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Target for cancer therapy: proliferating cells or stem cells

Leukemia volume 20, pages 385–391 (2006)Cite this article

Abstract

Tumor stem cells are quiescent and, therefore, resistant to therapy, yet harbor the capacity to replenish a tumor after therapy. Therefore, it is tempting to explain all therapeutic failures by the persistence of tumor stem cells. Yet, this explanation is relevant only to initial stages of stem-cell-dependent tumors (such as chronic myeloid leukemia) that, actually, are well controlled by therapy. In advanced cancers that poorly respond to therapy, quiescent tumor stem cells play a negligible role. Instead, proliferating cells determine disease progression, prognosis, therapeutic failures, and resistance to therapy. And therapy fails not because it eliminates only proliferating tumor cells, but because it does not eliminate them. With noticeable exceptions, it is the proliferating cell that should be targeted, whereas resting cancer cells including stem and dormant cells need to be targeted only when they ‘wake up’. Finally, I discuss a strategy of selectively killing dominant proliferating clones, including proliferating stem-like and drug-resistant cancer cells, while sparing normal cells.

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References

  1. Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.

    Article  CAS  Google Scholar 

  2. Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL . Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003; 17: 3029–3035.

    Article  CAS  Google Scholar 

  3. Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 2004; 6: 587–596.

    Article  CAS  Google Scholar 

  4. Dor Y, Melton DA . How important are adult stem cells for tissue maintenance? Cell Cycle 2004; 3: 1104–1106.

    Article  CAS  Google Scholar 

  5. Castor A, Nilsson L, Astrand-Grundstrom I, Buitenhuis M, Ramirez C, Anderson K et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 2005; 11: 630–637.

    Article  CAS  Google Scholar 

  6. Wang JC, Dick JE . Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005; 15: 494–501.

    Article  CAS  Google Scholar 

  7. Komarova NL . Cancer, aging and the optimal tissue design. Semin Cancer Biol 2005; 15: 494–505.

    Article  CAS  Google Scholar 

  8. Haase D, Feuring-Buske M, Konemann S, Fonatsch C, Troff C, Verbeek W et al. Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+ subpopulations. Blood 1995; 86: 2906–2912.

    CAS  PubMed  Google Scholar 

  9. Guan Y, Gerhard B, Hogge DE . Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood 2003; 101: 3142–3149.

    Article  CAS  Google Scholar 

  10. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M et al. Stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 2003; 100: 15178–15183.

    Article  CAS  Google Scholar 

  13. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004; 64: 7011–7021.

    Article  CAS  Google Scholar 

  14. Warner JK, Wang JC, Hope KJ, Jin L, Dick JE . Concepts of human leukemic development. Oncogene 2004; 23: 7164–7177.

    Article  CAS  Google Scholar 

  15. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF . Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 2004; 14: 43–47.

    Article  CAS  Google Scholar 

  16. Jordan CT, Guzman ML . Mechanisms controlling pathogenesis and survival of leukemic stem cells. Oncogene 2004; 23: 7178–7187.

    Article  CAS  Google Scholar 

  17. Beachy PA, Karhadkar SS, Berman DM . Tissue repair and stem cell renewal in carcinogenesis. Nature 2004; 432: 324–331.

    Article  CAS  Google Scholar 

  18. Huntly BJP, Gilliland DG . Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 2005; 5: 311–321.

    Article  CAS  Google Scholar 

  19. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005; 121: 823–835.

    Article  CAS  Google Scholar 

  20. Arai F, Hirao A, Suda T . Regulation of hematopoietic stem cells by the niche. Trends Cardiovasc Med 2005; 15: 75–79.

    Article  CAS  Google Scholar 

  21. Guan Y, Hogge DE . Proliferative status of primitive hematopoietic progenitors from patients with acute myelogenous leukemia (AML). Leukemia 2000; 14: 2135–2141.

    Article  CAS  Google Scholar 

  22. Glimm H, Oh IH, Eaves CJ . Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G(2)/M transit and do not reenter G(0). Blood 2000; 96: 4185–4193.

    CAS  Google Scholar 

  23. Wagner W, Ansorge A, Wirkner U, Eckstein V, Schwager C, Blake J et al. Molecular evidence for stem cell function of the slow-dividing fraction among human hematopoietic progenitor cells by genome-wide analysis. Blood 2004; 104: 675–686.

    Article  CAS  Google Scholar 

  24. Kurzrock R, Kantarjian H, Talpaz M . Chronic myelogenous leukemia in chronic phase. Curr Treat Options Oncol 2001; 2: 245–252.

    Article  CAS  Google Scholar 

  25. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657–667.

    Article  CAS  Google Scholar 

  26. Calabretta B, Perrotti D . The biology of CML blast crisis. Blood 2004; 103: 4010–4022.

    Article  CAS  Google Scholar 

  27. Dean M, Fojo T, Bates S . Tumour stem cells and drug resistance. Nat Rev Cancer 2005; 5: 275–284.

    Article  CAS  Google Scholar 

  28. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99: 319–325.

