Journal of Molecular Medicine

, 87:1079 | Cite as

Cancer stem cells: controversies in multiple myeloma

Review

Abstract

Increasing data suggest that the initiation, relapse, and progression of human cancers are driven by specific cell populations within an individual tumor. However, inconsistencies have emerged in precisely defining phenotypic markers that can reliably identify these “cancer stem cells” in nearly every human malignancy studied to date. Multiple myeloma, one of the first tumors postulated to be driven by a rare population of cancer stem cells, is no exception. Similar to other diseases, controversy surrounds the exact phenotype and biology of multiple myeloma cells with the capacity for clonogenic growth. Here, we review the studies that have led to these controversies and discuss potential reasons for these disparate findings. Moreover, we speculate how these inconsistencies may be resolved through studies by integrating advancements in both myeloma and stem cell biology.

Keywords

Multiple myeloma B cells Cancer stem cells Animal models 

Notes

Acknowledgments

Supported in part by National Institutes of Health grants R01CA127574 and K23CA107040, the Multiple Myeloma Research Foundation, the International Myeloma Foundation, and the Sidney Kimmel Foundation for Cancer Research. William Matsui is a scholar of the Leukemia and Lymphoma Society.

Conflicting interests

We have no conflicting interests related to this review article or the studies discussed in the manuscript.

