Implications of Cancer Stem Cells for Cancer Therapy

  • Liang ChengEmail author
  • Shaobo Zhang
  • Darrell D. Davidson
  • Rodolfo Montironi
  • Antonio Lopez-Beltran
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Our contemporary understanding of cancer biology is based on the stem cell hypothesis. This framework explains regression of premalignant lesions, radiation and drug resistant tumor cell subsets, relapse after complete therapeutic response, clonal similarity of metastatic implants and stromal requirements for cancer cultivation. The stem cell hypothesis also brings with it a new paradigm for cancer treatment. New therapies will increasingly target stem cell specific surface molecules, oncoproteins, regulation pathway elements, resistance mediators and stromal niche support factors. As our understanding of stem cell markers expands for various tumor subclasses, this knowledge of cancer stem cell biology and clinical significance will lead to more effective and safer treatments for human cancers.

Key Words

Cancer stem cell pathway targeting targeted therapy personalized medicine mesenchymal stem cell stromal biology 


  1. 1.
    Lapidot T, Sirard C, Vormoor J, et al: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–8, 1994PubMedCrossRefGoogle Scholar
  2. 2.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, et al: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–8, 2003PubMedCrossRefGoogle Scholar
  3. 3.
    Jordan CT, Guzman ML, Noble M: Cancer stem cells. N Engl J Med 355:1253–61, 2006PubMedCrossRefGoogle Scholar
  4. 4.
    Pan CX, Zhu W, Cheng L: Implications of cancer stem cells in the treatment of cancer. Future Oncol 2:723–31, 2006PubMedCrossRefGoogle Scholar
  5. 5.
    Cheng L, Zhang D: Molecular Genetic Pathology. Totowa, NJ, Humana Press, 2008CrossRefGoogle Scholar
  6. 6.
    Reya T, Morrison SJ, Clarke MF, et al: Stem cells, cancer, and cancer stem cells. Nature 404:105–11, 2001CrossRefGoogle Scholar
  7. 7.
    Jordan CT, Guzman ML: Mechanisms controlling pathogenesis and survival of leukemic stem cells. Oncogene 23:7178–87, 2004PubMedCrossRefGoogle Scholar
  8. 8.
    Gao JX: Cancer stem cells: the lessons from pre-cancerous stem cells. J Cell Mol Med 12:67–96, 2008PubMedCrossRefGoogle Scholar
  9. 9.
    Houghton J, Stoicov C, Nomura S, et al: Gastric cancer originating from bone marrow-derived cells. Science 306:1568–71, 2004PubMedCrossRefGoogle Scholar
  10. 10.
    Tateishi K, Ohta M, Kanai F, et al: Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract. Clin Cancer Res 12:6960–6, 2006PubMedCrossRefGoogle Scholar
  11. 11.
    Shen R, Ye Y, Chen L, et al: Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS ONE 3:e1652, 2008PubMedCrossRefGoogle Scholar
  12. 12.
    Prindull G, Zipori D: Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 103:2892–9, 2004PubMedCrossRefGoogle Scholar
  13. 13.
    Chapuy B, Koch R, Radunski U, et al: Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. Leukemia 22:1576–86, 2008PubMedCrossRefGoogle Scholar
  14. 14.
    Tang C, Ang BT, Pervaiz S: Cancer stem cell: target for anti-cancer therapy. FASEB J 21:3777–85, 2007PubMedCrossRefGoogle Scholar
  15. 15.
    Maitland NJ, Collins AT: Prostate cancer stem cells: a new target for therapy. J Clin Oncol 26:2862–70, 2008PubMedCrossRefGoogle Scholar
  16. 16.
    Blagosklonny MV: Why therapeutic response may not prolong the life of a cancer patient: selection for oncogenic resistance. Cell Cycle 4:1693–8, 2005PubMedCrossRefGoogle Scholar
  17. 17.
    Wicha MS: Cancer stem cells and metastasis: lethal seeds. Clin Cancer Res 12:5606–7, 2006PubMedCrossRefGoogle Scholar
  18. 18.
    Lang JE, Hall CS, Singh B, et al: Significance of micrometastasis in bone marrow and blood of operable breast cancer patients: research tool or clinical application? Expert Rev Anticancer Ther 7:1463–72, 2007PubMedCrossRefGoogle Scholar
  19. 19.
    Steeg PS: Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904, 2006PubMedCrossRefGoogle Scholar
  20. 20.
    Kaplan RN, Psaila B, Lyden D: Niche-to-niche migration of bone-marrow-derived cells. Trends Mol Med 13:72–81, 2007PubMedCrossRefGoogle Scholar
