Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity

Nature Cell Biology volume 15, pages 274–283 (2013)Cite this article

Subjects

Abstract

A key issue in cancer biology is whether oncogenic transformation of different cell types of origin within an adult tissue gives rise to distinct tumour subtypes that differ in their prognosis and/or treatment response. We now show that initiation of prostate tumours in basal or luminal epithelial cells in mouse models results in tumours with distinct molecular signatures that are predictive of human patient outcomes. Furthermore, our analysis of untransformed basal cells reveals an unexpected assay dependence of their stem cell properties in sphere formation and transplantation assays versus genetic lineage tracing during prostate regeneration and adult tissue homeostasis. Although oncogenic transformation of basal cells gives rise to tumours with luminal phenotypes, cross-species bioinformatic analyses indicate that tumours of luminal origin are more aggressive than tumours of basal origin, and identify a molecular signature associated with patient outcome. Our results reveal the inherent plasticity of basal cells, and support a model in which different cells of origin generate distinct molecular subtypes of prostate cancer.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: High frequency of prostate basal stem/progenitor cells in sphere formation and tissue reconstitution assays.
Figure 2: Detection of rare bipotential basal progenitors during prostate regeneration in vivo.
Figure 3: Detection of rare bipotential basal progenitors during prostate homeostasis.
Figure 4: Basal cells are a cell type of origin for prostate tumours.
Figure 5: A luminal origin gene signature that is prognostic for human prostate cancer outcome.
Figure 6: Two models for prostate epithelial lineage relationships and cell of origin for cancer.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Visvader, J. E. Cells of origin in cancer. Nature 469, 314–322 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Shen, M. M. & Abate-Shen, C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 24, 1967–2000 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Goldstein, A. S., Stoyanova, T. & Witte, O. N. Primitive origins of prostate cancer: In vivo evidence for prostate-regenerating cells and prostate cancer-initiating cells. Mol. Oncol. 4, 385–396 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Moscatelli, D. & Wilson, E. L. PINing down the origin of prostate cancer. Sci. Transl. Med. 2, 43ps38 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wang, Z. A. & Shen, M. M. Revisiting the concept of cancer stem cells in prostate cancer. Oncogene 30, 1261–1271 (2011).

    Article  PubMed  Google Scholar 

  6. De Marzo, A. M., Nelson, W. G., Bieberich, C. J. & Yegnasubramanian, S. Prostate cancer: new answers prompt new questions regarding cell of origin. Nat. Rev. Urol. 7, 650–652 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Taylor, R. A., Toivanen, R. & Risbridger, G. P. Stem cells in prostate cancer: treating the root of the problem. Endocr. Relat. Cancer 17, R273–R285 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Lawson, D. A., Xin, L., Lukacs, R. U., Cheng, D. & Witte, O. N. Isolation and functional characterization of murine prostate stem cells. Proc. Natl Acad. Sci. USA 104, 181–186 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Richardson, G. D. et al. CD133, a novel marker for human prostatic epithelial stem cells. J. Cell Sci. 117, 3539–3545 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Burger, P. E. et al. Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue. Proc. Natl Acad. Sci. USA 102, 7180–7185 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xin, L., Lawson, D. A. & Witte, O. N. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc. Natl Acad. Sci. USA 102, 6942–6947 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Goldstein, A. S. et al. Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics. Proc. Natl Acad. Sci. USA 105, 20882–20887 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Goldstein, A. S., Huang, J., Guo, C., Garraway, I. P. & Witte, O. N. Identification of a cell of origin for human prostate cancer. Science 329, 568–571 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang, X. et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461, 495–500 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shibata, M. & Shen, M. M. The roots of cancer: stem cells and the basis for tumor heterogeneity. Bioessays http://dx.doi.org/10.1002/bies.201200101 (2012).

  16. Visvader, J. E. Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev. 23, 2563–2577 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lawson, D. A. et al. Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proc. Natl Acad. Sci. USA 107, 2610–2615 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Choi, N., Zhang, B., Zhang, L., Ittmann, M. & Xin, L. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell 21, 253–265 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rock, J. R. et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl Acad. Sci. USA 106, 12771–12775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xin, L., Lukacs, R. U., Lawson, D. A., Cheng, D. & Witte, O. N. Self-renewal and multilineage differentiation in vitro from murine prostate stem cells. Stem Cells 25, 2760–2769 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Park, J. H. et al. Prostatic intraepithelial neoplasia in genetically engineered mice. Am. J. Pathol. 161, 727–735 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sboner, A. et al. Molecular sampling of prostate cancer: a dilemma for predicting disease progression. BMC Med. Genom. 3, 8 (2010).

    Article  Google Scholar 

  26. Lapointe, J. et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl Acad. Sci. USA 101, 811–816 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tomlins, S. A. et al. Integrative molecular concept modeling of prostate cancer progression. Nat. Genet. 39, 41–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Singh, D. et al. Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 1, 203–209 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Yu, Y. P. et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J. Clin. Oncol. 22, 2790–2799 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Glinsky, G. V., Glinskii, A. B., Stephenson, A. J., Hoffman, R. M. & Gerald, W. L. Gene expression profiling predicts clinical outcome of prostate cancer. J. Clin. Invest. 113, 913–923 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Martin, N. E., Mucci, L. A., Loda, M. & Depinho, R. A. Prognostic determinants in prostate cancer. Cancer J. 17, 429–437 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Snippert, H. J. & Clevers, H. Tracking adult stem cells. EMBO Rep. 12, 113–122 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Taylor, R. A. et al. Lineage enforcement by inductive mesenchyme on adult epithelial stem cells across developmental germ layers. Stem Cells 27, 3032–3042 (2009).

