Actions of Estrogenic Endocrine Disrupting Chemicals on Human Prostate Stem/Progenitor Cells and Prostate Carcinogenesis

Substantial evidences from epidemiological and animal-based studies indicate that early exposure to endocrine disrupting chemicals (EDCs) during the developmental stage results in a variety of disorders including cancer. Previous studies have demonstrated that early estrogen exposure results in life-long reprogramming of the prostate gland that leads to an increased incidence of prostatic lesions with aging. We have recently documented that bisphenol A (BPA), one of the most studied EDCs with estrogenic activity has similar effects in increasing prostate carcinogenic potential, supporting the connection between EDCs exposure and prostate cancer risk. It is well accepted that stem cells play a crucial role in development and cancer. Accumulating evidence suggest that stem cells are regulated by extrinsic factors and may be the potential target of hormonal carcinogenesis. Estrogenic EDCs which interfere with normal hormonal signaling may perturb prostate stem cell fate by directly reprogramming stem cells or breaking down the stem cell niche. Transformation of stem cells into cancer stem cells may underlie cancer initiation accounting for cancer recurrence, which becomes a critical therapeutic target of cancer management. We therefore propose that estrogenic EDCs may influence the development and progression of prostate cancer through reprogramming and transforming the prostate stem and early stage progenitor cells. In this review, we summarize our current studies and have updated recent advances highlighting estrogenic EDCs on prostate carcinogenesis by possible targeting prostate stem/progenitor cells. Using novel stem cell assays we have demonstrated that human prostate stem/progenitor cells express estrogen receptors (ER) and are directly modulated by estrogenic EDCs. Moreover, employing anin vivohumanized chimeric prostate model, we further demonstrated that estrogenic EDCs initiate and promote prostatic carcinogenesis in an androgen-supported environment. These findings support our hypothesis that prostate stem/progenitor cells may be the direct targets of estrogenic EDCs as a consequence of developmental exposure which carry permanent reprogrammed epigenetic and oncogenic events and subsequently deposit into cancer initiation and progression in adulthood.

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ID: 82: DISTINCT ACTIONS OF ERα AND ERβ IN HUMAN PROSTATE STEM AND PROGENITOR CELL SELF-RENEWAL AND DIFFERENTIATION

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.36 ◽

2016 ◽

Vol 64 (4) ◽

pp. 928.1-928 ◽

Cited By ~ 1

Author(s):

D Hu ◽

W Hu ◽

S Majumdar ◽

T Gauntner ◽

Y Li ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Progenitor Cells ◽

Side Population ◽

Population Analysis ◽

Human Prostate ◽

Mrna Levels ◽

Self Renewal ◽

Prostate Carcinogenesis ◽

Prostate Epithelial Cells

Estrogens are implicated in prostate development and cancer, while stem cells are essential in tissue homeostasis and carcinogenesis. We have previously demonstrated that estradiol-17β (E2) treatment augments prostaspheres (PS) number and size, implicating them as direct estrogen targets. The present studies sought to elucidate specific roles for ERα and ERβ in prostate stem and progenitor cells.Prostate stem-progenitor cells were identified and isolated from normal primary prostate epithelial cells (PrEC) using long term BrdU retention in 3-D PS culture. FACS analyses (BrdU/ERα or ERβ) showed prostate stem and progenitor populations were both ERα+ and ERβ+. BrdU-retaining stem cells expressed high levels of ERβ and lower ERα as compared to non-label-retaining progenitor cells, suggesting ERβ dominance in the prostate stem cell. Estradiol increased BrdU-retaining cell numbers by enhancing stem cell self-renewal through symmetric division. While ERα siRNA blocked the E2-stimulated BrdU-retaining cells, ERβ knockdown augmented the E2-induced increase of BrdU-retaining cells. Together these findings suggest that ERα stimulates whereas ERβ suppresses stem cell self-renew. This conclusion is supported by separate studies on 2-D cultured PrEC with FACS stem-like cell side-population analysis using selective ER antagonists and siRNA. Although ERβ siRNA did not influence ERα mRNA levels, ERα siRNA doubled ERβ expression suggesting a suppressive role of ERα on ERβ action.In total, the present findings identify distinct localization patterns and roles for ERα and ERβ in human prostate stem-like and daughter progenitor cells with ERα driving self-renewal and ERβ braking division. We propose that a delicate balance between ERα and ERβ contributes to prostate stem cell niche homeostasis and that their dysregulation may contribute to prostate carcinogenesis and progression.

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Actions of Estrogenic Endocrine Disrupting Chemicals on Human Prostate Stem/Progenitor Cells and Prostate Carcinogenesis

The Open Biotechnology Journal ◽

10.2174/1874070720151112e019 ◽

2015 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Dan-Ping Hu ◽

Li-Shi Xie ◽

Ye Li ◽

Gail S. Prins ◽

Wen-Yang Hu

Keyword(s):

Progenitor Cells ◽

Endocrine Disrupting Chemicals ◽

Human Prostate ◽

Prostate Carcinogenesis ◽

Endocrine Disrupting ◽

Estrogenic Endocrine Disrupting Chemicals

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Keratin Profiling by Single-Cell RNA-Sequencing Identifies Human Prostate Stem Cell Lineage Hierarchy and Cancer Stem-Like Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22158109 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8109

Author(s):

Wen-Yang Hu ◽

Dan-Ping Hu ◽

Lishi Xie ◽

Larisa Nonn ◽

Ranli Lu ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Stem Cell ◽

Single Cell ◽

Progenitor Cells ◽

3D Culture ◽

Cell Lineage ◽

Gene Set Enrichment Analysis ◽

Human Prostate ◽

Stem Cell Lineage

Single prostate stem cells can generate stem and progenitor cells to form prostaspheres in 3D culture. Using a prostasphere-based label retention assay, we recently identified keratin 13 (KRT13)-enriched prostate stem cells at single-cell resolution, distinguishing them from daughter progenitors. Herein, we characterized the epithelial cell lineage hierarchy in prostaspheres using single-cell RNA-seq analysis. Keratin profiling revealed three clusters of label-retaining prostate stem cells; cluster I represents quiescent stem cells (PSCA, CD36, SPINK1, and KRT13/23/80/78/4 enriched), while clusters II and III represent active stem and bipotent progenitor cells (KRT16/17/6 enriched). Gene set enrichment analysis revealed enrichment of stem and cancer-related pathways in cluster I. In non-label-retaining daughter progenitor cells, three clusters were identified; cluster IV represents basal progenitors (KRT5/14/6/16 enriched), while clusters V and VI represent early and late-stage luminal progenitors, respectively (KRT8/18/10 enriched). Furthermore, MetaCore analysis showed enrichment of the “cytoskeleton remodeling–keratin filaments” pathway in cancer stem-like cells from human prostate cancer specimens. Along with common keratins (KRT13/23/80/78/4) in normal stem cells, unique keratins (KRT10/19/6C/16) were enriched in cancer stem-like cells. Clarification of these keratin profiles in human prostate stem cell lineage hierarchy and cancer stem-like cells can facilitate the identification and therapeutic targeting of prostate cancer stem-like cells.

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