Skip to main content
SpringerLink
Log in

Resolution of Cellular Heterogeneity in Human Prostate Cancers: Implications for Diagnosis and Treatment

  • Chapter
  • First Online:
Human Cell Transformation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1164))

Abstract

Prostate cancers have a justified reputation as one of the most heterogeneous human tumours. Indeed, there are some who consider that advanced and castration-resistant prostate cancers are incurable, as a direct result of this heterogeneity. However, tumour heterogeneity can be defined in different ways. To a clinician, prostate cancer is a number of different diseases, the treatments for which remain equally heterogeneous and uncertain. To the pathologist, the histopathological appearances of the tumours are notoriously heterogeneous. Indeed, the genius of Donald Gleason in the 1960s was to devise a classification system designed to take into account the heterogeneity of the tumours both individually and in the whole prostate context. To the cell biologist, a prostate tumour consists of multiple epithelial cell types, inter-mingled with various fibroblasts, neuroendocrine cells, endothelial cells, macrophages and lymphocytes, all of which interact to influence treatment responses in a patient-specific manner. Finally, genetic analyses of prostate cancers have been compromised by the variable gene rearrangements and paucity of activating mutations observed, even in large numbers of patient tumours with consistent clinical diagnoses and/or outcomes. Research into familial susceptibility has even generated the least tractable outcome of such studies: the genetic loci are of low penetrance and are of course heterogeneous. By fractionating the tumour (and patient-matched non-malignant tissues) heterogeneity can be resolved, revealing homogeneous markers of patient outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Gleason, D. F. (1966). Classification of prostatic carcinomas. Cancer Chemotherapy Reports. Part 1, 50(3), 125–128.

    CAS  PubMed  Google Scholar 

  2. Hamdy, F. C., Donovan, J. L., Lane, J. A., Mason, M., Metcalfe, C., Holding, P., et al. (2016). 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. The New England Journal of Medicine, 375(15), 1415–1424.

    Article  PubMed  Google Scholar 

  3. Schröder, F. H., Hugosson, J., Roobol, M. J., Tammela, T. L. J., Ciatto, S., Nelen, V., et al. (2009). Screening and prostate-cancer mortality in a randomized European study. The New England Journal of Medicine, 360(13), 1320–1328.

    Article  PubMed  Google Scholar 

  4. Klotz, L. (2013). Prostate cancer overdiagnosis and overtreatment. Current Opinion in Endocrinology & Diabetes and Obesity, 20(3), 204–209.

    Article  CAS  Google Scholar 

  5. Crawford, E. D., Schellhammer, P. F., McLeod, D. G., Moul, J. W., Higano, C. S., Shore, N., et al. (2018). Androgen receptor targeted treatments of prostate cancer: 35 years of progress with antiandrogens. The Journal of Urology, 200(5), 956–966.

    Article  CAS  PubMed  Google Scholar 

  6. Morse, D. L., Gray, H., Payne, C. M., & Gillies, R. J. (2005). Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells. Molecular Cancer Therapeutics, 4(10), 1495–1504.

    Article  CAS  PubMed  Google Scholar 

  7. Tannock, I. F., de Wit, R., Berry, W. R., Horti, J., Pluzanska, A., Chi, K. N., et al. (2004). Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. The New England Journal of Medicine, 351(15), 1502–1512.

    Article  CAS  PubMed  Google Scholar 

  8. Caubet, M., Dobi, E., Pozet, A., Almotlak, H., Montcuquet, P., Maurina, T., et al. (2015). Carboplatin-etoposide combination chemotherapy in metastatic castration-resistant prostate cancer: A retrospective study. Molecular and Clinical Oncology, 3(6), 1208–1212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Werahera, P. N., Glode, L. M., La Rosa, F. G., Lucia, M. S., Crawford, E. D., Easterday, K., et al. (2011). Proliferative tumor doubling times of prostatic carcinoma. Prostate Cancer, 2011(5), 301850–301857.

    PubMed  PubMed Central  Google Scholar 

  10. Epstein, J. I., Zelefsky, M. J., Sjoberg, D. D., Nelson, J. B., Egevad, L., Magi-Galluzzi, C., et al. (2016). A contemporary prostate cancer grading system: A validated alternative to the Gleason score. European Urology, 69(3), 428–435.

    Article  PubMed  Google Scholar 

  11. Packer, J. R., & Maitland, N. J. (2016). The molecular and cellular origin of human prostate cancer. Biochimica et Biophysica Acta, 1863(6 Pt A), 1238–1260.

