Skip to main content

Advertisement

SpringerLink
Log in

Cell surface markers of cancer stem cells: diagnostic macromolecules and targets for drug delivery

  • Review Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

The recognition that the persistence of cancer stem cells (CSCs) in patients following chemotherapy can result in disease relapse underscores the necessity to develop therapeutics against those cells. CSCs display a unique repertoire of cell surface macromolecules, which have proven essential for their characterization and isolation. Additionally, CSC-specific cell surface macromolecules or markers provide targets for the development of specific agents to destroy them. In this review, we compiled those cell surface molecules that have been validated as CSC markers for many common blood and solid tumors. We describe the unique chemical and structural features of the most common cell surface markers, as well as recent efforts to deliver chemotherapeutic agents into CSCs by targeting those macromolecules.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Al-Hajj M. Cancer stem cells and oncology therapeutics. Curr Opin Oncol. 2007;19:61–4.

    PubMed  Google Scholar 

  2. Behbod F, Rosen JM. Will cancer stem cells provide new therapeutic targets? Carcinogenesis. 2005;26:703–11.

    PubMed  CAS  Google Scholar 

  3. Dick JE. Stem cell concepts renew cancer research. Blood. 2008;112:4793–807.

    PubMed  CAS  Google Scholar 

  4. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.

    PubMed  CAS  Google Scholar 

  5. Saini V, Shoemaker RH. Potential for therapeutic targeting of tumor stem cells. Cancer Sci. 2010;101:16–21.

    PubMed  CAS  Google Scholar 

  6. Wang JCY. Evaluating therapeutic efficacy against cancer stem cells: new challenges posed by a new paradigm. Cell Stem Cell. 2007;1:497–501.

    CAS  Google Scholar 

  7. Ward RJ, Dirks PB. Cancer stem cells: at the headwaters of tumor development. Annu Rev Pathol-Mech. 2007;2:175–89.

    CAS  Google Scholar 

  8. Zhou BBS, Zhang HY, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 2009;8:806–23.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  10. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-cortes J, et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice. Nature. 1994;367:645–8.

    PubMed  CAS  Google Scholar 

  11. Fialkow PJ, Singer JW, Raskind WH, Adamson JW, Jacobson RJ, Bernstein ID, et al. Clonal development, stem-cell differentiation, and clinical remission in acute nonlymphocytic leukemia. New Engl J Med. 1987;317:468–73.

    PubMed  CAS  Google Scholar 

  12. Griffin JD, Lowenberg B. Clonogenic cells in acute myeloblastic leukemia. Blood. 1986;68:1185–95.

    PubMed  CAS  Google Scholar 

  13. McCulloch EA. Stem cells in normal and leukemic hematopoiesis (Henry Stratton Lecture). Blood. 1983;62:1–13.

    PubMed  CAS  Google Scholar 

  14. Li L, Bhatia R. Stem cell quiescence. Clin Cancer Res. 2011;17:4936–41.

    PubMed  CAS  Google Scholar 

  15. Sehl M, Zhou H, Sinsheimer JS, Lange KL. Extinction models for cancer stem cell therapy. Math Biosci. 2011;234:132–46.

    PubMed  Google Scholar 

  16. Dey M, Ulasov IV, Tyler MA, Sonabend AM, Lesniak MS. Cancer stem cells: the final frontier for glioma virotherapy. Stem Cell Rev Rep. 2011;7:119–29.

    Google Scholar 

  17. Natarajan K, Xie Y, Baer MR, Ross DD. Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol. 2012;83:1084–103.

    PubMed  CAS  Google Scholar 

  18. American Cancer Society. Cancer facts & figures 2011. ACS. 2011.

  19. Guzman ML, Rossi RM, Karnischky L, Li XJ, Peterson DR, Howard DS, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood. 2005;105:4163–9.

    PubMed  CAS  Google Scholar 

  20. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12:1167–74.

    PubMed  Google Scholar 

  21. Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A, et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol. 2010;28:275–80.

    PubMed  CAS  Google Scholar 

  22. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. New Engl J Med. 2001;344:1031–7.

