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Stem Cells in the Normal and Malignant Prostate

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Prostate Cancer

Part of the book series: Protein Reviews ((PRON,volume 16))

Abstract

Tissues and organs like the prostate are derived from multipotent stem cells, which themselves are the products of differentiation from an original pluripotent embryonic stem cell population. Stem cells that persist into the mature prostate gland are termed tissue stem cells and are required for replenishment of the epithelial and stromal populations after damage, for example, by inflammation or gland involution after castration. While there remains some controversy over the phenotype of these cells, their ability to regenerate tissues and their inherent resistance to mutagenic and cytotoxic insults confer a unique biology on tissue stem cells. When one considers the origins of prostate cancer, the extended life span of tissue stem cells, and their ability to accumulate over time the necessary founder mutations, would imply that this primitive SC population is the cell of origin for prostate cancer. In the cancers, cells with similar primitive phenotypes are rare, but can be identified in varying proportions, depending on the markers used for isolation and the purification techniques. The tumor-initiating capacity of these cancer stem cells is many orders of magnitude higher than the majority cell population in tumors, and they display treatment resistance characteristics, which are sometimes shared with the normal tissue stem cells. The cancer stem cells in prostate cancers may therefore represent a viable target for therapeutic intervention, but there remain real challenges in the design and execution of these stem cell treatments.

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Abbreviations

Acute myeloid leukemia (AML):

A rare cancer with the phenotype of an increase in the number of (myeloid) white blood cells in the bone marrow

Aldehyde dehydrogenase (ALDH):

A member of the aldehyde dehydrogenase enzyme family, whose elevated expression levels can be used to enrich for stem-like cells

Androgen receptor (AR):

Protein receptor for the male sex hormone androgen. Present at highest levels in the luminally differentiated cells in prostate

Basement membrane:

A complex proteinaceous boundary to each acinar unit of the prostate: It forms part of an active stem cell niche and signals to both stromal and epithelial components

Cancer cell type of origin (CCTO):

The cell type within prostate from which a tumor develops

Castration-resistant Nkx3.1-expressing cells (CARN cells):

A rare luminal stem cell population, which has been identified in the mouse prostate. CARN cells can give rise to both luminal and basal cells during prostate tissue regeneration induced by androgen depletion

Fluorescent-activated cell sorter (FACS):

Provides a method for sorting a disaggregated heterogeneous mixture of biological cells into two or more fractions, based upon the specific light scattering and fluorescent characteristics of each cell. It is particularly useful for the identification of rare cell populations

Gleason grading:

A morphological classification of the abnormal prostate gland, first established by Donald Gleason (in 1966). The loss of acinar morphology is broadly predictive of patient outcome

Hedgehog, wingless (wnt) and Notch:

Developmental signaling pathways originally defined in Drosophila melanogaster which also influence embryonic prostate development and adult prostate differentiation

Hematopoietic stem cells (HSCs):

Primitive cell type at the top of the hierarchy of cell types which differentiate into multiple cells types in the bloodstream and bone marrow (for example)

Induced pluripotent stem cells (iPS cells):

Biologically engineered stem cells, generated by in vitro treatment of already differentiated cells (e.g., skin fibroblasts) by a cocktail of (normally) four genes, which can differentiate into multiple cell types

Mesenchymal cells (also mesenchymal stem cells, MSCs):

Cells with a broadly stromal elongated morphology, which include an androgen-­receptor expressing population capable of changing the behavior of the epithelial cells by signaling through the basement membrane

Orthotopic xenografts:

Implantation into the tissue of origin (in this case, the murine prostate)

Prostate cancer stem cells (CSCs):

A generic term for the epithelial tumor-­initiating cell in prostate cancer, as like a normal tissue stem cell, CSCs can differentiate into multiple cell types. Also known as tumor-­initiating cells (TICs)

Prostate involution:

Shrinkage of the prostate gland as a consequence of castration, which is accompanied by the loss of structural acinar features

Prostate stem cells:

An epithelial cell, which can reconstitute all of the cells of the epithelial ­component of a prostatic acinus. Its basal/luminal phenotype remains controversial

Prostatic acinus (acinar morphology):

The base subunit of the prostate gland, which consists of an epithelial bilayer, surrounded by an intact basement membrane and bounded by complex fibroblastic (stromal) cells. Progressively disrupted through increasing Gleason grades of cancer

Stem cell quiescence:

A common feature of most reserve and stem cells in tissues, quiescence implies a lack of replicative activity, in the absence of complete cellular degenerative shut down. It can be considered as an inactive slowly metabolizing cell that is primed to respond to various stimuli, including injury

Subcutaneous xenografts:

Describes the implantation site under the skin of the mouse host

Tumor-initiating cells (TICs):

See CSCs

Urogenital sinus mesenchyme (UGM):

A powerful inductive androgen responsive mesenchymal component that defines the earliest stages of prostate gland (and acinar) development in embryos

Xenografts:

Implantation of (in this case) human tissues into an immune-­compromised mouse host

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Acknowledgments

I wish to thank all the members of the YCR Cancer Research Unit who have contributed in so many ways to the ideas and data I have described. In particular I would like to acknowledge the seminal contributions of Anne Collins and willingness of Fiona Frame and Jayant Rane to let me rework their artwork. Michelle Scaife heroically collated the reference list and transcribed the text. Finally, my sincere thanks are due to Yorkshire Cancer Research, which has supported my research on prostate cancer and stem cells since its inception.

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  1. YCR Cancer Research Unit, Department of Biology, University of York, Heslington, York, North Yorkshire, YO60 7SD, UK

    Norman J. Maitland B.Sc., Ph.D.

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  1. Norman J. Maitland B.Sc., Ph.D.
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Correspondence to Norman J. Maitland B.Sc., Ph.D. .

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  1. , Depts of Urology, and, Mayo Clinic College of Medicine, 200 1st Street SW., Rochester, 55905, Minnesota, USA

    Donald J. Tindall

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Maitland, N.J. (2013). Stem Cells in the Normal and Malignant Prostate. In: Tindall, D. (eds) Prostate Cancer. Protein Reviews, vol 16. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6828-8_1

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