Advertisement

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

  • Norman J. MaitlandEmail author
  • Fiona M. Frame
  • Jayant K. Rane
  • Holger H. Erb
  • John R. Packer
  • Leanne K. Archer
  • Davide Pellacani
Chapter
  • 376 Downloads
Part of the Advances in Experimental Medicine and Biology book series (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.

Keywords

Prostate cancer Heterogeneity Epigenetics Gene expression 

Notes

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.

References

  1. 1.
    Gleason, D. F. (1966). Classification of prostatic carcinomas. Cancer Chemotherapy Reports. Part 1, 50(3), 125–128.PubMedGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 4.
    Klotz, L. (2013). Prostate cancer overdiagnosis and overtreatment. Current Opinion in Endocrinology & Diabetes and Obesity, 20(3), 204–209.CrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 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.PubMedPubMedCentralGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 12.
    Lamouille, S., Xu, J., & Derynck, R. (2014). Molecular mechanisms of epithelial-mesenchymal transition. Nature Reviews. Molecular Cell Biology, 15(3), 178–196.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 31.
    Abrahamsson, P. A. (1999). Neuroendocrine differentiation and hormone-refractory prostate cancer. The Prostate, 39(2), 135–148.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.CrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Jain, P., & Di Croce, L. (2016). Mutations and deletions of PRC2 in prostate cancer. BioEssays, 38(5), 446–454.PubMedCrossRefGoogle Scholar
  54. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Wienholds, E., & Plasterk, R. H. A. (2005). MicroRNA function in animal development. FEBS Letters, 579(26), 5911–5922.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Norman J. Maitland
    • 1
    Email author
  • Fiona M. Frame
    • 1
  • Jayant K. Rane
    • 1
  • Holger H. Erb
    • 1
  • John R. Packer
    • 1
  • Leanne K. Archer
    • 1
  • Davide Pellacani
    • 1
    • 2
  1. 1.Cancer Research Unit, Department of BiologyUniversity of YorkYorkUK
  2. 2.Terry Fox Laboratory, BC Cancer AgencyVancouverCanada

Personalised recommendations