    PubMed  CAS  Google Scholar 

  23. Kantarjian H, Talpaz M, O’Brien SS, Garcia-Manero G, Verstovsek S, Giles F, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood. 2004;103:2873–8.

    PubMed  CAS  Google Scholar 

  24. Nicholson E, Holyoake T. The chronic myeloid leukemia stem cell. Clin Lymphoma Myeloma. 2009;9:S376–81.

    PubMed  CAS  Google Scholar 

  25. 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;99:319–25.

    PubMed  CAS  Google Scholar 

  26. Zoeller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 2011;11:254–67.

    CAS  Google Scholar 

  27. Garvalov BK, Acker T. Cancer stem cells: a new framework for the design of tumor therapies. J Mol Med-Jmm. 2011;89:95–107.

    Google Scholar 

  28. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65:10946–51.

    PubMed  CAS  Google Scholar 

  29. Clayton S, Mousa SA. Therapeutics formulated to target cancer stem cells: is it in our future? Cancer Cell Int. 2011;11:7.

    Google Scholar 

  30. Klonisch T, Wiechec E, Hombach-Klonisch S, Ande SR, Wesselborg S, Schulze-Osthoff K, et al. Cancer stem cell markers in common cancers—therapeutic implications. Trends Mol Med. 2008;14:450–60.

    PubMed  CAS  Google Scholar 

  31. Liu H-G, Chen C, Yang H, Pan Y-F, Zhang X-H. Cancer stem cell subsets and their relationships. J Transl Med. 2011;9:50.

    PubMed  Google Scholar 

  32. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.

    PubMed  CAS  Google Scholar 

  33. Gilbert CA, Ross AH. Cancer stem cells: cell culture, markers, and targets for new therapies. J Cell Biochem. 2009;108:1031–8.

    PubMed  CAS  Google Scholar 

  34. Alison MR, Lim SML, Nicholson LJ. Cancer stem cells: problems for therapy? J Pathol. 2011;223:147–61.

    PubMed  CAS  Google Scholar 

  35. Jordan CT. Cancer sten cell biology: from leukemia to solid tumors. Curr Opin Cell Biol. 2004;16:708–12.

    PubMed  CAS  Google Scholar 

  36. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    PubMed  Google Scholar 

  37. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212–36.

    PubMed  Google Scholar 

  38. Testa U. Leukemia stem cells. Ann Hematol. 2011;90:245–71.

    PubMed  CAS  Google Scholar 

  39. Blair A, Hogge DE, Ailles LE, Lansdorp PM, Sutherland HJ. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood. 1997;89:3104–12.

    PubMed  CAS  Google Scholar 

  40. Blair A, Hogge DE, Sutherland HJ. Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(-)/HLA-DR. Blood. 1998;92:4325–35.

    PubMed  CAS  Google Scholar 

  41. Blair A, Sutherland HJ. Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD 117). Exp Hematol. 2000;28:660–71.

    PubMed  CAS  Google Scholar 

  42. Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000;14:1777–84.

    PubMed  CAS  Google Scholar 

  43. Florian S, Sonneck K, Hauswirth AW, Krauth MT, Schernthaner GH, Sperr WR, et al. Detection of molecular targets on the surface of CD34+/CD38-stem cells in various myeloid malignancies. Leukemia Lymphoma. 2006;47:207–22.

    PubMed  CAS  Google Scholar 

  44. Dinndorf PA, Andrews RG, Benjamin D, Ridgway D, Wolff L, Bernstein ID. Expression of normal myeloid-associated antigens by acute leukemia cells. Blood. 1986;67:1048–53.

    PubMed  CAS  Google Scholar 

  45. Hauswirth AW, Florian S, Printz D, Sotlar K, Krauth MT, Fritsch G, et al. Expression of the target receptor CD33 in CD34(+)/CD38(−)/CD123(+) AML stem cells. Eur J Clin Invest. 2007;37:73–82.

    PubMed  CAS  Google Scholar 

  46. de Figueiredo-Pontes LL, Pintao M-CT, Oliveira LCO, Dalmazzo LFF, Jacomo RH, Garcia AB, et al. Determination of P-glycoprotein, MDR-related protein 1, breast cancer resistance protein, and lung-resistance protein expression in leukemic stem cells of acute myeloid leukemia. Cytom Part B-Clin Cy. 2008;74B:163–8.

