Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault - PubMed (original) (raw)

Review

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

J T Arnold et al. Endocr Relat Cancer. 2002 Mar.

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.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Stem cell model for the organization of the prostate epithelium. The prostate epithelial compartment is organized in a hierarchy of expanding stem cell units. There are a limited number of androgen-independent basal stem cells that, in dividing, create new basal stem cells as well as giving rise to a larger subset of androgen-sensitive amplifying basal cells. In the absence of androgen (as in the castrated prostate) the amplifying cells are in a steady-state with the rate of proliferation equal to the rate of cell death. If androgen is present, the majority of these androgen-sensitive amplifying cells differentiate into androgen-dependent transit glandular epithelial cells. Once the normal number of these androgen-dependent glandular cells is reached, the cell proliferation rate balances the cell death rate such that neither prostatic regression nor continuous glandular overgrowth occurs. Because of the clonally expansive nature of this hierarchical stem cell organization, the vast majority of the epithelial compartment is composed of androgen-dependent glandular cells, with lower numbers of androgen-sensitive basal cells and a limited number of androgen-independent basal stem cells.

Figure 2

Figure 2

Representation of inter-relationships within the prostatic microenvironment. The interplay between epithelial cells, stromal cells, ECM, steroid hormones, oxidative damage and carcinogens contribute to the homeostasis of tissue function (a). Dysequilibrium within the tissue results from initial insults even within one component (b) and causes minor imbalance of regulation (arrows) between the rest of components. Additional insults (c and d) in the same or additional components lead to increasingly chaotic state with loss of regulation of growth and function within the tissue.

Similar articles

Cited by

References

    1. Arnold JT, Kaufman DG, Seppälä M, Lessey BA. Endometrial stromal cells regulate epithelial cell growth in vitro: a new co-culture model. Human Reproduction. 2001;16:836–845. - PubMed
    1. Arnold JT, Lessey BA, Seppälä M, Kaufman DG. Effect of normal endometrial stroma on growth and differentiation in Ishikawa endometrial adenocarcinoma cells. Cancer Research. 2002;62:79–88. - PubMed
    1. Bayne CW, Ross M, Donnelly F, Chapman K, Buck C, Bollina P, Habib FK. Selective interactions between prostate fibroblast and epithelial cells in co-culture maintain the BPH phenotype. Urologia Internationalis. 1998;61:1–7. - PubMed
    1. Bigsby RM. Reciprocal tissue interactions in morphogenesis and hormonal responsiveness of the female reproductive tract. In: Lavia L, editor. Cellular Signals Controlling Uterine Function. New York: Plenum Press; 1989. pp. 11–29.
    1. Bissell MJ, Hall HG. Form and function in the mammary gland: the role of extracellular matrix. In: Neville MC, Daniel CW, editors. The Mammary Gland. New York: Plenum Publishing Corporation; 1987. pp. 97–146.

Publication types

MeSH terms

Substances

LinkOut - more resources