Advertisement

Tumor Dormancy and Slow-Cycling Cancer Cells

  • John E. DavisJr
  • Jason Kirk
  • Yibing Ji
  • Dean G. TangEmail author
Chapter
  • 469 Downloads
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1164)

Abstract

Cancer cell heterogeneity is a universal feature of human tumors and represents a significant barrier to the efficacy and duration of anticancer therapies, especially targeted therapeutics. Among the heterogeneous cancer cell populations is a subpopulation of relatively quiescent cancer cells, which are in the G0/G1 cell-cycle phase and refractory to anti-mitotic drugs that target proliferative cells. These slow-cycling cells (SCCs) preexist in untreated tumors and frequently become enriched in treatment-failed tumors, raising the possibility that these cells may mediate therapy resistance and tumor relapse. Here we review several general concepts on tumor cell heterogeneity, quiescence, and tumor dormancy. We discuss the potential relationship between SCCs and cancer stem cells (CSCs). We also present our current understanding of how SCCs and cancer dormancy might be regulated. Increasing knowledge of SCCs and tumor dormancy should lead to identification of novel molecular regulators and therapeutic targets of tumor relapse, residual diseases, and metastasis.

Keywords

Cancer stem cell Tumor dormancy Quiescence Slow-cycling cell Prostate cancer Tumor cell heterogeneity Label-retaining cell LRIG1 Cell cycle scRNA-Seq Lineage tracing Prostate stem cell TGF-beta Cell-of-origin Self-renewal Progenitor Plasticity CD44 

Notes

Acknowledgments

Work in the authors’ lab was supported by grants from the U.S. National Institutes of Health (NIH) (R01CA237027 and R21CA218635), Department of Defense (W81XWH-16-1-0575), and RPCCC and NCI grant P30CA016056.