  21. 21.
    Zeppernick F, Ahmadi R, Campos B, et al: Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14:123–9, 2008PubMedCrossRefGoogle Scholar
  22. 22.
    Kvinlaug BT, Huntly BJ: Targeting cancer stem cells. Expert Opin Ther Targets 11:915–27, 2007PubMedCrossRefGoogle Scholar
  23. 23.
    Ailles LE, Weissman IL: Cancer stem cells in solid tumors. Curr Opin Biotechnol 18:460–6, 2007PubMedCrossRefGoogle Scholar
  24. 24.
    Lichtman MA: Differentiation versus maturation of neoplastic hematopoietic cells: an important distinction. Blood Cells Mol Dis 27:649–52, 2001PubMedCrossRefGoogle Scholar
  25. 25.
    Bernstein ID: Monoclonal antibodies to the myeloid stem cells: therapeutic implications of CMA-676, a humanized anti-CD33 antibody calicheamicin conjugate. Leukemia 14:474–5, 2000PubMedCrossRefGoogle Scholar
  26. 26.
    Pagel JM, Appelbaum FR, Eary JF, et al: 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission. Blood 107:2184–91, 2006PubMedCrossRefGoogle Scholar
  27. 27.
    Hu Y, Swerdlow S, Duffy TM, et al: Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci USA 103:16870–5, 2006PubMedCrossRefGoogle Scholar
  28. 28.
    McCubrey JA, Steelman LS, Abrams SL, et al: Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 22:708–22, 2008PubMedCrossRefGoogle Scholar
  29. 29.
    Zhou H, Kim YS, Peletier A, et al: Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. Int J Radiat Oncol Biol Phys 58:344–52, 2004PubMedCrossRefGoogle Scholar
  30. 30.
    Druker BJ, Tamura S, Buchdunger E, et al: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–6, 1996PubMedCrossRefGoogle Scholar
  31. 31.
    Druker BJ, Sawyers CL, Kantarjian H, et al: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–42, 2001PubMedCrossRefGoogle Scholar
  32. 32.
    Kim PS, Lee PP, Levy D: Dynamics and potential impact of the immune response to chronic myelogenous leukemia. PLoS Comput Biol 4:e1000095, 2008PubMedCrossRefGoogle Scholar
  33. 33.
    Stingl J, Caldas C: Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nat Rev Cancer 7:791–9, 2007PubMedCrossRefGoogle Scholar
  34. 34.
    Schulenburg A, Ulrich-Pur H, Thurnher D, et al: Neoplastic stem cells: a novel therapeutic target in clinical oncology. Cancer 107:2512–20, 2006PubMedCrossRefGoogle Scholar
  35. 35.
    Chen JK, Taipale J, Young KE, et al: Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA 99:14071–6, 2002PubMedCrossRefGoogle Scholar
  36. 36.
    Schugar RC, Robbins PD, Deasy BM: Small molecules in stem cell self-renewal and differentiation. Gene Ther 15:126–35, 2008PubMedCrossRefGoogle Scholar
  37. 37.
    Rapp UR, Ceteci F, Schreck R: Oncogene-induced plasticity and cancer stem cells. Cell Cycle 7:45–51, 2008PubMedCrossRefGoogle Scholar
  38. 38.
    Goodell MA, Brose K, Paradis G, et al: Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183:1797–806, 1996PubMedCrossRefGoogle Scholar
  39. 39.
    Kakarala M, Wicha MS: Cancer stem cells: implications for cancer treatment and prevention. Cancer J 13:271–5, 2007PubMedCrossRefGoogle Scholar
  40. 40.
    Dean M, Fojo T, Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–84, 2005PubMedCrossRefGoogle Scholar
  41. 41.
    Bao S, Wu Q, McLendon RE, et al: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–60, 2006PubMedCrossRefGoogle Scholar
  42. 42.
    Gilbertson RJ, Rich JN: Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 7:733–6, 2007PubMedCrossRefGoogle Scholar
  43. 43.
    Yang ZJ, Wechsler-Reya RJ: Hit ’em where they live: targeting the cancer stem cell niche. Cancer Cell 11:3–5, 2007PubMedCrossRefGoogle Scholar
  44. 44.
    Fuchs E, Tumbar T, Guasch G: Socializing with the neighbors: stem cells and their niche. Cell 116:769–78, 2004PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Liang Cheng
    • 1
    Email author
  • Shaobo Zhang
    • 1
  • Darrell D. Davidson
    • 1
  • Rodolfo Montironi
    • 1
  • Antonio Lopez-Beltran
    • 1
  1. 1.Department of Pathology and UrologyIndiana School of MedicineIndianapolis

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