Stem cells in prostate cancer initiation and progression

OBJECTIVES/SPECIFIC AIMS: The primary goal of this project is to verify findings from a murine prostatitis model in the human setting. METHODS/STUDY POPULATION: Methods include primary cell isolation and culture, FACS, adoptive transfer, 3D cell culture, histology, immunofluorescence, xenograft, and tissue recombination. The study population includes patients undergoing HoLEP or radical prostatectomy due to hyperplasia or adjacent bladder or prostate cancer. RESULTS/ANTICIPATED RESULTS: Having verified similar sensitivities to androgen receptor (AR) inhibitors between naive murine and human basal prostate stem cells, we anticipate that autoimmune inflammation in humans affects the response of basal prostate stem cells in a manner similar to the murine setting as well. This includes increased proliferation, increased differentiation, and decreased response to AR inhibitors. DISCUSSION/SIGNIFICANCE OF IMPACT: The identification of survival mechanisms used by basal prostate stem cells in an androgen deprived environment may give insight to the process by which prostate cancer becomes androgen independent. The effect of inflammation on proliferation, survival, and AR signaling in these cells may also provide information relevant to cancer initiation and progression.

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Comment on basal epithelial stem cells as efficient targets for prostate cancer initiation

Stem Cell Research & Therapy ◽

10.1186/scrt16 ◽

2010 ◽

Vol 1 (2) ◽

pp. 16 ◽

Cited By ~ 1

Author(s):

Letitia Wong ◽

Wade Bushman

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Epithelial Stem Cells ◽

Cancer Initiation

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Basal epithelial stem cells are efficient targets for prostate cancer initiation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0913873107 ◽

2010 ◽

Vol 107 (6) ◽

pp. 2610-2615 ◽

Cited By ~ 191

Author(s):

D. A. Lawson ◽

Y. Zong ◽

S. Memarzadeh ◽

L. Xin ◽

J. Huang ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Epithelial Stem Cells ◽

Cancer Initiation

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2279

Journal of Clinical and Translational Science ◽

10.1017/cts.2017.216 ◽

2017 ◽

Vol 1 (S1) ◽

pp. 60-60

Author(s):

Paula Cooper ◽

Hsing-Hui Wang ◽

Meaghan Broman ◽

Hristos Kaimakliotis ◽

Bennett Elzey ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Cell Culture ◽

3D Cell Culture ◽

Autoimmune Inflammation ◽

Cancer Initiation ◽

Study Population ◽

Tissue Recombination ◽

Survival Mechanisms ◽

Androgen Independent

OBJECTIVES/SPECIFIC AIMS: The primary goal of this project is to verify murine findings in the human setting. METHODS/STUDY POPULATION: The methods include primary cell isolation and culture, FACS, adoptive transfer, 3D-cell culture, histology, immunofluorescence, xenograft, and tissue recombination. The study population includes patients undergoing radical prostatectomy due to hyperplasia or adjacent bladder or prostate cancer. RESULTS/ANTICIPATED RESULTS: Having verified similar sensitivities to androgen receptor (AR) inhibitors between naive murine and human basal prostate stem cells, we anticipate that autoimmune inflammation in humans affects the response of basal prostate stem cells in a manner similar to the murine setting as well. This includes increased proliferation, differentiation, and response to AR inhibitors. DISCUSSION/SIGNIFICANCE OF IMPACT: The identification of survival mechanisms used by basal prostate stem cells in an androgen deprived environment may give insight to the process by which prostate cancer becomes androgen independent. The effect of inflammation on proliferation, survival, and AR signaling in these cells may also provide information relevant to cancer initiation 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 ◽

10.2174/1874070701610010076 ◽

2016 ◽

Vol 10 (1) ◽

pp. 76-97 ◽

Cited By ~ 6

Author(s):

Dan-Ping Hu ◽

Wen-Yang Hu ◽

Lishi Xie ◽

Ye Li ◽

Lynn Birch ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Stem Cell ◽

Progenitor Cells ◽

Endocrine Disrupting Chemicals ◽

Human Prostate ◽

Cancer Management ◽

Prostate Carcinogenesis ◽

Endocrine Disrupting ◽

Cancer Initiation

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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