Stromal Cell Regulation of the Prostate Epithelial Stem Cell Niche
thesisposted on 17.02.2017, 00:00 by Timothy Gauntner
The molecular mechanisms underlying developmental morphogenesis have long been suspected to also play important roles in cancer. Stem cells, being fundamental to both of these processes, can be the cells-of-origin in those cancers whose pathogeneses involve subversion of developmental signaling pathways. Therefore, cells and signaling pathways that regulate stem cells during development are likely to also play a role in carcinogenesis. The prostate stroma is essential for normal androgenic development of the prostate gland, including epithelial growth and differentiation. Thus, it stands to reason that key aspects of stromal regulation of epithelial development are mediated through control of the epithelial stem cells, but this has yet to be proven. Given the compelling evidence that stem cells are preferential cells-of-origin in many cancers, it is essential that the regulatory mechanisms governing normal prostate stem cell homeostasis are elucidated so that this knowledge can be exploited towards development of novel treatments for prostate cancer growth regulation. Recent evidence from our laboratory suggests that estrogens are key modulators of prostate epithelial stem and progenitor cells. Furthermore, it has been shown by our laboratory and others that estrogens can act as carcinogens in rodent and human models of prostate cancer. When these two facts are considered along with the well-documented role of estrogen receptor signaling in prostate stromal cells, an intriguing model emerges whereby aberrant stromal estrogenic control of epithelial stem cells may contribute to prostate carcinogenesis. To test the hypothesis that prostate stromal cells secrete paracrine factors that regulate epithelial stem and progenitor cells in both normal and cancer niches, and that 17β-estradiol modulates the secretion of these factors, the following specific aims were proposed for this thesis work: 1. Elucidate how stromal cells modulate prostate stem and progenitor cell homeostasis within the normal adult human stem cell niche. 2. Determine how estrogen signaling modulates the stromal-epithelial signaling axis within the normal adult human stem cell niche. 3. Delineate the role of stromal cells in the prostate cancer stem cell niche. This work was performed using patient- and donor-derived primary cells in order to maximize the translational relevance of this work, while at the same time reducing artifacts often introduced by monoclonal, immortalized cell lines.