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Stem Cell Models for Functional Validation of Prostate Cancer Genes

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Stem Cells and Prostate Cancer

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Abstract

Prostate cancer is a genomically complex disease in which initiation, progression, and metastasis are regulated by numerous molecular processes including oncogene activation or tumor suppressor inactivation. Understanding the molecular mechanisms that drive prostate tumorigenesis has important clinical implications. Putative oncogenes or tumor suppressors are identified using technologies including SNP arrays, microarrays, and whole genome sequencing, but these targets must then be evaluated in cell and animal models to determine the functional consequences of these genomic alterations. Traditionally, potential prostate cancer genes have been validated with human prostate cancer cell line models (i.e., tissue culture and xenograft systems) or genetically engineered mouse (GEM) models. More recently, stem cell models have been utilized to evaluate candidate cancer genes. Because the normal adult prostate stem cell (PSC) shares many properties with the prostate tumor-initiating cell (TIC) including the capabilities for self-renewal, differentiation, and androgen independence, modeling gene alterations in PSCs may be more appropriate than traditional approaches. PSCs can be maintained in cell culture, genetically manipulated, and characterized using techniques including cell sorting, colony formation assays, and prostasphere assays in vitro and tissue recombination in vivo. A number of prostatic oncogenes and tumor suppressors including MYC, ERG, PTEN, P53, NKX3.1, and TAK1 have been evaluated using stem cell models. Compound genetic alterations have also been studied using PSC models. In this chapter we describe current approaches being used to investigate putative oncogenes and tumor suppressors in the context of the PSC and highlight a few examples of recent studies using stem cell models for target validation. We also discuss the limitations of existing models as well as strategies to improve upon these models for future studies.

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Acknowledgements

The authors thank the following individuals for their scientific contributions to this chapter: Lina Romero for FACS analysis and characterization of PrP/SCs from different genetic backgrounds; Molishree Joshi for isolation of Tak1L/L MPECs and microscopy; Wenhong Chen and Michael Lilly for Pim1 studies.

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  1. Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA

    Lindsey Ulkus Ph.D., Min Wu Ph.D. & Scott D. Cramer Ph.D.

  2. Cancer Biology Training Program, Wake Forest University School of Medicine, Winston-Salem, NC, 27145, USA

    Lindsey Ulkus Ph.D. & Scott D. Cramer Ph.D.

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  1. Lindsey Ulkus Ph.D.
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  2. Min Wu Ph.D.
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  3. Scott D. Cramer Ph.D.
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Correspondence to Scott D. Cramer Ph.D. .

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    Scott D. Cramer

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Ulkus, L., Wu, M., Cramer, S.D. (2013). Stem Cell Models for Functional Validation of Prostate Cancer Genes. In: Cramer, S. (eds) Stem Cells and Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6498-3_9

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