    CAS  PubMed  Google Scholar 

  34. Cunha, G. R. et al. The endocrinology and developmental biology of the prostate. Endocr. Rev. 8, 338–362 (1987).

    Article  CAS  PubMed  Google Scholar 

  35. Van Keymeulen, A. et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Lu, C. P. et al. Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair. Cell 150, 136–150 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu, J. et al. Regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate. Mol. Endocrinol. 25, 1849–1857 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ousset, M. et al. Multipotent and unipotent progenitors contribute to prostate postnatal development. Nat. Cell Biol. 14, 1131–1138 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Blackwood, J. K. et al. In situ lineage tracking of human prostatic epithelial stem cell fate reveals a common clonal origin for basal and luminal cells. J. Pathol. 225, 181–188 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Gaisa, N. T. et al. Clonal architecture of human prostatic epithelium in benign and malignant conditions. J. Pathol. 225, 172–180 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Doupe, D. P. et al. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337, 1091–1093 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Doupe, D. P., Klein, A. M., Simons, B. D. & Jones, P. H. The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. Dev. Cell 18, 317–323 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Markert, E. K., Mizuno, H., Vazquez, A. & Levine, A. J. Molecular classification of prostate cancer using curated expression signatures. Proc. Natl Acad. Sci. USA 108, 21276–21281 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lapointe, J. et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res. 67, 8504–8510 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Rubin, M. A., Maher, C. A. & Chinnaiyan, A. M. Common gene rearrangements in prostate cancer. J. Clin. Oncol. 29, 3659–3668 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Gibson, P. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Banach-Petrosky, W. et al. Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1; Pten mutant mice. Cancer Res. 67, 9089–9096 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Hu, Y. & Smyth, G. K. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J. Immunol. Methods 347, 70–78 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Croft, D. et al. Reactome: a database of reactions, pathways and biological processes. Nucleic Acids Res. 39, D691–D697 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Ogata, H. et al. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 27, 29–34 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank J. Rock and B. Hogan (Duke University Medical School, USA) for their generous gift of CK5–CreERT2 transgenic mice, O. Couronne and the Columbia University Genome Sequencing Facility for RNA-seq analysis, and R. DePinho (MD Anderson Cancer Center) for assistance in obtaining the Glinsky data set. This work was supported by a postdoctoral fellowship from the DOD Prostate Cancer Research Program (Z.A.W.), a postdoctoral Computing Innovation Fellowship (CIFellow) from NSF, CRA and CCC (A.M.), and by grants from the National Institutes of Health (C.A-S., A.C. and M.M.S.).

Author information

Authors and Affiliations

  1. Departments of Medicine and Genetics and Development, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    Zhu A. Wang, Sarah K. Bergren & Michael M. Shen

  2. Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    Zhu A. Wang, Antonina Mitrofanova, Sarah K. Bergren, Cory Abate-Shen, Andrea Califano & Michael M. Shen

  3. Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    Antonina Mitrofanova & Andrea Califano

  4. Departments of Urology and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    Cory Abate-Shen

  5. Center for Comparative Medicine and Department of Pathology, School of Medicine, University of California, Davis 95616, USA

    Robert D. Cardiff

Authors
  1. Zhu A. Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Antonina Mitrofanova
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Sarah K. Bergren
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Cory Abate-Shen
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Robert D. Cardiff
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Andrea Califano
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Michael M. Shen
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Z.A.W. carried out mouse experiments, Z.A.W. and S.K.B. performed transplantation experiments, A.M. performed bioinformatic analyses, and R.D.C. analysed tumour histology. Z.A.W. and M.M.S. designed the overall study, C.A-S., R.D.C., A.C. and M.M.S. supervised the data analysis, and Z.A.W., A.M. and M.M.S. wrote the manuscript, in consultation with C.A-S. and A.C. All authors provided discussion and comments on the manuscript.

Corresponding author

Correspondence to Michael M. Shen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1956 kb)

Supplementary Table S1

Supplementary Information (XLSX 50 kb)

Supplementary Table S2

Supplementary Information (XLSX 29 kb)

Supplementary Table S3

Supplementary Information (XLSX 38 kb)

Supplementary Table S4

Supplementary Information (XLSX 39 kb)

Supplementary Table S5

Supplementary Information (XLSX 38 kb)

Supplementary Table S6

Supplementary Information (XLSX 38 kb)

Supplementary Table S7

Supplementary Information (XLSX 38 kb)

Supplementary Table S8

Supplementary Information (XLSX 36 kb)

Supplementary Table S9

Supplementary Information (XLSX 20 kb)

Supplementary Table S10

Supplementary Information (XLSX 18 kb)

Supplementary Table S11

Supplementary Information (XLSX 51 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Z., Mitrofanova, A., Bergren, S. et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol 15, 274–283 (2013). https://doi.org/10.1038/ncb2697

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2697

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer