Cancer Stem Cells: A Revisitation of the “Anaplasia” Concept



Cancer stem cells (CSCs) are a subpopulation of cancer cells within a tumor originally characterized by the capability of initiating colonies in vitro or of forming tumors at high efficiency when injected into immunocompromised NOD/SCID mice. These cells have an undifferentiated phenotype and resemble normal stem cells in many ways, but are no longer under homeostatic control. CSC hypothesis permit to justify some intriguing and debated aspects of clinical oncology (radio- and chemoresistance, recidivism and metastasis). The definition of functional properties (cluster of differentiation, aberrant signaling pathways, high expression of drug efflux pumps of the MDR family, ALDH) of CSCs not only may permit their identification and isolation, but could permit to understand the mechanisms at the basis of their genomic and phenotypic instability. These peculiarities seem to induce a lethal genomic and phenotypic plasticity that is the molecular basis of cancer aggressiveness. The understanding of this high adaptability of CSC must represent the real target for a valid therapeutic and diagnostic approach to cancer.


Stem Cell Chronic Myeloid Leukemia Cancer Stem Cell Genetic Instability Clonal Evolution 
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  1. Al-Hajj M, Wicha MS, Benito-Hernandez A et al. (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–88.PubMedCrossRefGoogle Scholar
  2. Allen M, Louise Jones J (2011). Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J Pathol. 223: 162–76.PubMedGoogle Scholar
  3. Anderson K, Lutz C, van Delft FW et al (2011). Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469: 356–61.PubMedCrossRefGoogle Scholar
  4. Barbie DA, Hahn WC, Pelman DS (2008). Destabilization of cancer genome. In: Devita, Hellman & Rosenberg’s Cancer: Principles & Practice of Oncology 8th Ed. DeVita VT; Lawrence TS.; Rosenberg SA (Eds). Lippincott Williams & Wilkins. Philadelphia, PA, USA.PubMedCrossRefGoogle Scholar
  5. Beckman RA (2010) Efficiency of carcinogenesis: is the mutator phenotype inevitable? Semin Cancer Biol. 20: 340–52.PubMedCrossRefGoogle Scholar
  6. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3: 730–7.PubMedCrossRefGoogle Scholar
  7. Brégeon D, Doetsch PW (2011). Transcriptional mutagenesis: causes and involvement in tumour development. Nat Rev Cancer 11: 218–27.PubMedCrossRefGoogle Scholar
  8. Bristow RG, Hill RP (2008). Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8: 180–92.PubMedCrossRefGoogle Scholar
  9. Calabrese C, Poppleton H, Kocak M et al (2007). A perivascular niche for brain tumor stem cells. Cancer Cell 11: 69–82.PubMedCrossRefGoogle Scholar
  10. Clarke MF, Dick JE, Dirks PB et al. (2006) Cancer stem cells – perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res.66: 9339–9344.PubMedCrossRefGoogle Scholar
  11. Clevers H (2011). The cancer stem cell: premises, promises and challenges. Nat Med. 17: 313–9.PubMedCrossRefGoogle Scholar
  12. Collins AT, Berry PA, Hyde C (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65: 10946–51.PubMedCrossRefGoogle Scholar
  13. Conway AE, Lindgren A, Galic Z et al (2009). A self-renewal program controls the expansion of genetically unstable cancer stem cells in pluripotent stem cell-derived tumors. Stem Cells. 27: 18–28.Google Scholar
  14. Dayal D, Martin SM, Owens KM, et al. (2009). Mitochondrial complex II dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation. Radiat Res. 172:737–45.PubMedCrossRefGoogle Scholar
  15. Dick JE (2008) Stem cell concepts renew cancer research. Blood 112: 4793–807.PubMedCrossRefGoogle Scholar
  16. Gilbertson RJ and Rich JN (2007). Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nature Rev. Cancer 7: 733–736.CrossRefGoogle Scholar
  17. Greaves M (2010). Cancer stem cells: back to Darwin? Semin Cancer Biol. 20: 65–70.PubMedCrossRefGoogle Scholar
  18. Gupta PB, Chaffer CL, Weinberg RA (2009). Cancer stem cells: mirage or reality? Nat Med. 15: 1010–2.PubMedCrossRefGoogle Scholar
  19. Jamieson CH, Ailles LE, Dylla SJ et al (2004). Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 351: 657–67.PubMedCrossRefGoogle Scholar
  20. Janic A, Mendizabal L, Llamazares S et al (2010) Ectopic expression of germline genes drives malignant brain tumor growth in Drosophila. Science. 330: 1824–7.PubMedCrossRefGoogle Scholar
  21. LaBarge MA (2010). The difficulty of targeting cancer stem cell niches. Clin Cancer Res. 16: 3121–9.PubMedCrossRefGoogle Scholar
  22. Leder K, Holland EC, Michor F (2010). The therapeutic implications of plasticity of the cancer stem cell phenotype. PLoS One. 5: e14366.PubMedCrossRefGoogle Scholar
  23. Li C, Heidt DG, Dalerba P et al (2007). Identification of pancreatic cancer stem cells. Cancer Res. 67: 1030–7.PubMedCrossRefGoogle Scholar
  24. Liu W, Laitinen S, Khan S et al (2009). Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med. 15: 559–65.PubMedCrossRefGoogle Scholar
  25. Liu C, Kelnar K, Liu B et al (2011). The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 17: 211–5.PubMedCrossRefGoogle Scholar