    Google Scholar 

  47. van Rhenen A, van Dongen GAMS, Kelder A, Rombouts EJ, Feller N, Moshaver B, et al. The novel AML stem cell-associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood. 2007;110:2659–66.

    PubMed  Google Scholar 

  48. Hosen N, Park CY, Tatsumi N, Oji Y, Sugiyama H, Gramatzki M, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci USA. 2007;104:11008–13.

    PubMed  CAS  Google Scholar 

  49. Bendall LJ, Bradstock KF, Gottlieb DJ. Expression of CD44 variant exons in acute myeloid leukemia is more common and more complex than that observed in normal blood, bone marrow or CD34(+) cells. Leukemia. 2000;14:1239–46.

    PubMed  CAS  Google Scholar 

  50. Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S, et al. Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med. 2010;2:17ra9.

    Google Scholar 

  51. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs Jr KD, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138:286–99.

    PubMed  CAS  Google Scholar 

  52. Quijano CA, Moore D, Arthur D, Feusner J, Winter SS, Pallavicini MG. Cytogenetically aberrant cells are present in the CD34+CD33−38−19− marrow compartment in children with acute lymphoblastic leukemia. Leukemia. 1997;11:1508–15.

    PubMed  CAS  Google Scholar 

  53. Cobaleda C, Gutierrez-Cianca N, Perez-Losada J, Flores T, Garcia-Sanz R, Gonzalez M, et al. A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia. Blood. 2000;95:1007–13.

    PubMed  CAS  Google Scholar 

  54. Advani AS, Pendergast AM. Bcr-Abl variants: biological and clinical aspects. Leukemia Res. 2002;26:713–20.

    CAS  Google Scholar 

  55. Faderl S, Garcia-Manero G, Thomas DA, Kantarjian HM. Philadelphia chromosome-positive acute lymphoblastic leukemia— current concepts and future perspectives. Rev Clin Exp Hematol. 2002;6:142–60.

    PubMed  CAS  Google Scholar 

  56. 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;11:630–7.

    PubMed  CAS  Google Scholar 

  57. Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002;1:133–43.

    PubMed  CAS  Google Scholar 

  58. Cox CV, Evely RS, Oakhill A, Pamphilon DH, Goulden NJ, Blair A. Characterization of acute lymphoblastic leukemia progenitor cells. Blood. 2004;104:2919–25.

    PubMed  CAS  Google Scholar 

  59. Cox CV, Martin HM, Kearns PR, Virgo P, Evely RS, Blair A. Characterization of a progenitor cell population in childhood T-cell acute lymphoblastic leukemia. Blood. 2007;109:674–82.

    PubMed  CAS  Google Scholar 

  60. Cox CV, Diamanti P, Evely RS, Kearns PR, Blair A. Expression of CD133 on leukemia-initiating cells in childhood ALL. Blood. 2009;113:3287–96.

    PubMed  CAS  Google Scholar 

  61. Nishida H, Yamazaki H, Yamada T, Iwata S, Dang NH, Inukai T, et al. CD9 correlates with cancer stem cell potentials in human B-acute lymphoblastic leukemia cells. Biochem Bioph Res Co. 2009;382:57–62.

    CAS  Google Scholar 

  62. Yamazaki H, Nishida H, Iwata S, Dang NH, Morimoto C. CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells. Biochem Bioph Res Co. 2009;383:172–7.

    CAS  Google Scholar 

  63. Holyoake T, Jiang XY, Eaves C, Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1999;94:2056–64.

    PubMed  CAS  Google Scholar 

  64. DeSantis C, Siegel R, Bandi P, Jemal A. Breast cancer statistics. CA Cancer J Clin. 2011;61:409–18.

    PubMed  Google Scholar 

  65. Takahashi R, Takeshita F, Fujiwara T, Ono M, Ochiya T. Cancer stem cells in breast cancer. Cancers. 2011;3:1311–28.

    CAS  Google Scholar 

  66. 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;100:3983–8.