    Article  CAS  PubMed  Google Scholar 

  12. Lamouille, S., Xu, J., & Derynck, R. (2014). Molecular mechanisms of epithelial-mesenchymal transition. Nature Reviews. Molecular Cell Biology, 15(3), 178–196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Macintosh, C. A., Stower, M., Reid, N., & Maitland, N. J. (1998). Precise microdissection of human prostate cancers reveals genotypic heterogeneity. Cancer Research, 58(1), 23–28.

    CAS  PubMed  Google Scholar 

  14. Hall, J. A., Maitland, N. J., Stower, M., & Lang, S. H. (2002). Primary prostate stromal cells modulate the morphology and migration of primary prostate epithelial cells in type 1 collagen gels. Cancer Research, 62(1), 58–62.

    CAS  PubMed  Google Scholar 

  15. Olumi, A. F., Grossfeld, G. D., Hayward, S. W., Carroll, P. R., Tlsty, T. D., & Cunha, G. R. (1999). Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Research, 59(19), 5002–5011.

    CAS  PubMed  Google Scholar 

  16. Hayward, S. W., Wang, Y., Cao, M., Hom, Y. K., Zhang, B., Grossfeld, G. D., et al. (2001). Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Research, 61(22), 8135–8142.

    CAS  PubMed  Google Scholar 

  17. Basanta, D., Strand, D. W., Lukner, R. B., Franco, O. E., Cliffel, D. E., Ayala, G. E., et al. (2009). The role of transforming growth factor- -mediated tumor-stroma interactions in prostate cancer progression: An integrative approach. Cancer Research, 69(17), 7111–7120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jamal-Hanjani, M., Wilson, G. A., McGranahan, N., Birkbak, N. J., Watkins, T. B. K., Veeriah, S., et al. (2017). Tracking the evolution of non-small-cell lung cancer. The New England Journal of Medicine, 376(22), 2109–2121.

    Article  CAS  PubMed  Google Scholar 

  19. Williams, M. J., Werner, B., Barnes, C. P., Graham, T. A., & Sottoriva, A. (2016). Identification of neutral tumor evolution across cancer types. Nature Genetics, 48(3), 1–9.

    Article  CAS  Google Scholar 

  20. Robinson, D., Van Allen, E. M., Wu, Y.-M., Schultz, N., Lonigro, R. J., Mosquera, J. M., et al. (2015). Integrative clinical genomics of advanced prostate cancer. Cell, 161(5), 1215–1228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Taylor, B. S., Schultz, N., Hieronymus, H., Gopalan, A., Xiao, Y., Carver, B. S., et al. (2010). Integrative genomic profiling of human prostate cancer. Cancer Cell, 18(1), 11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Abeshouse, A., Ahn, J., Akbani, R., Ally, A., Amin, S., et al. (2015). The molecular taxonomy of primary prostate cancer. Cell, 163(4), 1011–1025.

    Article  CAS  Google Scholar 

  23. Cooper, C. S., Eeles, R., Wedge, D. C., Van Loo, P., Gundem, G., Alexandrov, L. B., et al. (2015). Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nature Genetics, 47(4), 1–9.

    Article  CAS  Google Scholar 

  24. Beltran, H., Prandi, D., Mosquera, J. M., Benelli, M., Puca, L., Cyrta, J., et al. (2016). Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nature Medicine, 22(3), 298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wyatt, A. W., & Gleave, M. E. (2015). Targeting the adaptive molecular landscape of castration-resistant prostate cancer. EMBO Molecular Medicine, 7(7), 878–894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. McDonald, O. G., Li, X., Saunders, T., Tryggvadottir, R., Mentch, S. J., Warmoes, M. O., et al. (2017). Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nature Genetics, 49(3), 367–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Adamson, R. E., Frazier, A. A., Evans, H., Chambers, K. F., Schenk, E., Essand, M., Birnie, R., Mitry, R. R., Dhawan, A., & Maitland, N. J. (2012). In vitro primary cell culture as a physiologically relevant method for preclinical testing of human oncolytic adenovirus. Human Gene Therapy, 23(2), 218–230.

    Article  CAS  PubMed  Google Scholar 

  28. Olmos, D., Brewer, D., Clark, J., Danila, D. C., Parker, C., Attard, G., et al. (2012). Prognostic value of blood mRNA expression signatures in castration-resistant prostate cancer: A prospective, two-stage study. The Lancet Oncology, 13(11), 1114–1124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dunne, P. D., McArt, D. G., Bradley, C. A., O’Reilly, P. G., Barrett, H. L., Cummins, R., et al. (2016). Challenging the Cancer molecular stratification dogma: Intratumoral heterogeneity undermines consensus molecular subtypes and potential diagnostic value in colorectal cancer. Clinical Cancer Research, 22(16), 4095–4104.