  26. Maenhaut C, Dumont J E, Roger P Pand van Staveren W C  G (2010). Cancer stem cells: a reality, a myth, a fuzzy concept or a misnomer? An analysis. Carcinogenesis 31: 149–158.PubMedCrossRefGoogle Scholar
  27. Mani SA, Guo W, Liao MJ et al (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133: 704–15.PubMedCrossRefGoogle Scholar
  28. Notta F, Mullighan CG, Wang JC et al (2011). Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469: 362–7.PubMedCrossRefGoogle Scholar
  29. O’Brien CA, Pollett A, Gallinger S, Dick JE (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445: 106–10.PubMedCrossRefGoogle Scholar
  30. Park SY, et al (2010). Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. J Clin Invest.120: 636-44.Google Scholar
  31. Perera S, Bapat B (2007). Genetic Instability in Cancer. Atlas Genet Cytogenet Oncol Haematol. January 2007. URL:
  32. Pierce GB, Speers WC (1988) Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation. Cancer Res 48: 1996–2004.PubMedGoogle Scholar
  33. Quintana E, Shackleton M, Sabel MS et al (2008) Efficient tumour formation by single human melanoma cells. Nature 456: 593–8.PubMedCrossRefGoogle Scholar
  34. Rapp UR, Ceteci F, Schreck R (2008). Oncogene-induced plasticity and cancer stem cells. Cell Cycle. 7: 45–51.PubMedCrossRefGoogle Scholar
  35. Raynaud CM, Sabatier L, Philipot O et al (2008). Telomere length, telomeric proteins and genomic instability during the multistep carcinogenic process. Crit Rev Oncol Hematol. 66: 99–117.PubMedCrossRefGoogle Scholar
  36. Reya T Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414: 105–11.PubMedCrossRefGoogle Scholar
  37. Ricci-Vitiani L, Pallini R, Biffoni M et al (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468: 824–8.PubMedCrossRefGoogle Scholar
  38. Roesch A, Fukunaga-Kalabis M, Schmidt EC et al (2010). A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141: 583–94.PubMedCrossRefGoogle Scholar
  39. Rosen JM, Jordan CT (2009) The increasing complexity of the cancer stem cell paradigm. Science 324: 1670–3.PubMedCrossRefGoogle Scholar
  40. Scatena R, Bottoni P, Giardina B (2008). Modulation of cancer cell line differentiation: A neglected proteomic analysis with potential implications in pathophysiology, diagnosis, prognosis, and therapy of cancer. Proteomics Clin Appl. 2: 229–37.PubMedCrossRefGoogle Scholar
  41. Scatena R, Bottoni P, Pontoglio A, Giardina B (2010). Revisiting the Warburg effect in cancer cells with proteomics. The emergence of new approaches to diagnosis, prognosis and therapy. Proteomics Clin Appl. 4: 143–58.PubMedCrossRefGoogle Scholar
  42. Scatena R, Bottoni P, Pontoglio A, Giardina B (2011). Cancer stem cells: the development of new cancer therapeutics. Expert Opin Biol Ther. 11: 875–92.Google Scholar
  43. Sell S, Leffert HL (2008). Liver cancer stem cells. J Clin Oncol. 26: 2800–5.PubMedCrossRefGoogle Scholar
  44. Singh SK, Clarke ID, Terasaki M (2003). Identification of a cancer stem cell in human brain tumors. Cancer Res. 63: 5821–8.PubMedGoogle Scholar
  45. Sodir NM, Swigart LB, Karnezis AN et al (2011). Endogenous Myc maintains the tumor microenvironment. Genes Dev. 25: 907–16.Google Scholar
  46. Stricker TP, Kumar V. Neoplasia (2010) In: Robbins and Cotran Pathologic Basis of Disease 8th Ed. Kumar V, Abbas AK, Fausto N, Aster JC (Eds) Saunders, Philadelphia.Google Scholar
  47. Tili E, Michaille JJ, Wernicke D (2011). Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer. Proc Natl Acad Sci USA. 108: 4908–13.PubMedCrossRefGoogle Scholar
  48. Valeri N, Gasparini P, Fabbri M (2010). Modulation of mismatch repair and genomic stability by miR-155. Proc Natl Acad Sci USA. 107: 6982–7.PubMedCrossRefGoogle Scholar
  49. Visvader JE and Lindeman GJ (2008).Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Rev. Cancer 8: 755–768.CrossRefGoogle Scholar
  50. Visvader JE (2011). Cells of origin in cancer. Nature. 469: 314–22.PubMedCrossRefGoogle Scholar
  51. Von Hoff DD, LoRusso PM, Rudin CM et al (2009). Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 361: 1164–72.CrossRefGoogle Scholar
  52. Yauch RL, Dijkgraaf GJ, Alicke B et al (2009) Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326: 572–4.PubMedCrossRefGoogle Scholar
  53. Wang JCY, Dick JE. Cancer Stem Cells. (2008) In: Devita, Hellman & Rosenberg’s Cancer: Principles & Practice of Oncology 8th Ed. DeVita VT; Lawrence TS.; Rosenberg SA (Eds). Lippincott Williams & Wilkins. Philadelphia, PA, USA, 135–143.Google Scholar
  54. Wang R, Chadalavada K, Wilshire J et al (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 468: 829–33.PubMedCrossRefGoogle Scholar
  55. Woodward WA, Sulman EP (2008). Cancer stem cells: markers or biomarkers? Cancer Metastasis Rev. 27: 459–70.PubMedCrossRefGoogle Scholar
  56. Zhou BB, Zhang H, Damelin M et al (2009). Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 8: 806–23.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Laboratory MedicineCatholic UniversityRomeItaly

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