Understanding a little about the prostate gland and its biology is not only interesting, but it allows us to ask some important questions that can positively inform our treatment decisions and eventually the outcomes. On the other hand, it also can add to the confusion we all face in making the best clinical decisions.

Like other organs in the human body the prostate is composed of many different types of cells as well as extracellular components. The normal prostate gland is composed of a series of repeating cellular units that contain both stromal and epithelial compartments. During prostate development, cellular interactions between the stromal cells and the prostate epithelial cells ultimately lead to the development of a mature prostate gland.

The epithelial compartment contains luminal epithelial cells, basal cells and a minor component of neuroendocrine cells. Their function is believed to be to regulate the growth, differentiation and secretory function of the prostate gland.

We also know that neuroendocrine cells are present in the cellular mix which is present in many prostate cancers.   Numerous studies showed that the number of neuroendocrine cells increases in high grade and high stage tumors. This is especially true in hormonally treated and hormone-refractory (castrate resistant) prostate cancer.

Hormone therapy (ADT) reduces the secretion of the androgens from the prostate stromal cells that are critical for the survival for prostate epithelial cells. There is also evidence that the androgen receptor is also required for the tumor-genesis of human prostate cancer, so androgen deprivation therapy (ADT) likely works through the inhibition of the androgen receptor in the prostate epithelium. The catch is that neuroendocrine cells lack the androgen receptor and so are likely to be androgen-independent from their inception.

Therefore, it is likely that hormonal therapy for advanced/metastatic prostate cancer, which consists of inhibiting androgen production and/or blocking androgen receptor function, will not affect the neuroendocrine cancer cells which will continue to grow and spread despite the hormonal therapy.

The paradox is that these neuroendocrine cells may become enriched after ADT and may establish networks to stimulate the androgen-independent proliferation of prostate cancer, leading to tumor recurrence and continued growth despite the therapy.

Am J Transl Res. 2009; 1(2): 148–162.

Published online 2009 Feb 5.

PMCID: PMC2776313


Neuroendocrine differentiation in prostate cancer