    PubMed  CAS  Google Scholar 

  67. Phillips TM, McBride WH, Pajonk F. The response of CD24−/low/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer I. 2006;98:1777–85.

    Google Scholar 

  68. Buess M, Rajski M, Vogel-Durrer BML, Herrmann R, Rochlitz C. Tumor-endothelial interaction links the CD44(+)/CD24(−) phenotype with poor prognosis in early-stage breast cancer. Neoplasia. 2009;11:987–1002.

    PubMed  CAS  Google Scholar 

  69. Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, et al. CD44+/CD24− breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 2006;8:59.

    Google Scholar 

  70. Donnelly DS, Zelterman D, Sharkis S, Krause DS. Functional activity of murine CD34(+) and CD34(−) hematopoietic stem cell populations. Exp Hematol. 1999;27:788–96.

    PubMed  CAS  Google Scholar 

  71. Neumeister V, Agarwal S, Bordeaux J, Camp RL, Rimm DL. In situ identification of putative cancer stem cells by multiplexing ALDH1, CD44, and cytokeratin identifies breast cancer patients with poor prognosis. Am J Pathol. 2010;176:2131–8.

    PubMed  CAS  Google Scholar 

  72. Cho RW, Wang X, Diehn M, Shedden K, Chen GY, Sherlock G, et al. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Stem Cells. 2008;26:364–71.

    PubMed  CAS  Google Scholar 

  73. Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski L. Brca1 breast tumors contain distinct CD44+/CD24−/CD133+ cells with cancer stem cell characteristics. Breast Cancer Res. 2008;10:10.

    Google Scholar 

  74. Zhao P, Lu Y, Jiang X, Li X. Clinicopathological significance and prognostic value of CD133 expression in triple-negative breast carcinoma. Cancer Sci. 2011;102:1107–11.

    PubMed  CAS  Google Scholar 

  75. Liu Q, Li J-g, Zheng X-y, Jin F, Dong H-t. Expression of CD133, PAX2, ESA, and GPR30 in invasive ductal breast carcinomas. Chinese Med J-Peking. 2009;122:2763–9.

    Google Scholar 

  76. Lin W-M, Karsten U, Goletz S, Cheng R-C, Cao Y. Co-expression of CD173 (H2) and CD174 (Lewis Y) with CD44 suggests that fucosylated histo-blood group antigens are markers of breast cancer-initiating cells. Vichows Arch. 2010;456:403–9.

    CAS  Google Scholar 

  77. Lin W-M, Karsten U, Goletz S, Cheng R-C, Cao Y. Expression of CD176 (Thomsen-Friedenreich antigen) on lung, breast and liver cancer-initiating cells. Int J Exp Pathol. 2011;92:97–105.

    PubMed  Google Scholar 

  78. Vassilopoulos A, Wang R-H, Petrovas C, Ambrozak D, Koup R, Deng C-X. Identification and characterization of cancer initiating cells from BRCA1 related mammary tumors using markers for normal mammary stem cells. Int J Biol Sci. 2008;4:133–42.

    PubMed  CAS  Google Scholar 

  79. Shipitsin M, Campbell LL, Argani P, Werernowicz S, Bloushtain-Qimron N, Yao J, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11:259–73.

    PubMed  CAS  Google Scholar 

  80. Dalerba P, Dylla SJ, Park I-K, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA. 2007;104:10158–63.

    PubMed  CAS  Google Scholar 

  81. O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10.

    PubMed  Google Scholar 

  82. 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;445:111–5.

    PubMed  CAS  Google Scholar 

  83. Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133− metastatic colon cancer cells initiate tumors. J Clin Invest. 2008;118:2111–20.

    PubMed  CAS  Google Scholar 

  84. Du L, Wang H, He L, Zhang J, Ni B, Wang X, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 2008;14:6751–60.

    PubMed  CAS  Google Scholar 

  85. Horst D, Kriegl L, Engel J, Kirchner T, Jung A. Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer. Cancer Invest. 2009;27:844–50.

    PubMed  Google Scholar 

  86. Lugli A, Iezzi G, Hostettler I, Muraro MG, Mele V, Tornillo L, et al. Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer. Brit J Cancer. 2010;103:382–90.

