Stem Cells as Hormone Targets That Lead to Increased Cancer Susceptibility

Abstract

Major advances during the past decade have permitted a clearer understanding of processes that regulate stem cell self-renewal and lineage commitment toward differentiated progeny that populate all tissues. Considerable evidence has also accumulated to indicate that aberrations in the stem and progenitor cell populations can lead to increased cancer risk in specific organs systems. It is long recognized that environmental factors play a major role in cancer etiology, and emerging data suggest that endocrine-disrupting chemicals (EDCs) may contribute to an increased cancer risk. Using the prostate gland as a model system, the present review highlights recent data that find that estrogens and EDCs can reprogram prostate stem and progenitor cell populations, leading to increased cancer susceptibility. We propose that stem cell programming during early development in hormone-regulated tissues may lead to heightened sensitivity to early-life EDC exposures and that aberrant stem cell reprogramming by EDCs may contribute to the developmental basis of adult cancer risk.

Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution

“…4A, S2C). Our laboratory recently identified robust ER activity in PS cells with ERβ enrichment in BrdU + retaining cells and ERα enrichment in progenitor cells (Hu et al, 2011; Prins et al, 2015). Notably, estrogen exposure enhances stem cell symmetric self-renewal and progenitor cell amplification, effects mediated in part through membrane-initiated ER signaling that includes MAPK/ERK and PI3K/AKT activation (Prins et al, 2014), together providing biologic support for GSEA enrichment of this pathway.…”

Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression

“…The basal cell layer of the prostatic epithelium harbors a small stem cell population (<1%) which is characterized by a panel of surface stem cell markers (such as CD44, α2ß1 integrin, CD133, CD117, Sca‐1, Trop2, and CD49f) and equipped with ERα and ERβ, indicating that human prostate stem cells may be direct estrogen targets . To assess the actions of estrogens on prostate stem and progenitor cells, Prins at al have isolated and enriched adult human prostate stem cells to form prostaspheres (PS). These PS containing AR negative, and ERα and ERβ positive human prostate stem cells were combined with inductive rat urogenital sinus mesenchyme and grafted under the renal capsule of adult male nude mice.…”

“…After mature glandular prostate (human) tissue was formed, treatment with elevated estradiol levels along with testosterone supplementation induced prostatic carcinogenesis in the human prostatic epithelium via HGPIN in the host mice. To test whether xenoestrogens such as bisphenol (BPA) could influence this process, host mice were orally exposed to low doses of BPA, which, in turn, increased prostate cancer development to about 35% and up to 45% when human stem cell containing prostaspheres were also exposed to BPA (reviewed by Prins et al). These elegant experimental data demonstrate that prostate cancer can be induced from human prostate stem cells exposed to estradiol, and that low doses of BPA increase the susceptibility of the human prostate epithelium to estrogen‐driven carcinogenesis .…”

“…To test whether xenoestrogens such as bisphenol (BPA) could influence this process, host mice were orally exposed to low doses of BPA, which, in turn, increased prostate cancer development to about 35% and up to 45% when human stem cell containing prostaspheres were also exposed to BPA (reviewed by Prins et al). These elegant experimental data demonstrate that prostate cancer can be induced from human prostate stem cells exposed to estradiol, and that low doses of BPA increase the susceptibility of the human prostate epithelium to estrogen‐driven carcinogenesis . It is noteworthy that BPA‐based plastic is found in a wide range of consumer products (such as water bottles, and as coatings on the inside of many food and beverage cans, and on sales receipts) and is one of highest volume of chemicals produced worldwide.…”

Effects of long-term endocrine disrupting compound exposure on Macaca mulatta embryonic stem cells

“…These chemicals are known or suspected of disrupting endocrine signaling with a myriad of downstream effects on development, reproduction, immune function, behavior, cognition, diabetes, cancer, and many other diseases and disorders in individuals and their progeny [1]. The broad spectrum of effects, particularly in progeny, reflects the abilities of EDCs to exert significant effects on nuclear programming in the stem cells that contribute to embryogenesis, organogenesis, organ homeostasis, and cancer later in life [2–6]. …”