References

  1. 1.
    Liu, X., et al. (2015). Systematic dissection of phenotypic, functional, and tumorigenic heterogeneity of human prostate cancer cells. Oncotarget, 6(27), 23959–23986.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Moore, N., & Lyle, S. (2011). Quiescent, slow-cycling stem cell populations in cancer: A review of the evidence and discussion of significance. Journal of Oncology, 2011, 396076.CrossRefGoogle Scholar
  3. 3.
    Tang, D. G. (2012). Understanding cancer stem cell heterogeneity and plasticity. Cell Research, 22(3), 457–472.CrossRefGoogle Scholar
  4. 4.
    Aguirre-Ghiso, J. A. (2007). Models, mechanisms and clinical evidence for cancer dormancy. Nature Reviews. Cancer, 7(11), 834–846.CrossRefGoogle Scholar
  5. 5.
    Salm, S., Burger, P. E., & Wilson, E. L. (2012). TGF-beta and stem cell factor regulate cell proliferation in the proximal stem cell niche. Prostate, 72(9), 998–1005.CrossRefGoogle Scholar
  6. 6.
    Salm, S. N., et al. (2005). TGF-beta maintains dormancy of prostatic stem cells in the proximal region of ducts. The Journal of Cell Biology, 170(1), 81–90.CrossRefGoogle Scholar
  7. 7.
    Santoni-Rugiu, E., et al. (2005). Progenitor cells in liver regeneration: Molecular responses controlling their activation and expansion. APMIS, 113(11–12), 876–902.CrossRefGoogle Scholar
  8. 8.
    Mishra, L., et al. (2005). The role of TGF-β and Wnt signaling in gastrointestinal stem cells and cancer. Oncogene, 24(37), 5775–5789.CrossRefGoogle Scholar
  9. 9.
    Wilson, A., & Trumpp, A. (2006). Bone-marrow haematopoietic-stem-cell niches. Nature Reviews. Immunology, 6(2), 93–106.CrossRefGoogle Scholar
  10. 10.
    Yadav, A. S., et al. (2018). The biology and therapeutic implications of tumor dormancy and reactivation. Frontiers in Oncology, 8, 72.CrossRefGoogle Scholar
  11. 11.
    Sun, Q., et al. (2012). Immunotherapy using slow-cycling tumor cells prolonged overall survival of tumor-bearing mice. BMC Medicine, 10, 172.CrossRefGoogle Scholar
  12. 12.
    Almog, N. (2010). Molecular mechanisms underlying tumor dormancy. Cancer Letters, 294(2), 139–146.CrossRefGoogle Scholar
  13. 13.
    Sosa, M. S., Bragado, P., & Aguirre-Ghiso, J. A. (2014). Mechanisms of disseminated cancer cell dormancy: An awakening field. Nature Reviews. Cancer, 14(9), 611–622.CrossRefGoogle Scholar
  14. 14.
    Jeter, C. R., et al. (2009). Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells, 27(5), 993–1005.CrossRefGoogle Scholar
  15. 15.
    Qin, J., et al. (2012). The PSA(−/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell, 10(5), 556–569.CrossRefGoogle Scholar
  16. 16.
    Tang, D. G., et al. (2007). Prostate cancer stem/progenitor cells: Identification, characterization, and implications. Molecular Carcinogenesis, 46(1), 1–14.CrossRefGoogle Scholar
  17. 17.
    Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3(7), 730–737.CrossRefGoogle Scholar
  18. 18.
    Collins, A. T., et al. (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Research, 65(23), 10946–10951.CrossRefGoogle Scholar
  19. 19.
    Singh, S. K., et al. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Research, 63(18), 5821–5828.PubMedGoogle Scholar
  20. 20.
    Wright, M. H., et al. (2008). Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Research, 10(1), R10.CrossRefGoogle Scholar
  21. 21.
    Roesch, A., et al. (2010). A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell, 141(4), 583–594.CrossRefGoogle Scholar
  22. 22.
    Roesch, A., et al. (2013). Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell, 23(6), 811–825.CrossRefGoogle Scholar
  23. 23.
    Kester, L., & van Oudenaarden, A. (2018). Single-cell transcriptomics meets lineage tracing. Cell Stem Cell, 23(2), 166–179.CrossRefGoogle Scholar
  24. 24.
    Zhao, T., et al. (2018). Single-cell RNA-Seq reveals dynamic early embryonic-like programs during chemical reprogramming. Cell Stem Cell, 23(1), 31–45.e7.CrossRefGoogle Scholar
  25. 25.
    Li, L., & Clevers, H. (2010). Coexistence of quiescent and active adult stem cells in mammals. Science, 327(5965), 542–545.CrossRefGoogle Scholar
  26. 26.
    Zhang, D., et al. (2018). Histone 2B-GFP label-retaining prostate luminal cells possess progenitor cell properties and are intrinsically resistant to castration. Stem Cell Reports, 10(1), 228–242.CrossRefGoogle Scholar
  27. 27.
    Sakaue-Sawano, A., et al. (2008). Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell, 132(3), 487–498.CrossRefGoogle Scholar
  28. 28.
    Zielke, N., & Edgar, B. A. (2015). FUCCI sensors: Powerful new tools for analysis of cell proliferation. Wiley Interdisciplinary Reviews: Developmental Biology, 4(5), 469–487.CrossRefGoogle Scholar
  29. 29.
    Drost, J., & Clevers, H. (2018). Organoids in cancer research. Nature Reviews. Cancer, 18(7), 407–418.CrossRefGoogle Scholar
  30. 30.
    Miller, M. A., & Weissleder, R. (2017). Imaging of anticancer drug action in single cells. Nature Reviews. Cancer, 17(7), 399–414.CrossRefGoogle Scholar
  31. 31.
    van der Toom, E. E., Verdone, J. E., & Pienta, K. J. (2016). Disseminated tumor cells and dormancy in prostate cancer metastasis. Current Opinion in Biotechnology, 40, 9–15.CrossRefGoogle Scholar
  32. 32.
    Chen, X., et al. (2016). Defining a population of stem-like human prostate cancer cells that can generate and propagate castration-resistant prostate Cancer. Clinical Cancer Research, 22(17), 4505–4516.CrossRefGoogle Scholar
  33. 33.