    PubMed  CAS  Google Scholar 

  87. Vermeulen L, Todaro M, Mello FdS, Sprick MR, Kemper K, Alea MP, et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci USA. 2008;105:13427–32.

    PubMed  CAS  Google Scholar 

  88. Eguchi S, Kanematsu T, Arii S, Omata M, Kudo M, Sakamoto M, et al. Recurrence-free survival more than 10 years after liver resection for hepatocellular carcinoma. Brit J Surg. 2011;98:552–7.

    PubMed  CAS  Google Scholar 

  89. Ma S, Chan K-W, Hu L, Lee TK-W, Wo JY-H, Ng I-L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132:2542–56.

    PubMed  CAS  Google Scholar 

  90. Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, et al. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer. 2010;126:2067–78.

    PubMed  CAS  Google Scholar 

  91. Kimura O, Takahashi T, Ishii N, Inoue Y, Ueno Y, Kogure T, et al. Characterization of the epithelial cell adhesion molecule (EpCAM) plus cell population in hepatocellular carcinoma cell lines. Cancer Sci. 2010;101:2145–55.

    PubMed  CAS  Google Scholar 

  92. Yamashita T, Ji JF, Budhu A, Forgues M, Yang W, Wang H-Y, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136:1012–24.

    PubMed  CAS  Google Scholar 

  93. Haraguchi N, Ishii H, Mimori K, Tanaka F, Ohkuma M, Kim HM, et al. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 2010;120:3326–39.

    PubMed  CAS  Google Scholar 

  94. Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, et al. Significance of CD90(+) cancer stem cells in human liver cancer. Cancer Cell. 2008;13:153–66.

    PubMed  CAS  Google Scholar 

  95. Polakis P. Wnt signaling and cancer. Gene Dev. 2000;14:1837–51.

    PubMed  CAS  Google Scholar 

  96. Yang W, Yan H-X, Chen L, Liu Q, He Y-Q, Yu L-X, et al. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008;68:4287–95.

    PubMed  CAS  Google Scholar 

  97. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96.

    PubMed  Google Scholar 

  98. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030–7.

    PubMed  CAS  Google Scholar 

  99. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.

    PubMed  CAS  Google Scholar 

  100. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    PubMed  Google Scholar 

  101. Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 2005;65:9328–37.

    PubMed  CAS  Google Scholar 

  102. Monzani E, Facchetti F, Galmozzi E, Corsini E, Benetti A, Cavazzin C, et al. Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer. 2007;43:935–46.

    PubMed  CAS  Google Scholar 

  103. Grichnik JM, Burch JA, Schulteis RD, Shan S, Liu J, Darrow TL, et al. Melanoma, a tumor based on a mutant stem cell? J Invest Dermatol. 2006;126:142–53.

    PubMed  CAS  Google Scholar 

  104. Fusi A, Reichelt U, Busse A, Ochsenreither S, Rietz A, Maisel M, et al. Expression of the stem cell markers Nestin and CD133 on circulating melanoma cells. J Invest Dermatol. 2011;131:487–94.

    PubMed  CAS  Google Scholar 

  105. Schatton T, Frank NY, Frank MH. Identification and targeting of cancer stem cells. Bioessays. 2009;31:1038–49.

    PubMed  CAS  Google Scholar 

  106. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, et al. Identification of cells initiating human melanomas. Nature. 2008;451:345–9.

    PubMed  CAS  Google Scholar 

  107. Davis FG, Kupelian V, Freels S, McCarthy B, Surawicz T. Prevalence estimates for primary brain tumors in the United States by behavior and major histology groups. Neuro-Oncology. 2001;3:152–8.

    PubMed  CAS  Google Scholar 

  108. Khalatbari MR, Hamidi M, Moharamzad Y. Glioblastoma multiforme with very rapid growth and long-term survival in children: report of two cases and review of the literature. Child Nerv Syst. 2011;27:1347–52.

    Google Scholar 

  109. Eyler CE, Rich JN. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol. 2008;26:2839–45.

    PubMed  CAS  Google Scholar 

  110. Binello E, Germano IM. Targeting glioma stem cells: a novel framework for brain tumors. Cancer Sci. 2011;102:1958–66.