References

  1. 1.
    Kyle RA, Rajkumar SV (2004) Multiple myeloma. N Engl J Med 351:1860–1873CrossRefPubMedGoogle Scholar
  2. 2.
    Pilarski LM, Hipperson G, Seeberger K, Pruski E, Coupland RW, Belch AR (2000) Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice. Blood 95:1056–1065PubMedGoogle Scholar
  3. 3.
    Pilarski LM, Seeberger K, Coupland RW, Eshpeter A, Keats JJ, Taylor BJ, Belch AR (2002) Leukemic B cells clonally identical to myeloma plasma cells are myelomagenic in NOD/SCID mice. Exp Hematol 30:221–228CrossRefPubMedGoogle Scholar
  4. 4.
    Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, Smith BD, Civin CI, Jones RJ (2004) Characterization of clonogenic multiple myeloma cells. Blood 103:2332–2336CrossRefPubMedGoogle Scholar
  5. 5.
    Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I, McNiece I, Lin L, Ambinder RF, Peacock C, Watkins DN, Huff CA, Jones RJ (2008) Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 68:190–197CrossRefPubMedGoogle Scholar
  6. 6.
    Yaccoby S, Barlogie B, Epstein J (1998) Primary myeloma cells growing in SCID-hu mice: a model for studying the biology and treatment of myeloma and its manifestations. Blood 92:2908–2913PubMedGoogle Scholar
  7. 7.
    Yaccoby S, Epstein J (1999) The proliferative potential of myeloma plasma cells manifest in the SCID-hu host. Blood 94:3576–3582PubMedGoogle Scholar
  8. 8.
    Cox CV, Evely RS, Oakhill A, Pamphilon DH, Goulden NJ, Blair A (2004) Characterization of acute lymphoblastic leukemia progenitor cells. Blood 104:2919–2925CrossRefPubMedGoogle Scholar
  9. 9.
    George AA, Franklin J, Kerkof K, Shah AJ, Price M, Tsark E, Bockstoce D, Yao D, Hart N, Carcich S, Parkman R, Crooks GM, Weinberg K (2001) Detection of leukemic cells in the CD34+CD38{-} bone marrow progenitor population in children with acute lymphoblastic leukemia. Blood 97:3925CrossRefPubMedGoogle Scholar
  10. 10.
    Hotfilder M, Rottgers S, Rosemann A, Jurgens H, Harbott J, Vormoor J (2002) Immature CD34+CD19- progenitor/stem cells in TEL/AML1-positive acute lymphoblastic leukemia are genetically and functionally normal. Blood 100:640–646CrossRefPubMedGoogle Scholar
  11. 11.
    Hotfilder M, Rottgers S, Rosemann A, Schrauder A, Schrappe M, Pieters R, Jurgens H, Harbott J, Vormoor J (2005) Leukemic Stem Cells in Childhood High-Risk ALL/t(9;22) and t(4;11) Are Present in Primitive Lymphoid-Restricted CD34+CD19- Cells. Cancer Res 65:1442–1449CrossRefPubMedGoogle Scholar
  12. 12.
    Wang L, O'Leary H, Fortney J, Gibson LF (2007) Ph+/VE-cadherin+ identifies a stem cell like population of acute lymphoblastic leukemia sustained by bone marrow niche cells. Blood 110:3334–3344CrossRefPubMedGoogle Scholar
  13. 13.
    O'Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110CrossRefPubMedGoogle Scholar
  14. 14.
    Dalerba P, Dylla SJ, Ik P, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, Clarke MF (2007) Phenotypic characterization of human colorectal cancer stem cells. Proceedings of the National Academy of Sciences 104:10158–10163CrossRefGoogle Scholar
  15. 15.
    Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037CrossRefPubMedGoogle Scholar
  16. 16.
    Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:313–323CrossRefPubMedGoogle Scholar
  17. 17.
    He X, Marchionni L, Hansel DE, Wayne Yu, Sood A, Yang J, Parmigiani G, Matsui W, Berman DM (2009) Differentiation of a Highly Tumorigenic Basal Cell Compartment in Urothelial Carcinoma. Stem Cells 27:1487–1495CrossRefPubMedGoogle Scholar
  18. 18.
    Chan K, Espinosa I, Kim J, Ailles L, Zahilay G, Gill H, Presti J, van de Rijn M, Beachy P, Shortliffe L, Weissman I (2008) Molecular profiling reveals heterogeneity of active self-renewal pathways in bladder cancer stem cells. AACR Meeting Abstracts 2008:4998Google Scholar
  19. 19.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401CrossRefPubMedGoogle Scholar
  20. 20.
    Read T-A, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW, Febbo PG, Wechsler-Reya RJ (2009) Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of Medulloblastoma. Cancer Cell 15:135–147CrossRefPubMedGoogle Scholar
  21. 21.
    Al Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988CrossRefPubMedGoogle Scholar
