Stem cells, estrogens and local hormone action in prostate health and disease. (#195)
Endocrinology is the study of hormones secreted by glands of the endocrine system directly into the blood, but researchers in this field were the first to discover and identify the importance of cell-cell signalling in tissues and organs. This has been a primary focus of my work over 25 years, and we have learnt how perturbations of the normal biology of cell-cell interactions in endocrine organs, causes disease. In organs that are subject to master control by systemic hormones, proving and then interrogating these local mechanisms, required nifty techniques that deconstructed and then reconstructed the cellular components. This was done with two cell types but has now extended to multiple cellular interactions. We have used tissue recombination, to study stromal-epithelial signalling, and 3D cell cultures, to mimic more accurately the structural organisation of tissues and cell polarity. As therapies require the targeting of specific cell types, there is a need to identify and show action on select sub-populations of cells (e.g. stem/progenitor cells, cancer stem cells or drug resistant cell types), increasing the difficulty and complexity of reconstructing the normal or abnormal tissue/organ. Studies using human cells and tissues are imperative for preclinical work, which increases the challenge.
The problems have been overcome with the development of sophisticated in vitro and in vivo systems to investigate regulatory mechanisms in the human prostate gland during health and disease. We have proved that estrogens (as well as androgens) promote beneficial and adverse effects in the human prostate. In healthy organs, estrogens prevent disease, acting in concert with androgens to control cell proliferation and differentiation. In disease, estrogens act in a co-ordinate way with inflammatory cells, to establish peri-tumoural regulatory loops that promote and maintain tumorigenesis. Whilst most prostatic epithelial cells are regulated by androgens, the stem/progenitor cells are estrogen responsive. Thus, estrogen-based therapies have significant potential, particularly in lethal castrate resistant prostate cancer.
With increasing usage of -omics technologies, it has emerged that local endocrine effects are key to interpreting and refining our arrays of information and ultimately, this approach will lead to the development of personalised treatments for men with prostatic disease including prostate cancer.