Skip to main content
SpringerLink
Log in

Cancer Stem Cells in the Immune Microenvironment

  • Chapter
  • First Online:
Translational Research in Breast Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1187))

Abstract

Cancer stem cells are a subpopulation of cancer cells responsible for the most demanding and aggressive cancer cell phenotypes: therapy resistance, a self-protective feature of stem cells; distant metastasis, requiring anchorage independence for survival in the circulation; and recurrence, which is related to the dormant-active cycling of stem cells. Normal tissues are composed of parenchymal cells, supportive connective components, and cellular disposal systems for removing the products of physiological wear and tear. Cancer stem cells develop from normal counterparts and progressively interact with their microenvironments, modifying and conditioning the cancer microenvironment. Cancer-associated myeloid cells constitute a major element of the cancer microenvironment. During the process of carcinogenesis, cancer stem cells and their intimately associated myeloid cells mutually interact and evolve, such that the cancer cells potentiate the activity of the myeloid cells and, in return, the myeloid cells increase cancer stem cell characteristics. Normal myeloid cells function as key accessory cells to maintain homeostasis in normal tissues and organs; in cancers, these cells co-evolve with the malignant parenchymal cells and are involved in every aspect of cancer cell biology, including proliferation, invasion, distant metastasis, and the development of resistance to therapy. In this way, cancer-associated myeloid cells provide two of the key hallmarks of cancer: evasion of immune destruction and cancer-promoting inflammation.

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 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
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. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–8.

    Article  CAS  PubMed  Google Scholar 

  2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730–7.

    Article  CAS  PubMed  Google Scholar 

  3. Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5(7):738–43.

    Article  CAS  PubMed  Google Scholar 

  4. O'Brien CA, Kreso A, Dick JE. Cancer stem cells in solid tumors: an overview. Semin Radiat Oncol. 2009;19(2):71–7.

    Article  PubMed  Google Scholar 

  5. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009;138(5):822–9.

    Article  CAS  PubMed  Google Scholar 

  6. Huntly BJ, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer. 2005;5(4):311–21.

    Article  CAS  PubMed  Google Scholar 

  7. Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV, et al. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer. 2012;12(11):767–75.

    Article  CAS  PubMed  Google Scholar 

  8. Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14(3):275–91.

    Article  CAS  PubMed  Google Scholar 

  9. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17(3):313–9.

    Article  CAS  PubMed  Google Scholar 

  10. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717–28. Review. https://doi.org/10.1016/j.stem.2012.05.007.

    Article  CAS  PubMed  Google Scholar 

  11. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.

    Article  CAS  PubMed  Google Scholar 

  13. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.

    Article  CAS  PubMed  Google Scholar 

  14. Pützer BM, Solanki M, Herchenröder O. Advances in cancer stem cell targeting: how to strike the evil at its root. Adv Drug Deliv Rev. 2017;120:89–107.

    Article  PubMed  CAS  Google Scholar 

  15. Weinberg RA. The biology of cancer. 2nd ed. New York: Garland Science; 2014. p. 77–83.

    Google Scholar 

  16. Ablett MP, Singh JK, Clarke RB. Stem cells in breast tumours: are they ready for the clinic? Eur J Cancer. 2012;48(14):2104–16.

    Article  CAS  PubMed  Google Scholar 

  17. Yang F, Xu J, Tang L, Guan X. Breast cancer stem cell: the roles and therapeutic implications. Cell Mol Life Sci. 2017;74(6):951–66.

    Article  CAS  PubMed  Google Scholar 

  18. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23(10):1124–34.

    Article  CAS  PubMed  Google Scholar 

  19. Rutkowski MR, Svoronos N, Perales-Puchalt A, Conejo-Garcia JR. The tumor macroenvironment: cancer-promoting networks beyond tumor beds. Adv Cancer Res. 2015;128:235–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Roberts KJ, Kershner AM, Beachy PA. The stromal niche for epithelial stem cells: a template for regeneration and a brake on malignancy. Cancer Cell. 2017;32(4):404–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Castaño Z, Fillmore CM, Kim CF, McAllister SS. The bed and the bugs: interactions between the tumor microenvironment and cancer stem cells. Semin Cancer Biol. 2012;22(5–6):462–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C, Marini FC. Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res. 2016;18(1):84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Nair N, Calle AS, Zahra MH, Prieto-Vila M, Oo AKK, Hurley L, et al. A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment. Sci Rep. 2017;7(1):6838.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Kotas ME, Medzhitov R. Homeostasis, inflammation, and disease susceptibility. Cell. 2015;160(5):816–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Okabe Y, Medzhitov R. Tissue biology perspective on macrophages. Nat Immunol. 2016;17(1):9–17.

    Article  CAS  PubMed  Google Scholar 

  26. Perdiguero EG, Geissmann F. The development and maintenance of resident macrophages. Nat Immunol. 2016;17(1):2–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12(4):253–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ugel S, De Sanctis F, Mandruzzato S, Bronte V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest. 2015;125(9):3365–76.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest. 2011;121(10):3804–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chin AR, Wang SE. Cytokines driving breast cancer stemness. Mol Cell Endocrinol. 2014;382(1):598–602. https://doi.org/10.1016/j.mce.2013.03.024.

