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Novel Human Prostate Epithelial Cell Culture Models for the Study of Carcinogenesis and of Normal Stem Cells and Cancer Stem Cells

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Human Cell Transformation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 720))

Abstract

Research into the mechanisms of prostate cancer progression has been limited by the lack of suitable in vitro systems. A hurdle in understanding the molecular genetic changes in prostate cancer has been the difficulty in establishing premalignant lesions and primary prostate tumors as in vitro cell cultures. Primary prostate epithelial cells grow for a finite life span and then senesce. Immortalization is defined by continuous growth of otherwise senescing cells and is believed to represent an early stage in tumor progression. To examine these early stages, we and others have developed in vitro models of prostate epithelial cell immortalization. Generation of primary human prostate epithelial (HPE) cells has been achieved using the serum-free condition. Retrovirus containing human telomerase reverse transcriptase (hTERT) was successfully used for the immortalization of primary HPE cells. Putative stem cell markers CD133 and CXCR4 were further identified in hTERT-immortalized primary nonmalignant and malignant tumor-derived HPE lines. In addition, an hTERT-immortlaized nonmalignant HPE cell were found to retain the properties of multipotent stem cells. These in vitro prostate cell culture models should be useful for the study of carcinogenesis and of normal and cancer stem cells. Prostate cancer is the most common male cancer in the Western World and second leading cause of male cancer death in the United States [1]. The therapy most widely used against advanced disease is androgen ablation and, initially, it almost always produces objective clinical responses. However, most patients eventually relapse with ablation-resistant prostate cancer and develop metastatic disease; currently, there is no treatment that will cure progressive hormone-refractory metastatic prostate cancer. The mechanisms of progression of prostate cancer have been extensively studied, yet are poorly understood. One of the concepts that has been evolved is that cancer arises from the neoplastic transformation of normal prostate epithelial stem cells or transit amplifying cells. Understanding normal stem cells and cancer stem cells (CSCs) may provide insight into the origin of and new therapeutics for prostate cancer. However, research in this field is limited by the lack of suitable in vitro systems.

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References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics 2007. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  2. Yasunaga Y, Nakamura K, Ewing CM, Isaacs WB, Hukku B, Rhim JS (2001) A novel human cell culture model for the study of familial prostate cancer. Cancer Res 61:5969–5973

    PubMed  CAS  Google Scholar 

  3. Gu Y, Li H, Miki J, Kim KH, Furusato B, Sesterhenn IA et al (2006) Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines. Exp Cell Res 312:831–8434

    Article  PubMed  CAS  Google Scholar 

  4. Rhim JS (2000) In vitro human cell models for the study of prostate cancer. Prostate Cancer Prostatic Dis 3:229–235

    Article  PubMed  Google Scholar 

  5. Ratsch SB, Gao Q, Srinivasan DE, Wazer DE, Band V (2001) Multiple genetic changes are required for efficient immortalization of different subtypes of normal human mammary epithelial cells. Radiat Res 155:143–150

    Article  PubMed  CAS  Google Scholar 

  6. Lee C, Sutkowski DM, Sensibar JA et al (1995) Regulation of proliferation and production of prostate-specific antigenin androgen-sensitive prostate cancer cells, LNCaP, by dihydrotestosterone. Endocrinology 136:796–803

    Article  PubMed  CAS  Google Scholar 

  7. de Launoit Y, Veilleux R, Dufour M et al (1991) Characteristics of the biphasic action of androgens and of the potent antiproliferative effects of the new pure antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells. Cancer Res 51:5165–5170

    PubMed  Google Scholar 

  8. Lou J, Zha S, Jage WR et al (2002) Alpha-methylacyl-CoA racemase; a new molecular marker for prostate cancer. Cancer Res 62:2220–2226

    Google Scholar 

  9. Miki J, Rhim JS (2008) Prostate cell culture as in vitro models for the study of normal stem cells and cancer stem cells. Prostate Cancer Prostatic Dis 11:32–39

    Article  PubMed  CAS  Google Scholar 

  10. Miki J, Furusato B, Li H et al (2007) Identification of putative stem cell markers, CD133 and CXCR4 in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens. Cancer Res 67:3153–3161

    Article  PubMed  CAS  Google Scholar 

  11. Li H, Zhou J, Miki J, Furusato B, Gu Y et al (2008) Telomerase-immortalized non-malignant human prostate epithelial cells retain the properties of multipotent stem cells. Exp Cell Res 314:92–102

    Article  PubMed  CAS  Google Scholar 

  12. Isaacs JT, Coffey DS (1989) Etiology and disease process of benign prostatic hyperplasia. Prostate Suppl 2:33–50

    Article  PubMed  CAS  Google Scholar 

  13. Bonkhoff H (1996) Role of the basal cells in premalignant changes of the human prostate; a stem cell concept for the development of prostate cancer. Eur Urol 30:201–205

    PubMed  CAS  Google Scholar 

  14. Xin L, Ide H, Kim Y et al (2003) In vivo regeneration of murine prostate from dissociated cell populations of postnatal epithelia and urogenital sinus mesenchyme. Proc Natl Acad Sci USA 100(suppl 1):11896–11903