  22. 22.
    Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567CrossRefPubMedGoogle Scholar
  23. 23.
    Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang TC-CJ, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648CrossRefPubMedGoogle Scholar
  24. 24.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737CrossRefPubMedGoogle Scholar
  25. 25.
    Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proceedings of the National Academy of Sciences 100:15178–15183CrossRefGoogle Scholar
  26. 26.
    Aigner S, Ramos C, Hafezi-Moghadam A, Lawrence M, Friederichs J, Altevogt P, Ley K (1998) CD24 mediates rolling of breast carcinoma cells on P-selectin. FASEB J 12:1241–1251PubMedGoogle Scholar
  27. 27.
    Joensuu H, Klemi PJ, Toikkanen S, Jalkanen S (1993) Glycoprotein CD44 expression and its association with survival in breast cancer. Am J Pathol 143:867–874PubMedGoogle Scholar
  28. 28.
    Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proceedings of the National Academy of Sciences 104:973–978CrossRefGoogle Scholar
  29. 29.
    Goodell MA, Rosenzweig M, Kim H, Marks DF, DeMaria M, Paradis G, Grupp SA, Sieff CA, Mulligan RC, Johnson RP (1997) Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 3:1337–1345CrossRefPubMedGoogle Scholar
  30. 30.
    Hess DA, Meyerrose TE, Wirthlin L, Craft TP, Herrbrich PE, Creer MH, Nolta JA (2004) Functional characterization of highly purified human hematopoietic repopulating cells isolated according to aldehyde dehydrogenase activity. Blood 104:1648–1655CrossRefPubMedGoogle Scholar
  31. 31.
    Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, Pickell K, Aguilar J, Lazetic S, Smith-Berdan S, Clarke MF, Hoey T, Lewicki J, Gurney AL (2008) Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE 3:e2428CrossRefPubMedGoogle Scholar
  32. 32.
    Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea—a paradigm shift. Cancer Res 66:1883–1890CrossRefPubMedGoogle Scholar
  33. 33.
    Jones RJ, Gocke CD, Kasamon YL, Miller CB, Perkins B, Barber JP, Vala MS, Gerber JM, Gellert LL, Siedner M, Lemas MV, Brennan S, Ambinder RF, Matsui W (2009) Circulating clonotypic B cells in classic Hodgkin lymphoma. Blood 113:5920–5926. doi: 10.1182/blood-2008-11-189688 CrossRefPubMedGoogle Scholar
  34. 34.
    Taussig DC, Miraki-Moud F, njos-Afonso F, Pearce DJ, Allen K, Ridler C, Lillington D, Oakervee H, Cavenagh J, Agrawal SG, Lister TA, Gribben JG, Bonnet D (2008) Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood 112:568–575CrossRefPubMedGoogle Scholar
  35. 35.
    Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, Van Belle PA, Xu X, Elder DE, Herlyn M (2005) A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 65:9328–9337CrossRefPubMedGoogle Scholar
  36. 36.
    Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH (2008) Identification of cells initiating human melanomas. Nature 451:345–349CrossRefPubMedGoogle Scholar
  37. 37.
    Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598CrossRefPubMedGoogle Scholar
  38. 38.
    Bakkus MH, Heirman C, Van Riet I, Van Camp B, Thielemans K (1992) Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation. Blood 80:2326–2335PubMedGoogle Scholar
  39. 39.
    Sahota SS, Leo R, Hamblin TJ, Stevenson FK (1997) Myeloma VL and VH gene sequences reveal a complementary imprint of antigen selection in tumor cells. Blood 89:219–226PubMedGoogle Scholar
  40. 40.
    Bakkus MH, Van RI, Van Camp B, Thielemans K (1994) Evidence that the clonogenic cell in multiple myeloma originates from a pre-switched but somatically mutated B cell. Br J Haematol 87:68–74CrossRefPubMedGoogle Scholar
  41. 41.
    Billadeau D, Ahmann G, Greipp P, Van Ness B (1993) The bone marrow of multiple myeloma patients contains B cell populations at different stages of differentiation that are clonally related to the malignant plasma cell. J Exp Med 178:1023–1031CrossRefPubMedGoogle Scholar
  42. 42.
    Bergsagel PL, Smith AM, Szczepek A, Mant MJ, Belch AR, Pilarski LM (1995) In multiple myeloma, clonotypic B lymphocytes are detectable among CD19+ peripheral blood cells expressing CD38, CD56, and monotypic Ig light chain. Blood 85:436–447PubMedGoogle Scholar