    Article  CAS  Google Scholar 

  29. Elrick LJ, Jorgensen HG, Mountford JC, Holyoake TL . Punish the parent not the progeny. Blood 2005; 105: 1862–1866.

    Article  CAS  Google Scholar 

  30. Holtz MS, Forman SJ, Bhatia R . Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli. Leukemia 2005; 19: 1034–1041.

    Article  CAS  Google Scholar 

  31. Talpaz M, Estrov Z, Kantarjian H, Ku S, Foteh A, Kurzrock R . Persistence of dormant leukemic progenitors during interferon-induced remission in chronic myelogenous leukemia. Analysis by polymerase chain reaction of individual colonies. J Clin Invest 1994; 94: 1383–1389.

    Article  CAS  Google Scholar 

  32. Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003; 101: 4701–4707.

    Article  CAS  Google Scholar 

  33. Horoszewicz JS, Leong SS, Carter WA . Noncycling tumor cells are sensitive targets for the antiproliferative activity of human interferon. Science 1979; 206: 1091–1093.

    Article  CAS  Google Scholar 

  34. Chaudhary PM, Roninson IB . Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 1991; 66: 85–94.

    Article  CAS  Google Scholar 

  35. Scharenberg CW, Harkey MA, Torok-Storb B . The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood 2002; 99: 507–512.

    Article  CAS  Google Scholar 

  36. Kim M, Turnquist H, Jackson J, Sgagias M, Yan Y, Gong M et al. The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res 2002; 8: 22–28.

    CAS  Google Scholar 

  37. Doyle LA, Ross DD . Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 2003; 22: 7340–7358.

    Article  Google Scholar 

  38. Raaijmakers MH, de Grouw EP, Heuver LH, van der Reijden BA, Jansen JH, Scheper RJ et al. Breast cancer resistance protein in drug resistance of primitive CD34+38− cells in acute myeloid leukemia. Clin Cancer Res 2005; 11: 2436–2444.

    Article  CAS  Google Scholar 

  39. Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U et al. A distinct ‘side population’ of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 2004; 101: 14228–14233.

    Article  CAS  Google Scholar 

  40. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG . Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res 2005; 65: 6207–6219.

    Article  CAS  Google Scholar 

  41. Kojika S, Sugita K, Inukai T, Saito M, Iijima K, Tezuka T et al. Mechanisms of glucocorticoid resistance in human leukemic cells: implication of abnormal 90 and 70 kDa heat shock proteins. Leukemia 1996; 10: 994–999.

    CAS  Google Scholar 

  42. Kaspers GJ, Pieters R, Van Zantwijk CH, Van Wering ER, Van Der Does-Van Den Berg A, Veerman AJ . Prednisolone resistance in childhood acute lymphoblastic leukemia: vitro–vivo correlations and cross-resistance to other drugs. Blood 1998; 92: 259–266.

    CAS  Google Scholar 

  43. Blagosklonny MV . Tissue-selective therapy of cancer. Br J Cancer 2003; 89: 1147–1151.

    Article  CAS  Google Scholar 

  44. Zietman AL, Dallow KC, McManus PA, Heney NM, Shipley WU . Time to second prostate-specific antigen failure is a surrogate endpoint for prostate cancer death in a prospective trial of therapy for localized disease. Urology 1996; 47: 236–239.

    Article  CAS  Google Scholar 

  45. Blagosklonny MV . Why therapeutic response may not prolong the life of a cancer patient: selection for oncogenic resistance. Cell Cycle 2005; 4: 1693–1698.

    Article  CAS  Google Scholar 

  46. Druker BJ, David A . Karnofsky Award lecture. Imatinib as a paradigm of targeted therapies. J Clin Oncol 2003; 21: 239s–245s.

    Article  Google Scholar 

  47. Deininger M, Buchdunger E, Druker BJ . The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005; 105: 2640–2653.

    Article  CAS  Google Scholar 

  48. La Rosee P, Shen L, Stoffregen EP, Deininger M, Druker BJ . No correlation between the proliferative status of Bcr-Abl positive cell lines and the proapoptotic activity of imatinib mesylate (Gleevec/Glivec). Hematol J 2003; 4: 413–419.

    Article  CAS  Google Scholar 

  49. Zong Y, Zhou S, Sorrentino BP . Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia 2005; 19: 1590–1596.

    Article  CAS  Google Scholar 

  50. Michor F, Hughes TP, Iwasa Y, Branford S, Shah NP, Sawyers CL et al. Dynamics of chronic myeloid leukaemia. Nature 2005; 435: 1267–1270.

    Article  CAS  Google Scholar 

  51. Olavarria E, Ottmann OG, Deininger M, Clark RE, Bandini G, Byrne J et al. Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia 2003; 17: 1707–1712.

    Article  CAS  Google Scholar 

  52. Chu S, Xu H, Shah NP, Snyder DS, Forman SJ, Sawyers CL et al. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 2005; 105: 2098.