    Article  CAS  PubMed  Google Scholar 

  31. Oh K, Park HB, Byoun OJ, Shin DM, Jeong EM, Kim YW, et al. Epithelial transglutaminase 2 is needed for T cell interleukin-17 production and subsequent pulmonary inflammation and fibrosis in bleomycin-treated mice. J Exp Med. 2011;208(8):1707–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Oh K, Ko E, Kim HS, Park AK, Moon HG, Noh DY, et al. Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells. Breast Cancer Res. 2011;13(5):R96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Oh K, Lee OY, Park Y, Seo MW, Lee DS. IL-1β induces IL-6 production and increases invasiveness and estrogen-independent growth in a TG2-dependent manner in human breast cancer cells. BMC Cancer. 2016;16(1):724.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Oh K, Lee OY, Shon SY, Nam O, Ryu PM, Seo MW, et al. A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model. Breast Cancer Res. 2013;15(5):R79.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121(9):3375–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Scheller J, Chalaris A, Garbers C, Rose-John S. ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol. 2011;32(8):380–7.

    Article  CAS  PubMed  Google Scholar 

  37. Pruessmeyer J, Ludwig A. The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer. Semin Cell Dev Biol. 2009;20(2):164–74.

    Article  CAS  PubMed  Google Scholar 

  38. Chalaris A, Gewiese J, Paliga K, Fleig L, Schneede A, Krieger K, et al. ADAM17-mediated shedding of the IL6R induces cleavage of the membrane stub by gamma-secretase. Biochim Biophys Acta. 2010;1803(2):234–45.

    Article  CAS  PubMed  Google Scholar 

  39. Lu H, Clauser KR, Tam WL, Fröse J, Ye X, Eaton EN, et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol. 2014;16(11):1105–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bruttel VS, Wischhusen J. Cancer stem cell immunology: key to understanding tumorigenesis and tumor immune escape? Front Immunol. 2014;5:360.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015;125(9):3356–64.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37(3):208–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chawla A, Alatrash G, Wu Y, Mittendorf EA. Immune aspects of the breast tumor microenvironment. Breast Cancer Manag. 2013;2(3):231–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36(4):265–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Speiser DE, Utzschneider DT, Oberle SG, Münz C, Romero P, Zehn D. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? Nat Rev Immunol. 2014;14(11):768–74. https://doi.org/10.1038/nri3740.

    Article  CAS  PubMed  Google Scholar 

  46. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56–61.

    Article  CAS  PubMed  Google Scholar 

  47. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Collin M. Immune checkpoint inhibitors: the battle of giants. Pharm Pat Anal. 2017;6(4):135–7.

    Article  CAS  PubMed  Google Scholar 

  50. Xu-Monette ZY, Zhang M, Li J, Young KH. PD-1/PD-L1 blockade: have we found the key to unleash the antitumor immune response? Front Immunol. 2017;8:1597.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol. 2014;14(6):377–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vonderheide RH, Domchek SM, Clark AS. Immunotherapy for breast cancer: what are we missing? Clin Cancer Res. 2017;23(11):2640–6.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Hirohashi Y, Torigoe T, Tsukahara T, Kanaseki T, Kochin V, Sato N. Immune responses to human cancer stem-like cells/cancer-initiating cells. Cancer Sci. 2016;107(1):12–7.

    Article  CAS  PubMed  Google Scholar 

  54. Fiori ME, Villanova L, De Maria R. Cancer stem cells: at the forefront of personalized medicine and immunotherapy. Curr Opin Pharmacol. 2017;35:1–11.

    Article  CAS  PubMed  Google Scholar 

  55. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kunz M, Hölzel M. The impact of melanoma genetics on treatment response and resistance in clinical and experimental studies. Cancer Metastasis Rev. 2017;36(1):53–75.

    Article  CAS  PubMed  Google Scholar 

  57. Nathanson T, Ahuja A, Rubinsteyn A, Aksoy BA, Hellmann MD, Miao D, et al. Somatic mutations and neoepitope homology in melanomas treated with CTLA-4 blockade. Cancer Immunol Res. 2017;5(1):84–91.

    Article  CAS  PubMed  Google Scholar 

  58. Cho JH. Immunotherapy for non-small-cell lung cancer: current status and future obstacles. Immune Netw. 2017;17(6):378–91.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Seoul National University College of Medicine, Seoul, Republic of Korea

    Dong-Sup Lee

  2. SillaJen, Inc., Seoul, Republic of Korea

    Keunhee Oh

Authors
  1. Dong-Sup Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keunhee Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong-Sup Lee .

Editor information

Editors and Affiliations

  1. Department of Surgery, College of Medicine, Seoul National University, Seoul, Korea (Republic of)

    Dong-Young Noh

  2. College of Medicine, Seoul National University College of Medicine, Seoul, Korea (Republic of)

    Wonshik Han

  3. Graduate School of Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Masakazu Toi

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lee, DS., Oh, K. (2021). Cancer Stem Cells in the Immune Microenvironment. In: Noh, DY., Han, W., Toi, M. (eds) Translational Research in Breast Cancer. Advances in Experimental Medicine and Biology, vol 1187. Springer, Singapore. https://doi.org/10.1007/978-981-32-9620-6_12

Download citation

Publish with us

Policies and ethics

Search

Navigation