    PubMed  CAS  Google Scholar 

  111. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.

    PubMed  CAS  Google Scholar 

  112. 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.

    PubMed  CAS  Google Scholar 

  113. Tchoghandjian A, Baeza N, Colin C, Cayre M, Metellus P, Beclin C, et al. A2B5 cells from human glioblastoma have cancer stem cell properties. Brain Pathol. 2010;20:211–21.

    PubMed  Google Scholar 

  114. Ogden AT, Waziri AE, Lochhead RA, Fusco D, Lopez K, Ellis JA, et al. Identification of A2B5+CD133− tumor-initiating cells in adult human gliomas. Neurosurgery. 2008;62:505–14.

    PubMed  Google Scholar 

  115. Wang J, Sakariassen PO, Tsinkalovsky O, Immervoll H, Boe SO, Svendsen A, et al. CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer. 2008;122:761–8.

    PubMed  CAS  Google Scholar 

  116. Bao S, Wu Q, Li Z, Sathornsumetee S, Wang H, McLendon RE, et al. Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res. 2008;68:6043–8.

    PubMed  CAS  Google Scholar 

  117. Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006;66:7843–8.

    PubMed  CAS  Google Scholar 

  118. Son MJ, Woolard K, Nam D-H, Lee J, Fine HA. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell. 2009;4:440–52.

    PubMed  CAS  Google Scholar 

  119. Read T-A, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW, et al. Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell. 2009;15:135–47.

    PubMed  CAS  Google Scholar 

  120. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–84.

    PubMed  CAS  Google Scholar 

  121. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2007;15:504–14.

    PubMed  Google Scholar 

  122. Dinney CPN, McConkey DJ, Millikan RE, Wu XF, Bar-Eli M, Adam L, et al. Focus on bladder cancer. Cancer Cell. 2004;6:111–6.

    PubMed  CAS  Google Scholar 

  123. Su Y, Qiu Q, Zhang X, Jiang Z, Leng Q, Liu Z, et al. Aldehyde dehydrogenase 1 A1-positive cell population is enriched in tumor-initiating cells and associated with progression of bladder cancer. Cancer Epidem Biomar. 2010;19:327–37.

    CAS  Google Scholar 

  124. Chan KS, Espinosa I, Chao M, Wong D, Ailles L, Diehn M, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Nat Acad Sci. 2009;106:14016–21.

    PubMed  CAS  Google Scholar 

  125. Yang YM, Chang JW. Bladder cancer initiating cells (BCICs) are among EMA−CD44v6+ subset: novel methods for isolating undetermined cancer stem (initiating) cells. Cancer Invest. 2008;26:725–33.

    PubMed  CAS  Google Scholar 

  126. Ning ZF, Huang YJ, Lin TX, Zhou YX, Jiang C, Xu KW, et al. Subpopulations of stem-like cells in side population cells from the human bladder transitional cell cancer cell line T24. J Int Med Res. 2009;37:621–30.

    PubMed  CAS  Google Scholar 

  127. Oates JE, Grey BR, Addla SK, Samuel JD, Hart CA, Ramani VAC, et al. Hoechst 33342 side population identification is a conserved and unified mechanism in urological cancers. Stem Cells Dev. 2009;18:1515–21.

    PubMed  CAS  Google Scholar 

  128. Bostwick DG, Eble JN. Urological surgical pathology. 2nd ed. New York, NY. Mosby; 2007.

  129. Mulholland DJ, Xin L, Morim A, Lawson D, Witte O, Wu H. Lin−Sca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model. Cancer Res. 2009;69:8555–62.

    PubMed  CAS  Google Scholar 

  130. Beltran H, Beer TM, Carducci MA, de Bono J, Gleave M, Hussain M, et al. New therapies for castration-resistant prostate cancer: efficacy and safety. Eur Urol. 2011;60:279–90.

    PubMed  CAS  Google Scholar 

  131. Liu AY, True LD, LaTray L, Nelson PS, Ellis WJ, Vessella RL, et al. Cell–cell interaction in prostate gene regulation and cytodifferentiation. Proc Natl Acad Sci USA. 1997;94:10705–10.