    Article  PubMed  CAS  Google Scholar 

  15. Tsujimura A, Koikawa Y, Salm S et al (2002) Proximal location of mouse prostate epithelial stem cells: a model of prostate homeostasis. J Cell Biol 157:1257–1265

    Article  PubMed  CAS  Google Scholar 

  16. Taylor RA, Cowin PA, Cunha GR et al (2006) Formation of human prostate tissue from embryonic stem cells. Nat Methods 3:179–181

    Article  PubMed  CAS  Google Scholar 

  17. Schalken JA, van Leenders G (2003) Cellular and molecular biology of the prostate stem cell biology. Urology 62:11–20

    Article  PubMed  Google Scholar 

  18. Hudson DL, O’Hare M, Watt F, Masters JR (2000) Proliferative heterogeneity in the human prostate evidence from epithelial stem cells. Lab Invest 80:1243–1250

    Article  PubMed  CAS  Google Scholar 

  19. Collins AT, Habib FK, Maitland NJ, Neal DF (2001) Identification and isolation of human prostate epithelial stem cells based on alpha(2)beta(1)-integrin expression. J Cell Sci 114:3865–3872

    PubMed  CAS  Google Scholar 

  20. Richardson GD, Robson CN, Lang SH et al (2004) CD133, a novel marker for human prostate epithelial stem cells. J Cell Sci 117:3539–3545

    Article  PubMed  CAS  Google Scholar 

  21. Nichols J, Zevnik B, Anastassiadis K et al (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379–391

    Article  PubMed  CAS  Google Scholar 

  22. Park IK, Qian D, Kiel M et al (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423:302–305

    Article  PubMed  CAS  Google Scholar 

  23. Molofsky AV, Pardal R, Iwashita T et al (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962–967

    Article  PubMed  CAS  Google Scholar 

  24. Reya T, Morrison SJ, Clarke MF et al (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  PubMed  CAS  Google Scholar 

  25. Karhadkar SS, Bova GS, Abdallah N (2004) Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431:707–712

    Article  PubMed  CAS  Google Scholar 

  26. Litvinov IV, Vander Griend DJ, Xu Y et al (2006) Low-calcium serum-free defined medium selects for growth of normal prostatic epithelial stem cells. Cancer Res 66:8598–8607

    Article  PubMed  CAS  Google Scholar 

  27. Gu G, Yuan J, Wills M et al (2007) Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res 67:4807–4815

    Article  PubMed  CAS  Google Scholar 

  28. Harrington L (2004) Does the reservoir for self-renewal stem from the ends? Oncogene 23:7283–7289

    Article  PubMed  CAS  Google Scholar 

  29. Soda H, Raymond E, Sharma S (2000) Effects of androgens on telomerase activity in normal and malignant prostate cells in vitro. Prostate 43:161–168

    Article  PubMed  CAS  Google Scholar 

  30. Sommerfeld HJ, Meeker AK, Piatyszek MA et al (1996) Telomerase activity: a prevalent marker of malignant human prostate tissue. Cancer Res 56:218–222

    PubMed  CAS  Google Scholar 

  31. Ju Z, Rudolph KL (2006) Telomeres and telomerase in cancer stem cells. Eur J Cancer 42:1197–1203

    Article  PubMed  CAS  Google Scholar 

  32. Bieberich CJ, Fujita K, He WW et al (1996) Prostate-specific and androgen-dependent expression of a novel homeobox gene. J Biol Chem 271:31779–31782

    Article  PubMed  CAS  Google Scholar 

  33. Reiter RE, Gu Z, Watabe T (1998) Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc Natl Acad Sci USA 95:1735–1740

    Article  PubMed  CAS  Google Scholar 

  34. Signoretti S, Waltregny D, Dilks J (2000) p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 157:1769–1775

    Article  PubMed  CAS  Google Scholar 

  35. Signoretti S, Pires MM, Lindauer M (2005) p63 regulates commitment to the prostate cell lineage. Proc Natl Acad Sci USA 102:11355–11360

    Article  PubMed  CAS  Google Scholar 

  36. Signoretti S, Loda M (2006) Defining cell lineages in the prostate epithelium. Cell Cycle 5:138–141

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was funded by grant from the US Army Medical Research and Material Command and also supported by a Department of Defence Prostate Cancer Research Program (PCO30694).

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Authors and Affiliations

  1. Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA

    Johng S. Rhim & Bungo Furusato

  2. Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Hongzhen Li

  3. Department of Genitourinary Pathology, Armed Forces Institutes of Pathology, Washington, DC, USA

    Bungo Furusato

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  1. Johng S. Rhim
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  2. Hongzhen Li
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  3. Bungo Furusato
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Correspondence to Johng S. Rhim .

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Editors and Affiliations

  1. Uniformed Services, Department of Surgery, University of the Health Sciences, South Glen Road 11455, Bethesda, 20854, Maryland, USA

    Johng S. Rhim

  2. , Department of Medicine, McGill University Health Centre, Pine Ave 687, Montreal, Québec, Canada

    Richard Kremer

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Rhim, J.S., Li, H., Furusato, B. (2011). Novel Human Prostate Epithelial Cell Culture Models for the Study of Carcinogenesis and of Normal Stem Cells and Cancer Stem Cells. In: Rhim, J., Kremer, R. (eds) Human Cell Transformation. Advances in Experimental Medicine and Biology, vol 720. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0254-1_6

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