Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault.

Abstract

The acquisition of an androgen-independent phenotype by prostate cancer cells is presently a death sentence for patients. In order to have a realistic chance of changing this outcome, an understanding of what drives the progression to androgen independence is critical. We review here a working hypothesis based on the position that the development of androgen-independent epithelial cells is the result of a series of cellular and molecular events within the whole tissue that culminates in the loss of normal tissue-maintained growth control. This tissue includes the epithelial and stromal cells, the supporting extracellular matrix and circulating hormones. This review discusses the characteristics of these malignant cells, the role of stromal cells involved in growth and the differentiation of epithelial cells, and the role of the extracellular matrix as a mediator of the phenotypes of stromal and epithelial cells. In addition, environmental, neuroendocrine and immune factors that may contribute to disturbance of the fine balance of the epithelial-stromal-extracellular matrix connection are considered. While the goal of many therapeutic approaches to prostate cancer has been androgen ablation or targeting the androgen receptor (AR) of epithelial cells, these therapies become ineffective as the cells progress beyond dependence on androgen for growth control. Twenty years ago Sir David Smithers debated that cancer is the result of loss of tolerance within tissues and the organizational failure of normal growth-control mechanisms. This is precipitated by prolonged or abnormal demands for regeneration or repair, rather than of any inherent disorder peculiar to each of the individual components involved. He wrote 'It is not the cell itself that is disorderly, but its relationship with the rest of the tissue'. We have gained significantly large amounts of precise data on the effects of androgenic ablation on cancerous prostate cells and on the role of the AR in prostate cancer. The need has come to compile this information towards a perspective of dysregulation of tissue as a whole, and to develop experimental systems to address this broader perspective to find and develop therapies for treatment and prevention.

A role for the androgen-receptor in clinically localized and advanced prostate cancer

“…[20] These clinical observations were supported by preclinical data using the Cunha model, [26,27] where tumor stroma supported carcinogenesis of the overlying epithelium. Furthermore, Rowley [28] and Arnold and Isaacs [29] reviewed the data that supported the hypothesis that stroma produces a reciprocal inhibition of epithelia and that the suppressive effect of the stroma is lost in CaP and contributes to CaP progression. AR immunostaining in stroma was more carefully evaluated by Olapade-Olaopa et al [30] using a monoclonal AR antibody and archival TURP and radical prostatectomy specimens from 17 patients with BPH and 39 age-matched patients with CaP.…”

Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation

“…Androgen ablation in rats by castration leads to decreased proliferation and increased apoptosis of prostate luminal epithelial cells, resulting in the regression of the prostate gland (reviewed by Isaacs, 1999). When physiological levels of androgens are replaced in a castrated rat, prostate epithelial (PrEC) cell proliferation is increased and apoptosis is decreased, leading to reconstitution of a normal prostate (Arnold and Isaacs, 2002). All the data accumulated thus far strongly suggest that androgens, through the activity of AR, regulate the rate of cellular proliferation while inhibiting the rate of cell death in the prostate (Isaacs, 1984(Isaacs, , 1994.…”

c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation

“…In normal prostate development, androgen signaling plays mainly a differentiative role, whereas in prostate cancer the role switches to a proproliferative one (reviewed in Jenster, 1999). This molecular switch makes the growth of prostate cancer cells dependent on androgens and AR (reviewed in Jenster, 1999;Arnold and Isaacs, 2002). Indeed, there is increasing evidence that not only prostate cancer initiation but also its progression to the lethal androgen-independent and metastatic form are all dependent on androgens and AR (Isaacs, 1999;Arnold and Isaacs, 2002).…”

“…This molecular switch makes the growth of prostate cancer cells dependent on androgens and AR (reviewed in Jenster, 1999;Arnold and Isaacs, 2002). Indeed, there is increasing evidence that not only prostate cancer initiation but also its progression to the lethal androgen-independent and metastatic form are all dependent on androgens and AR (Isaacs, 1999;Arnold and Isaacs, 2002). It was recently reported that AR overexpression converts prostate cancer from androgen-sensitive to androgen-insensitive (Chen et al, 2005).…”