    PubMed  CAS  Google Scholar 

  132. Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 2006;25:1696–708.

    PubMed  CAS  Google Scholar 

  133. Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+alpha 2 beta 1+ cell population is enriched in tumor-initiating cells. Cancer Res. 2007;67:6796–805.

    PubMed  CAS  Google Scholar 

  134. Suzuki A, Nakano T, Mak TW, Sasaki T. Portrait of PTEN: messages from mutant mice. Cancer Sci. 2008;99:209–13.

    PubMed  CAS  Google Scholar 

  135. Zhang S, Balch C, Chan MW, Lai H-C, Matei D, Schilder JM, et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008;68:4311–20.

    PubMed  CAS  Google Scholar 

  136. Choi YP, Shim HS, Gao M-Q, Kang S, Cho NH. Molecular portraits of intratumoral heterogeneity in human ovarian cancer. Cancer Lett. 2011;307:62–71.

    PubMed  CAS  Google Scholar 

  137. Ferrandina G, Bonanno G, Pierelli L, Perillo A, Procoli A, Mariotti A, et al. Expression of CD133-1 and CD133-2 in ovarian cancer. Int J Gynecol Cancer. 2008;18:506–14.

    PubMed  CAS  Google Scholar 

  138. Curley MD, Therrien VA, Cummings CL, Sergent PA, Koulouris CR, Friel AM, et al. CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells. 2009;27:2875–83.

    PubMed  CAS  Google Scholar 

  139. Gao MQ, Choi YP, Kang S, Youn JH, Cho NH. CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene. 2010;29:2672–80.

    PubMed  CAS  Google Scholar 

  140. Wei X, Dombkowski D, Meirelles K, Pieretti-Vanmarcke R, Szotek PP, Chang HL, et al. Mullerian inhibiting substance preferentially inhibits stem/progenitors in human ovarian cancer cell lines compared with chemotherapeutics. Proc Natl Acad Sci USA. 2010;107:18874–9.

    PubMed  CAS  Google Scholar 

  141. Gupta PB, Onder TT, Jiang GZ, Tao K, Kuperwasser C, Weinberg RA, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645–59.

    PubMed  CAS  Google Scholar 

  142. Shmelkov SV, St Clair R, Lyden D, Rafii S. AC133/CD133/prominin-1. Int J Biochem Cell B. 2005;37:715–9.

    CAS  Google Scholar 

  143. Griguer CE, Oliva CR, Gobin E, Marcorelles P, Benos DJ, Lancaster Jr JR, et al. CD133 is a marker of bioenergetic stress in human glioma. PLoS One. 2008;3.

  144. Weigmann A, Corbeil D, Hellwig A, Huttner WB. Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc Natl Acad Sci USA. 1997;94:12425–30.

    PubMed  CAS  Google Scholar 

  145. Rappa G, Fodstad O, Lorico A. The stem cell-associated antigen CD133 (prominin-1) is a molecular therapeutic target for metastatic melanoma. Stem Cells. 2008;26:3008–17.

    PubMed  CAS  Google Scholar 

  146. Wu YJ, Wu PY. CD133 as a marker for cancer stem cells: progresses and concerns. Stem Cells Dev. 2009;18:1127–34.

    PubMed  CAS  Google Scholar 

  147. Bidlingmaier S, Zhu X, Liu B. The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med-Jmm. 2008;86:1025–32.

    CAS  Google Scholar 

  148. Swaminathan SK, Olin MR, Forster CL, Cruz KSS, Panyam J, Ohlfest JR. Identification of a novel monoclonal antibody recognizing CD133. J Immunol Methods. 2010;361:110–5.

    PubMed  CAS  Google Scholar 

  149. Wang C-H, Chiou S-H, Chou C-P, Chen Y-C, Huang Y-J, Peng C-A. Photothermolysis of glioblastoma stem-like cells targeted by carbon nanotubes conjugated with CD133 monoclonal antibody. Nanomed-Nanotechnol. 2011;7:69–79.

    CAS  Google Scholar 

  150. Bourseau-Guilmain E, Bejaud J, Griveau A, Lautram N, Hindre F, Weyland M, et al. Development and characterization of immuno-nanocarriers targeting the cancer stem cell marker AC133. Int J Pharm. 2012;423:93–101.

