Actions of estrogens and endocrine disrupting chemicals on human prostate stem/progenitor cells and prostate cancer risk

Abstract

Estrogen reprogramming of the prostate gland as a function of developmental exposures (aka developmental estrogenization) results in permanent alterations in structure and gene expression that lead to an increased incidence of prostatic lesions with aging. Endocrine disrupting chemicals (EDCs) with estrogenic activity have been similarly linked to an increased prostate cancer risk. Since it has been suggested that stem cells and cancer stem cells are potential targets of cancer initiation and disease management, it is highly possible that estrogens and EDCs influence the development and progression of prostate cancer through reprogramming and transforming the prostate stem and early stage progenitor cells. In this article, we review recent literature highlighting the effects of estrogens and EDCs on prostate cancer risk and discuss recent advances in prostate stem/progenitor cell research. Our laboratory has recently developed a novel prostasphere model using normal human prostate stem/progenitor cells and established that these cells express estrogen receptors (ERs) and are direct targets of estrogen action. Further, using a chimeric in vivo prostate model derived from these normal human prostate progenitor cells, we demonstrated for the first time that estrogens initiate and promote prostatic carcinogenesis in an androgen-supported environment. We herein discuss these findings and highlight new evidence using our in vitro human prostasphere assay for perturbations in human prostate stem cell self-renewal and differentiation by natural steroids as well as EDCs. These findings support the hypothesis that tissue stem cells may be direct EDC targets which may underlie life-long reprogramming as a consequence of developmental and/or transient adult exposures.

Introduction

Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer deaths in North American men (Jemal et al., 2010). It is known that steroids play a role in the initiation and progression of prostate cancer, which is the basis for hormonal treatment strategies that include androgen ablation and androgen receptor (AR) blockade (Eisenberger et al., 1998, Huggins and Hodges, 1941). Increasing evidence indicates that in addition to androgens, estrogens play key roles in prostate carcinogenesis and progression, although the mechanisms are not fully understood (Ellem and Risbridger, 2007, Hu et al., 2011, Leung et al., 2010, Nelles et al., 2011, Prins et al., 2007, Prins and Korach, 2008). In men, chronically elevated estrogens have been associated with increased risk of prostate cancer (Modugno et al., 2001) while in rodents, estrogens in combination with androgens induce prostate cancer (Bosland, 1996). It is recognized that age, race, genetics (family history), diet, and environmental factors can impact prostate cancer risk (Reuben et al., 2010). Endocrine disrupting chemicals (EDCs) are a class of environmental toxicants that interfere with endocrine signaling pathways. In addition to direct effects in adults, strong evidence indicates that developing tissues are particularly sensitive to EDCs and that early-life EDC exposures promote specific disorders in adults (Foran et al., 2002, Heindel, 2005), a phenomenon referred to as the developmental basis of adult disease.

Recent advances in stem cell research indicate that stem cells and early stage progenitor cells may be direct carcinogenic targets and the cells of origin in cancer initiation and progression. Together with our previous findings in animal models which show that early-life exposures to natural and environmental estrogens increase susceptibility to prostate carcinogenesis through structural and epigenomic reorganization (Ho et al., 2006, Prins, 1992, Prins and Birch, 1997, Prins et al., 1993, Prins, 1997, Prins et al., 2008, Prins et al., 2011, Prins and Ho, 2010), we hypothesize that developmental reprogramming of the prostate gland by EDCs may involve epigenomic alterations in prostate stem/progenitor cells during early gland formation, thus predisposing to prostate cancer upon aging. At present, there is a critical need to determine whether early life estrogenic reprogramming of prostate cells similarly occurs in humans. To meet this current need, we have recently developed novel in vitro and in vivo models using stem and early stage progenitor cells isolated from normal human prostates and used these to initiate hormonal carcinogenesis (Hu et al., 2011). Importantly, these in vitro prostasphere and in vivo chimeric prostate models with carcinogenic induction can serve as suitable models for examining stem cell perturbations and carcinogenic actions of EDCs on human prostate cells. In the current review, we will briefly assess available evidence for EDCs and increased prostate cancer risks, discuss recent advances in prostate stem cell research, and present evidence for reprogramming of human prostate stem/progenitor cells by estrogens and EDCs using our novel human prostasphere and chimeric prostate models.