Concise Review: Androgen Receptor Differential Roles in Stem/Progenitor Cells Including Prostate, Embryonic, Stromal, and Hematopoietic Lineages

Abstract

Stem/progenitor (S/P) cells are special types of cells that have the ability to generate tissues throughout their entire lifetime and play key roles in the developmental process. Androgen and the androgen receptor (AR) signals are the critical determinants in male gender development, suggesting that androgen and AR signals might modulate the behavior of S/P cells. In this review, we summarize the AR effects on the behavior of S/P cells, including self-renewal, proliferation, apoptosis, and differentiation in normal S/P cells, as well as proliferation, invasion, and self-renewal in prostate cancer S/P cells. AR plays a protective role in the oxidative stress-induced apoptosis in embryonic stem cells. AR inhibits the self-renewal of embryonic stem cells, bone marrow stromal cells, and prostate S/P cells, but promotes their differentiation except for adipogenesis. However, AR promotes the proliferation of hematopoietic S/P cells and stimulates hematopoietic lineage differentiation. In prostate cancer S/P cells, AR suppresses their self-renewal, metastasis, and invasion. Together, AR differentially influences the characteristics of normal S/P cells and prostate cancer S/P cells, and targeting AR might improve S/P cell transplantation therapy, especially in embryonic stem cells and bone marrow stromal cells.

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

“…Surprisingly, knockdown of SOCS3 also reduced the induction of the stemness genes. This paradoxical effect could be explained by the increased androgen receptor activity upon knockdown of SOCS3, which is known to induce differentiation and suppress self-renewal (19). On the basis of these findings, we speculate that patients with SOCS3 promoter hypermethylation undergoing anti-androgen therapy could benefit from combinatorial treatment with DNA methyltransferase inhibitors, such as azacitidine and decitabine, clinically approved drugs for treatment of myelodysplastic syndromes and acute myeloid leukemia (49).…”

“…Thus, the IL6/JAK/STAT3 and AR signaling pathways, which are investigated in this study, are linked to prostate cancer progression and the development of castration resistance. In addition, several groups have demonstrated that activation of the IL6/JAK/STAT3 pathway is required for maintenance of stem cell properties in human malignancies (5,(16)(17)(18), whereas androgen receptor activity is known to induce differentiation and suppress self-renewal and proliferation of prostate cancer cells (19).…”

Sexual dimorphism in cancer

“…The role of ERα signaling in breast cancer initiating cells is an area of active investigation 39,40 , and so is that of AR in prostate cancer 41,42 . By contrast, the role that these pathways play in self-renewal of initiating cancer cells of other types is a mostly unexplored topic and important area of future investigation.…”

Effect of testosterone and hypoxia on the expansion of umbilical cord blood CD34+ cells in vitro

“…These effects may be reduced or counter-balanced by increasing erythropoietin (EPO) levels (43) and one acknowledged mechanism involved in the hematological effects of androgens is the promotion of erythroid progenitor expansion by increasing EPO levels (44). Furthermore, androgen and androgen receptor signals may promote the proliferation of HSCs/HPCs and stimulate hematopoietic lineage differentiation (45). Another potential mechanism may be that the addition of testosterone may enhance the G1-S transition rate in the cell cycle and the survival of HSCs (32).…”

“…The control groups were treated without hormones and at the same oxygen concentration as other groups. The concentrations of these hormones were determined as previously described (18)(19)(20)(21)(22)(23). Cells were incubated in an atmosphere containing 20% O 2 (normoxic conditions) using a Heal Force Tris-gas incubator (HF240; Heal Force Bio-meditech Holdings Limited, Shanghai, China) or 1% O 2 (hypoxic conditions; HF100; Heal Force Bio-meditech Holdings Limited) containing 5% CO 2 at 37˚C.…”