    Article  Google Scholar 

  53. Willis SG, Lange T, Demehri S, Otto S, Crossman L, Niederwieser D et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 2005; 106: 2128–2137.

    Article  CAS  Google Scholar 

  54. Jaiswal S, Traver D, Miyamoto T, Akashi K, Lagasse E, Weissman IL . Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias. Proc Natl Acad Sci USA 2003; 100: 10002–10007.

    Article  CAS  Google Scholar 

  55. Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA working party on chronic myeloid leukemia. J Clin Oncol 2005; 23: 4100–4109.

    Article  CAS  Google Scholar 

  56. Pitha-Rowe I, Petty WJ, Kitareewan S, Dmitrovsky E . Retinoid target genes in acute promyelocytic leukemia. Leukemia 2003; 17: 1723–1730.

    Article  CAS  Google Scholar 

  57. Lallemand-Breitenbach V, Zhu J, Kogan S, Chen Z, de The H . Opinion: how patients have benefited from mouse models of acute promyelocytic leukaemia. Nat Rev Cancer 2005; 5: 821–827.

    Article  CAS  Google Scholar 

  58. Han ZT, Zhu XX, Yang RY, Sun JZ, Tian GF, Liu XJ et al. Effect of intravenous infusions of 12-O-tetradecanoylphorbol-13-acetate (TPA) in patients with myelocytic leukemia: preliminary studies on therapeutic efficacy and toxicity. Proc Natl Acad Sci USA 1998; 95: 5357–5361.

    Article  CAS  Google Scholar 

  59. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005; 352: 978–986.

    Article  CAS  Google Scholar 

  60. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997–1003.

    Article  CAS  Google Scholar 

  61. Bussolati B, Bruno S, Grange C, Buttiglieri S, Deregibus MC, Cantino D et al. Isolation of renal progenitor cells from adult human kidney. Am J Pathol 2005; 166: 545–555.

    Article  CAS  Google Scholar 

  62. Logothetis CJ, Samuels ML, Selig D, Swanson D, Johnson DE, von Eschenbach AC . Improved survival with cyclic chemotherapy for nonseminomatous germ cell tumors of the testis. J Clin Oncol 1985; 3: 326–335.

    Article  CAS  Google Scholar 

  63. Frei III E . Curative cancer chemotherapy. Cancer Res 1985; 45: 6523–6537.

    PubMed  Google Scholar 

  64. de Bono JS, Tolcher AW, Rowinsky EK . The future of cytotoxic therapy: selective cytotoxicity based on biology is the key. Breast Cancer Res 2003; 5: 154–159.

    Article  CAS  Google Scholar 

  65. Foran JM, Cunningham D, Coiffier B, Solal-Celigny P, Reyes F, Ghielmini M et al. Treatment of mantle-cell lymphoma with Rituximab (chimeric monoclonal anti-CD20 antibody): analysis of factors associated with response. Ann Oncol 2000; 11 (Suppl 1): 117–121.

    Article  Google Scholar 

  66. Roninson IB, Broude EV, Chang BD . If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist Update 2001; 4: 303–313.

    Article  CAS  Google Scholar 

  67. Blagosklonny MV, Pardee AB . Exploiting cancer cell cycling for selective protection of normal cells. Cancer Res 2001; 61: 4301–4305.

    CAS  PubMed  Google Scholar 

  68. Carvajal D, Tovar C, Yang H, Vu BT, Heimbrook DC, Vassilev LT . Activation of p53 by MDM2 antagonists can protect proliferating cells from mitotic inhibitors. Cancer Res 2005; 65: 1918–1924.

    Article  CAS  Google Scholar 

  69. Blagosklonny MV . Treatment with inhibitors of caspases, that are substrates of drug transporters, selectively permits chemotherapy-induced apoptosis in multidrug-resistant cells but protects normal cells. Leukemia 2001; 15: 936–994.

    Article  CAS  Google Scholar 

  70. Blagosklonny MV . Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal. Leukemia 1999; 13: 2031–2035.

    Article  CAS  Google Scholar 

  71. Demidenko ZN, Halicka D, Kunicki J, McCubrey JA, Darzynkiewicz Z, Blagosklonny MV . Selective killing of adriamycin-resistant (G2 checkpoint-deficient and MRP1-expressing) cancer cells by docetaxel. Cancer Res 2005; 65: 4401–4407.

    Article  CAS  Google Scholar 

  72. Glinsky GV, Berezovska O, Glinskii AB . Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest 2005; 115: 1503–1521.

    Article  CAS  Google Scholar 

  73. Al-Hajj M, Clarke MF . Self-renewal and solid tumor stem cells. Oncogene 2004; 23: 7274–7282.

    Article  CAS  Google Scholar 

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Acknowledgements

I thank Dr Errin Lagow for critical reading of the manuscript.

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    M V Blagosklonny

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Blagosklonny, M. Target for cancer therapy: proliferating cells or stem cells. Leukemia 20, 385–391 (2006). https://doi.org/10.1038/sj.leu.2404075

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