    Article  CAS  PubMed  Google Scholar 

  30. Shah, R. B., Kunju, L. P., Shen, R., LeBlanc, M., Zhou, M., & Rubin, M. A. (2004). Usefulness of basal cell cocktail (34betaE12 + p63) in the diagnosis of atypical prostate glandular proliferations. American Journal of Clinical Pathology, 122(4), 517–523.

    Article  PubMed  Google Scholar 

  31. Abrahamsson, P. A. (1999). Neuroendocrine differentiation and hormone-refractory prostate cancer. The Prostate, 39(2), 135–148.

    Article  CAS  PubMed  Google Scholar 

  32. Yuan, T. C. (2006). Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. Endocrine-Related Cancer, 13(1), 151–167.

    Article  CAS  PubMed  Google Scholar 

  33. Li, Y., Donmez, N., Sahinalp, C., Xie, N., Wang, Y., Xue, H., et al. (2017). SRRM4 drives neuroendocrine transdifferentiation of prostate adenocarcinoma under androgen receptor pathway inhibition. European Urology, 71(1), 68–78.

    Article  CAS  PubMed  Google Scholar 

  34. Maitland, N. J., Frame, F. M., Polson, E. S., Lewis, J. L., & Collins, A. T. (2011). Prostate cancer stem cells: Do they have a basal or luminal phenotype? Hormones and Cancer, 2(1), 47–61.

    Article  PubMed  Google Scholar 

  35. Studer, U. E., Whelan, P., Albrecht, W., Casselman, J., de Reijke, T., Hauri, D., et al. (2006). Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) trial 30891. Journal of Clinical Oncology, 24(12), 1868–1876.

    Article  PubMed  Google Scholar 

  36. Frame, F. M., Pellacani, D., Collins, A. T., & Maitland, N. J. (2016). Harvesting human prostate tissue material and culturing primary prostate epithelial cells. Methods in Molecular Biology, 1443(2), 181–201.

    Article  CAS  PubMed  Google Scholar 

  37. Birnie, R., Bryce, S. D., Roome, C., Dussupt, V., Droop, A., et al. (2008). Gene expression profiling of human prostate cancer stem cells reveals a pro-inflammatory phenotype and the importance of extracellular matrix interactions. Genome Biology, 9(5), R83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Rane, J. K., Droop, A. P., Pellacani, D., Polson, E. S., Simms, M. S., Collins, A. T., et al. (2014). Conserved two-step regulatory mechanism of human epithelial differentiation. Stem Cell Reports, 2(2), 180–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rivera-Gonzalez, G. C., Droop, A. P., Rippon, H. J., Tiemann, K., Pellacani, D., Georgopoulos, L. J., et al. (2012). Retinoic acid and androgen receptors combine to achieve tissue specific control of human prostatic transglutaminase expression: A novel regulatory network with broader significance. Nucleic Acids Research, 40(11), 4825–4840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tapscott, S. J. (2005). The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription. Development, 132(12), 2685–2695.

    Article  CAS  PubMed  Google Scholar 

  41. Neilson, J. R., Zheng, G. X. Y., Burge, C. B., & Sharp, P. A. (2007). Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes & Development, 21(5), 578–589.

    Article  CAS  Google Scholar 

  42. Rane, J. K., Scaravilli, M., Ylipää, A., Pellacani, D., Mann, V. M., Simms, M. S., et al. (2015). MicroRNA expression profile of primary prostate cancer stem cells as a source of biomarkers and therapeutic targets. European Urology, 67(1), 7–10.

    Article  CAS  PubMed  Google Scholar 

  43. Liu, C., Kelnar, K., Vlassov, A. V., Brown, D., Wang, J., & Tang, D. G. (2012). Distinct microRNA expression profiles in prostate Cancer stem/progenitor cells and tumor-suppressive functions of let-7. Cancer Research, 72(13), 3393–3404.

    Article  CAS  PubMed  Google Scholar 

  44. Chivukula, R. R., Shi, G., Acharya, A., Mills, E. W., Zeitels, L. R., Anandam, J. L., et al. (2014). An essential mesenchymal function for miR-143/145 in intestinal epithelial regeneration. Cell, 157(5), 1104–1116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rane, J. K., Ylipää, A., Adamson, R., Mann, V. M., Simms, M. S., Collins, A. T., et al. (2015). Construction of therapeutically relevant human prostate epithelial fate map by utilising miRNA and mRNA microarray expression data. British Journal of Cancer, 113(4), 611–615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Frame, F. M., Pellacani, D., Collins, A. T., Simms, M. S., Mann, V. M., Jones, G. D. D., et al. (2013). HDAC inhibitor confers radiosensitivity to prostate stem-like cells. British Journal of Cancer, 109(12), 3023–3033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dansranjavin, T., Krehl, S., Mueller, T., Mueller, L. P., Schmoll, H.-J., & Dammann, R. H. (2009). The role of promoter CpG methylation in the epigenetic control of stem cell related genes during differentiation. Cell Cycle, 8(6), 916–924.