  43. 43.
    Chen BJ, Epstein J (1996) Circulating clonal lymphocytes in myeloma constitute a minor subpopulation of B cells. Blood 87:1972–1976PubMedGoogle Scholar
  44. 44.
    Rasmussen T, Kastrup J, Knudsen LM, Johnsen HE (1999) High numbers of clonal CD19+ cells in the peripheral blood of a patient with multiple myeloma. Br J Haematol 105:265–267PubMedGoogle Scholar
  45. 45.
    Caligaris-Cappio F, Bergui L, Tesio L, Pizzolo G, Malavasi F, Chilosi M, Campana D, van CB, Janossy G (1985) Identification of malignant plasma cell precursors in the bone marrow of multiple myeloma. J Clin Invest 76:1243–1251CrossRefPubMedGoogle Scholar
  46. 46.
    Bergui L, Schena M, Gaidano G, Riva M, Caligaris-Cappio F (1989) Interleukin 3 and interleukin 6 synergistically promote the proliferation and differentiation of malignant plasma cell precursors in multiple myeloma. J ExpMed 170:613–618CrossRefGoogle Scholar
  47. 47.
    Hamburger AW, Salmon SE (1977) Primary bioassay of human tumor stem cells. Science 197:461–463CrossRefPubMedGoogle Scholar
  48. 48.
    Kirshner J, Thulien KJ, Martin LD, Debes Marun C, Reiman T, Belch AR, Pilarski LM (2008) A unique three-dimensional model for evaluating the impact of therapy on multiple myeloma. Blood 112:2935–2945. doi: 10.1182/blood-2008-02-142430 CrossRefPubMedGoogle Scholar
  49. 49.
    Scadden DT (2006) The stem-cell niche as an entity of action. Nature 441:1075–1079CrossRefPubMedGoogle Scholar
  50. 50.
    Mitsiades CS, Mitsiades NS, Richardson PG, Munshi NC, Anderson KC (2007) Multiple myeloma: a prototypic disease model for the characterization and therapeutic targeting of interactions between tumor cells and their local microenvironment. J Cell Biochem 101:950–968CrossRefPubMedGoogle Scholar
  51. 51.
    Chng WJ, Glebov O, Bergsagel PL, Kuehl WM (2007) Genetic events in the pathogenesis of multiple myeloma. Best Practice & Research Clinical Haematology 20:571–596CrossRefGoogle Scholar
  52. 52.
    Boylan KLM, Gosse MA, Staggs SE, Janz S, Grindle S, Kansas GS, Van Ness BG (2007) A transgenic mouse model of plasma cell malignancy shows phenotypic, cytogenetic, and gene expression heterogeneity similar to human multiple myeloma. Cancer Res 67:4069–4078CrossRefPubMedGoogle Scholar
  53. 53.
    Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann R, Valdez R, Palmer SE, Haas SS, Stewart AK, Fonseca R, Kremer R, Cattoretti G, Bergsagel PL (2008) AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 13:167–180CrossRefPubMedGoogle Scholar
  54. 54.
    Carrasco DR, Sukhdeo K, Protopopova M, Sinha R, Enos M, Carrasco DE, Zheng M, Mani M, Henderson J, Pinkus GS, Munshi N, Horner J, Ivanova EV, Protopopov A, Anderson KC, Tonon G, DePinho RA (2007) The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 11:349–360CrossRefPubMedGoogle Scholar
  55. 55.
    Jamieson CHM, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL (2004) Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351:657–667CrossRefPubMedGoogle Scholar
  56. 56.
    Hanamura I, Stewart JP, Huang Y, Zhan F, Santra M, Sawyer JR, Hollmig K, Zangarri M, Pineda-Roman M, van Rhee F, Cavallo F, Burington B, Crowley J, Tricot G, Barlogie B, Shaughnessy JD Jr (2006) Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 108:1724–1732CrossRefPubMedGoogle Scholar
  57. 57.
    Fonseca R, Van Wier S, Chng W, Ketterling R, Lacy M, Dispenzieri A, Bergsagel P, Rajkumar S, Greipp P, Litzow M (2006) Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. Leukemia 20:2034–2040CrossRefPubMedGoogle Scholar
  58. 58.
    Drach J, Ackermann J, Fritz E, Kromer E, Schuster R, Gisslinger H, DeSantis M, Zojer N, Fiegl M, Roka S, Schuster J, Heinz R, Ludwig H, Huber H (1998) Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood 92:802–809PubMedGoogle Scholar
  59. 59.
    Portier M, Moles JP, Mazars GR, Jeanteur P, Bataille R, Klein B, Theillet C (1992) p53 and RAS gene mutations in multiple myeloma. Oncogene 7:2539–2543PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Division of Hematologic MalignanciesThe Sidney Kimmel Comprehensive Cancer CenterBaltimoreUSA
  2. 2.Department of OncologyJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations