On the other hand, we recently learned from the study of Wang et al
July 2, 2021
On the other hand, we recently learned from the study of Wang et al. of the body. As development proceeds, pluripotent ESCs disappear as more restricted (multipotent) somatic stem cells, such as haematopoietic stem cells and neural stem cells, that can only give rise to cell types within a particular lineage. Although the privilege of differentiating into any of the hundreds of cell types in the human body is reserved for the ESCs, adult somatic stem cells residing within an organ or tissue nevertheless retain some characteristics of their early ESC counterparts, including the capacity to self-renew while keeping their repertoire of differentiation Tiliroside programs on hold. Deciphering the regulatory circuitry underlying stem cell pluripotency and self-renewal is an important key to understanding both normal and, in the case of cancer, abnormal development. Here, we review the recent advances that demonstrate the presence and involvement of the androgen receptor (AR) in both normal stem cells and cancer stem cells (CSCs), particularly those associated with the prostate. We will discuss how the AR fits into the molecular circuitry that maintains the pluripotent and self-renewal state. The role of the stem cell niche in regulating the AR will be analyzed, together with the clinical implications. 2. The AR as a Regulator of the Stem Cell State The AR is a ligand-inducible transcription factor that in response to androgens (namely, testosterone and 5in vitroandin vivo(Table 1). Thus, the AR may serve a currently underappreciated role in shaping the properties and defining the potential of stem cells. Table 1 The effect of androgens and/or AR expression on stem cell populations. in vitroin vitroexperiments infer that prostate stem cells reside within the basal cell layer as basal cells not only are slow cycling and express many stem cell associated genes such as telomerase, bcl-2, and p63, but also have low level of the AR [11C13]. On the other hand, we recently learned from the study of Wang et al. a small subset of luminal cells that survive castration (termed CARNs for castration-resistant Nkx3.1-expressing cells) can self-renewin vivoand regenerate a prostate in renal grafts . It is important to note that despite a luminal phenotype, the origin of CARN cells is unknown and it is possible that basal cells adapt a CARN cell phenotype in castrated mice. Despite these complexities, the overwhelming consensus is that prostate stem cells have a basal origin. For instance, prospectively purified Lin? /Sca-1+/CD49f+ basal cells can establish spheres and coloniesin vitroas well as regenerate prostate ducts in renal grafts . Notably, the expression of the AR was found to be very low in these cells. In another study, a single Lin?/Sca-1+/CD133+/CD44+/CD117+ basal cell was capable of reconstituting a prostate in the kidney capsule of recipient mice . Garraway et al. demonstrate that a small population of human prostate cells with a basal phenotype and low AR expression Tiliroside is sufficient to induce prostatic gland structuresin vivo. Finally, elegant lineage-marking experiments identified a population of AR-negative basal multipotent stem cells with the capacity to differentiate into each of the prostate epithelial lineages (basal, luminal, and neuroendocrine cells) . Thus, it can be concluded that prostate stem cells are most likely AR-negative. 3. The AR in Prostate Cancer Stem Cells There is increasingly awareness that deregulated stem cells may be the real culprit for cancer growth, dissemination, and therapy resistance [19C21]. Colloquially referred to as cancer stem cells it is not yet understood if these cells are the progeny of mutated somatic stem cells [22C25] or if they arisede novofrom reactivation of stem Tiliroside cell transcriptional networks in more differentiated cell types [26C28]. Irrespective of their origin, parallels can be drawn between Rabbit polyclonal to NF-kappaB p105-p50.NFkB-p105 a transcription factor of the nuclear factor-kappaB ( NFkB) group.Undergoes cotranslational processing by the 26S proteasome to produce a 50 kD protein. somatic stem cells and CSCs. Both types of cells self-renew, although somatic stem cells do so in a highly regulated manner while CSCs are more poorly controlled. Moreover, both types of cells differentiate; Tiliroside somatic stem cells generate normal, mature cells whereas CSCs generate phenotypically diverse nontumorigenic cancer cells . The phenotypic similarity between normal and cancer stem cells raises the possibility that CSCs are diseased stem cells and thus targeting stem cell-associated signaling nodes may represent a rational strategy to improve cancer therapy. 3.1. The Origin of Prostate Cancer Stem Cells It has been suggested that normal stem cells acquire genetic and/or epigenetic alterations to.