 years, since Clarence V. Hodges and Charles B. Huggins reported that prostate cancer depends on androgens for growth, a discovery that led to a Nobel Prize for Huggins. Despite this treatment, most tumors eventually become refractory to androgen ablation. At that point, the options are limited to treatments such as bisphosphonates, mitoxantrone, and steroids. These therapies are palliative and do not increase survival. In this issue of the Journal, Tannock et al. (pages 1502–1512) and Petrylak et al. (pages 1513–1520) report studies of the first treatments that can increase the survival of patients with androgen-refractory prostate cancer.

    During the development of the normal prostate and of prostate cancer, cell survival depends primarily on the androgen receptor. This steroid receptor is bound to heat-shock proteins in the cytoplasm of prostate cells. The active androgen dihydrotestosterone, formed from the testicular androgen testosterone, binds to the androgen receptor, thereby dissociating it from heat-shock proteins and allowing it to be translocated into the nucleus. In the nucleus, the androgen receptor dimerizes, binds to androgen-response elements in DNA, and activates the transcription of genes involved in the growth and survival of the cell.

    Since androgens are essential to the survival of prostate cells, a major question is how a prostate cell survives after androgen-ablation therapy. Recent findings from a number of investigators suggest that the androgen receptor plays a critical role in the development of androgen-refractory prostate cancer. Indeed, a recent study showed that the androgen-receptor gene is the only gene that is consistently up-regulated during tumor progression in different experimental models of androgen-refractory prostate cancer.1 We can now divide the mechanisms of the development of androgen-refractory prostate cancer into two pathways — those involving the androgen receptor and those that bypass the receptor (see Figure). These pathways are not mutually exclusive and frequently coexist in androgen-refractory prostate cancer.

    Figure. 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 receptor 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 phosphorylate 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 induce the growth of adjacent cells, and thus prostate cancer may survive therapeutic interventions.

    The pathways involving androgen-receptor–mediated survival of prostate-cancer cells include amplification or mutations of the receptor, deregulation of growth factors or cytokines, and alteration of coactivators.2 In about a third of patients with androgen-refractory prostate cancer, there is an amplification of the androgen-receptor gene, which is not present when the tumors are hormone-dependent. This amplification leads to an increase in the expression of the androgen receptor and enhanced activation of the receptor by low levels of androgens. However, patients with androgen-refractory prostate cancer and amplification of the androgen-receptor gene survive longer than patients without amplification of this gene.

    Androgen-refractory tumors may contain mutations in the androgen-receptor gene. These mutations increase the number of ligands that can activate the receptor. Thus, a receptor that is normally activated specifically by dihydrotestosterone can, if mutated, respond to other steroids as well as to antiandrogens. Although this effect has been studied extensively, the frequency of cases of androgen-refractory prostate cancer in which there is a mutant androgen-receptor gene is low. A third pathway that involves the androgen receptor relies on alterations in growth factors such as insulin-like growth factor I and cytokines such as interleukin-6, which activate the receptor. These pathways frequently involve an alteration of the function or expression of the androgen-receptor coactivators that facilitate such "promiscuous" activation of the receptor. Several of these growth factors and coactivators are overexpressed in androgen-refractory prostate cancer.

    Androgen-refractory prostate-cancer cells may also use survival pathways that completely bypass the androgen receptor.3 One important pathway is related to the neuroendocrine differentiation of prostate-cancer cells. Neuroendocrine cells are more prevalent in androgen-refractory prostate cancer than in androgen-dependent disease. The low rate of proliferation of neuroendocrine cells allows them to survive treatment with most chemotherapeutic agents, as well as endocrine and radiation treatments. Meanwhile, neuroendocrine cells secrete neuropeptides such as serotonin and bombesin, which can increase the proliferation of neighboring cancer cells, thereby allowing progression of androgen-refractory prostate cancer. Neuroendocrine cells are present in 40 percent to 100 percent of patients with androgen-refractory prostate cancer, depending on the study.

    One of the most important pathways that bypasses the androgen receptor involves the deregulation of apoptotic genes. In this regard, the tumor-suppressor gene PTEN (for phosphatase and tensin homologue) and the antiapoptotic gene Bcl-2 play important roles in androgen-refractory prostate cancer. In normal cells, PTEN inhibits the phosphatidylinositol 3-kinase pathway. Activation of this pathway stimulates a protein called Akt, which inactivates several proapoptotic proteins, thus enhancing cell survival. In the normal prostate, PTEN allows cells to undergo apoptosis, whereas in cancer cells (including androgen-refractory prostate-cancer cells), the loss of PTEN increases Akt activity and blocks apoptosis. Loss of PTEN function is a common event in a number of cancers, and although relatively infrequent in androgen-dependent prostate cancer, the inactivation of PTEN is considerably more likely to occur in androgen-refractory prostate cancer.

    One of the primary targets of Akt, when it is blocking apoptosis, is Bcl-2. Activated Akt frees Bcl-2 (which is bound to a protein called Bad), allowing it to increase cell survival. Overexpression of Bcl-2 has been implicated in the progression to androgen-refractory prostate cancer. Moreover, several studies show that forced expression of Bcl-2 protects cells from apoptosis induced by androgen withdrawal.

    Petrylak et al. and Tannock et al. investigated the use of docetaxel as a therapy for androgen-refractory prostate cancer. Docetaxel is a taxoid that inhibits the depolymerization of microtubules. Polymerized microtubules cannot disassemble — a condition that leads to the disruption of the normal mitotic process and ultimately to apoptosis. However, docetaxel also induces apoptosis by inhibiting Bcl-2. Docetaxel phosphorylates Bcl-2 at serine residues, which inactivates this protein and leads to the activation of the caspase cascade and apoptosis. But docetaxel also inhibits the growth of Bcl-2–negative tumors and is believed to do so by inducing overexpression of the cell-cycle inhibitor p27. It should be noted that p27 is frequently lost in androgen-refractory prostate cancer.

    Despite the latest advances in research on prostate cancer, the mechanisms by which a prostate-cancer cell survives after androgen-ablation therapy are still not entirely understood. Nonetheless, the search for therapies aimed at decreasing the likelihood of survival of prostate-cancer cells is beginning to pay off. In the near future, as more cell-survival pathways are defined, the specific targeting of genes involved in such pathways may further increase the chances of survival for patients with androgen-refractory prostate cancer.

    Dr. Tindall reports having received lecture fees from GlaxoSmithKline and holding a patent for a method of detecting micrometastatic prostate cancer.

    Source Information

    From the Departments of Urology and Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minn.

    References

    Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10:33-39.

    Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer 2001;1:34-35.

    Grossman ME, Huang H, Tindall DJ. Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst 2001;93:1687-1697.(Jose D. Debes, M.D., and )