    Article  CAS  PubMed  Google Scholar 

  48. Pellacani, D., Packer, R. J., Frame, F. M., Oldridge, E. E., Berry, P. A., Labarthe, M.-C., et al. (2011). Regulation of the stem cell marker CD133 is independent of promoter hypermethylation in human epithelial differentiation and cancer. Molecular Cancer, 10(1), 94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pellacani, D., Kestoras, D., Droop, A. P., Frame, F. M., Berry, P. A., Lawrence, M. G., et al. (2014). DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation. Cell Death and Differentiation, 21(5), 761–773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pellacani, D., Droop, A. P., Frame, F. M., Simms, M. S., Mann, V. M., Collins, A. T., et al. (2018). Phenotype-independent DNA methylation changes in prostate cancer. British Journal of Cancer, 119(9), 1133–1143. https://doi.org/10.1038/s41416-018-0236-1.

    Article  CAS  PubMed  Google Scholar 

  51. Arechederra, M., Daian, F., Yim, A., Bazai, S. K., Richelme, S., Dono, R., et al. (2018). Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer. Nature Communications, 9(1), 3164.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Simmonds, P., Loomis, E., & Curry, E. (2017). DNA methylation-based chromatin compartments and ChIP-seq profiles reveal transcriptional drivers of prostate carcinogenesis. Genome Medicine, 9(1), 54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Jain, P., & Di Croce, L. (2016). Mutations and deletions of PRC2 in prostate cancer. BioEssays, 38(5), 446–454.

    Article  CAS  PubMed  Google Scholar 

  54. Deb, G., Thakur, V. S., & Gupta, S. (2013). Multifaceted role of EZH2 in breast and prostate tumorigenesis: Epigenetics and beyond. Epigenetics, 8(5), 464–476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sowalsky, A. G., Ye, H., Bubley, G. J., & Balk, S. P. (2013). Clonal progression of prostate cancers from Gleason grade 3 to grade 4. Cancer Research, 73(3), 1050–1055.

    Article  CAS  PubMed  Google Scholar 

  56. Penney, K. L., Stampfer, M. J., Jahn, J. L., Sinnott, J. A., Flavin, R., Rider, J. R., et al. (2013). Gleason grade progression is uncommon. Cancer Research, 73(16), 5163–5168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wienholds, E., & Plasterk, R. H. A. (2005). MicroRNA function in animal development. FEBS Letters, 579(26), 5911–5922.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank all members of the York CRU in recent years for their obvious or unconscious support in the preparation of this review. The underpinning research was funded by Yorkshire Cancer Research (NJM-Y257PA), York against Cancer (JRP), Prostate Cancer UK (Innovation Award RIA15-ST2-022(FMF) and Studentship S13-016 (LKA)), Charity Soul, with the major contributions from The Freemasons of the Province of Yorkshire (North and East Ridings), The Masonic Samaritan Fund (DP) and the EU Marie Curie ProNEST Network (JKR). Finally, we wish to acknowledge the generosity of the many prostate cancer patients and their families who donated tissues under our ethical protocol for research purposes.

Author information

Authors and Affiliations

  1. Cancer Research Unit, Department of Biology, University of York, York, UK

    Norman J. Maitland, Fiona M. Frame, Jayant K. Rane, Holger H. Erb, John R. Packer, Leanne K. Archer & Davide Pellacani

  2. Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada

    Davide Pellacani

Authors
  1. Norman J. Maitland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fiona M. Frame
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jayant K. Rane
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Holger H. Erb
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John R. Packer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leanne K. Archer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Davide Pellacani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norman J. Maitland .

Editor information

Editors and Affiliations

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

    Johng S. Rhim

  2. Georgetown University Medical Center, Washington, DC, USA

    Anatoly Dritschilo

  3. Department of Medicine, McGill University Health Centre, Montréal, QC, Canada

    Richard Kremer

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Maitland, N.J. et al. (2019). Resolution of Cellular Heterogeneity in Human Prostate Cancers: Implications for Diagnosis and Treatment. In: Rhim, J., Dritschilo, A., Kremer, R. (eds) Human Cell Transformation. Advances in Experimental Medicine and Biology, vol 1164. Springer, Cham. https://doi.org/10.1007/978-3-030-22254-3_16

Download citation

Publish with us

Policies and ethics

Search

Navigation