    Horning, A. M., et al. (2018). Single-cell RNA-seq reveals a subpopulation of prostate cancer cells with enhanced cell-cycle-related transcription and attenuated androgen response. Cancer Research, 78(4), 853–864.CrossRefGoogle Scholar
  34. 34.
    Perego, M., et al. (2018). A slow-cycling subpopulation of melanoma cells with highly invasive properties. Oncogene, 37(3), 302–312.CrossRefGoogle Scholar
  35. 35.
    Tsujimura, A., et al. (2002). Proximal location of mouse prostate epithelial stem cells: A model of prostatic homeostasis. The Journal of Cell Biology, 157(7), 1257–1265.CrossRefGoogle Scholar
  36. 36.
    Lawson, D. A., et al. (2007). Isolation and functional characterization of murine prostate stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104(1), 181–186.CrossRefGoogle Scholar
  37. 37.
    Burger, P. E., et al. (2005). Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue. Proceedings of the National Academy of Sciences of the United States of America, 102(20), 7180–7185.CrossRefGoogle Scholar
  38. 38.
    Lawson, D. A., et al. (2010). Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proceedings of the National Academy of Sciences of the United States of America, 107(6), 2610–2615.CrossRefGoogle Scholar
  39. 39.
    Xin, L., Lawson, D. A., & Witte, O. N. (2005). The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 102(19), 6942–6947.CrossRefGoogle Scholar
  40. 40.
    Xin, L., et al. (2007). Self-renewal and multilineage differentiation in vitro from murine prostate stem cells. Stem Cells, 25(11), 2760–2769.CrossRefGoogle Scholar
  41. 41.
    Wang, Z. A., et al. (2013). Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nature Cell Biology, 15(3), 274–283.CrossRefGoogle Scholar
  42. 42.
    Choi, N., et al. (2012). Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell, 21(2), 253–265.CrossRefGoogle Scholar
  43. 43.
    Wang, X., et al. (2009). A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature, 461(7263), 495–500.CrossRefGoogle Scholar
  44. 44.
    Karthaus, W. R., et al. (2014). Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell, 159(1), 163–175.CrossRefGoogle Scholar
  45. 45.
    Ousset, M., et al. (2012). Multipotent and unipotent progenitors contribute to prostate postnatal development. Nature Cell Biology, 14(11), 1131–1138.CrossRefGoogle Scholar
  46. 46.
    Zhang, D., et al. (2017). Developing a novel two-dimensional culture system to enrich human prostate luminal progenitors that can function as a cell of origin for prostate Cancer. Stem Cells Translational Medicine, 6(3), 748–760.CrossRefGoogle Scholar
  47. 47.
    Zhang, D., et al. (2016). Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer. Nature Communications, 7, 10798.CrossRefGoogle Scholar
  48. 48.
    Bhatia, B., et al. (2008). Critical and distinct roles of p16 and telomerase in regulating the proliferative life span of normal human prostate epithelial progenitor cells. The Journal of Biological Chemistry, 283(41), 27957–27972.CrossRefGoogle Scholar
  49. 49.
    Rycaj, K., et al. (2016). Longitudinal tracking of subpopulation dynamics and molecular changes during LNCaP cell castration and identification of inhibitors that could target the PSA-/lo castration-resistant cells. Oncotarget, 7(12), 14220–14240.CrossRefGoogle Scholar
  50. 50.
    Patrawala, L., et al. (2006). Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene, 25(12), 1696–1708.CrossRefGoogle Scholar
  51. 51.
    Patrawala, L., et al. (2005). Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Research, 65(14), 6207–6219.CrossRefGoogle Scholar
  52. 52.
    Patrawala, L., et al. (2007). Hierarchical organization of prostate cancer cells in xenograft tumors: The CD44+alpha2beta1+ cell population is enriched in tumor-initiating cells. Cancer Research, 67(14), 6796–6805.CrossRefGoogle Scholar
  53. 53.
    Patrawala, L. T., & G, D. (2007). CD44 as a functional cancer stem cell marker and a potential therapeutic target. In Autologous and cancer stem cell gene therapy (pp. 317–334). Singapore: World Scientific Publishing.CrossRefGoogle Scholar
  54. 54.
    Choi, E., et al. (2018). Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut, 67(9), 1595–1605.CrossRefGoogle Scholar
  55. 55.
    Jensen, K. B., et al. (2009). Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell Stem Cell, 4(5), 427–439.CrossRefGoogle Scholar
  56. 56.
    Jensen, K. B., & Watt, F. M. (2006). Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proceedings of the National Academy of Sciences of the United States of America, 103(32), 11958–11963.CrossRefGoogle Scholar
  57. 57.
    Powell, A. E., et al. (2012). The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell, 149(1), 146–158.CrossRefGoogle Scholar
  58. 58.
    Wang, Y., Poulin, E. J., & Coffey, R. J. (2013). LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor. British Journal of Cancer, 108(9), 1765–1770.CrossRefGoogle Scholar
  59. 59.
    Wong, V. W., et al. (2012). Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nature Cell Biology, 14(4), 401–408.CrossRefGoogle Scholar
  60. 60.
    Linde, N., Fluegen, G., & Aguirre-Ghiso, J. A. (2016). The relationship between dormant cancer cells and their microenvironment. Advances in Cancer Research, 132, 45–71.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • John E. DavisJr
    • 1
  • Jason Kirk
    • 1
  • Yibing Ji
    • 1
  • Dean G. Tang
    • 1
    Email author
  1. 1.Department of Pharmacology and TherapeuticsRoswell Park Comprehensive Cancer CenterBuffaloUSA

Personalised recommendations