    PubMed  CAS  Google Scholar 

  151. van der Gun BTF, Melchers LJ, Ruiters MHJ, de Leij LFMH, McLaughlin PMJ, Rots MG. EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis. 2010;31:1913–21.

    PubMed  Google Scholar 

  152. Winter MJ, Nagelkerken B, Mertens AEE, Rees-Bakker HAM, Briaire-de Bruijn IH, Litvinov SV. Expression of Ep-CAM shifts the state of cadherin-mediated adhesions from strong to weak. Exp Cell Res. 2003;285:50–8.

    PubMed  CAS  Google Scholar 

  153. Litvinov SV, Velders MP, Bakker HAM, Fleuren GJ, Warnaar SO. Ep-CAM—a human epithelial antigen is a homophilic cell–cell adhesion molecule. J Cell Biol. 1994;125:437–46.

    PubMed  CAS  Google Scholar 

  154. Ruf P, Gires O, Jager M, Fellinger K, Atz J, Lindhofer H. Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer. Brit J Cancer. 2007;97:315–21.

    PubMed  CAS  Google Scholar 

  155. Chelius D, Ruf P, Gruber P, Ploscher M, Liedtke R, Gansberger E, et al. Structural and functional characterization of the trifunctional antibody catumaxomab. MABS. 2010;2:309–19.

    PubMed  Google Scholar 

  156. Lindhofer H, Schoberth A, Pelster D, Hess J, Herold J, Jager M. Elimination of cancer stem cells (CD133+/EpCAM+) from malignant ascites by the trifunctional antibody catumaxomab: results from a pivotal phase II/III study. J Clin Oncol. 2009;27.

  157. Jager M, Schoberth A, Ruf P, Hess J, Hennig M, Schmalfeldt B, et al. Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3). Cancer Res. 2012;72:24–32.

    PubMed  Google Scholar 

  158. Seimetz D, Lindhofer H, Bokemeyer C. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev. 2010;36:458–67.

    PubMed  CAS  Google Scholar 

  159. Brischwein K, Schlereth B, Guller B, Steiger C, Wolf A, Lutterbuese R, et al. MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors. Mol Immunol. 2006;43:1129–43.

    PubMed  CAS  Google Scholar 

  160. Baeuerle PA, Kufer P, Bargou R. BiTE: teaching antibodies to engage T-cells for cancer therapy. Curr Opin Mol Ther. 2009;11:22–30.

    PubMed  CAS  Google Scholar 

  161. Amann M, Brischwein K, Lutterbuese P, Parr L, Petersen L, Lorenczewski G, et al. Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3. Cancer Res. 2008;68:143–51.

    PubMed  CAS  Google Scholar 

  162. Herrmann I, Baeuerle PA, Friedrich M, Murr A, Filusch S, Ruttinger D, et al. Highly efficient elimination of colorectal tumor-initiating cells by an EpCAM/CD3-bispecific antibody engaging human T cells. PLoS One. 2010;5.

  163. Haas C, Krinner E, Brischwein K, Hoffmann P, Lutterbuese R, Schlereth B, et al. Mode of cytotoxic action of T cell-engaging BiTE antibody MT110. Immunobiology. 2009;214:441–53.

    PubMed  CAS  Google Scholar 

  164. Balzar M, Winter MJ, de Boer CJ, Litvinov SV. The biology of the 17-1A antigen (Ep-CAM). J Mol Med-Jmm. 1999;77:699–712.

    CAS  Google Scholar 

  165. Riethmuller G, Schneidergadicke E, Schlimok G, Schmiegel W, Raab R, Hoffken K, et al. Randomized trial of monoclonal-antibody for adjuvant therapy of resected Dukes-C colorectal-carcinoma. Lancet. 1994;343:1177–83.

    PubMed  CAS  Google Scholar 

  166. Braun S, Hepp F, Kentenich CRM, Janni W, Pantel K, Riethmuller G, et al. Monoclonal antibody therapy with Edrecolomab in breast cancer patients: monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clin Cancer Res. 1999;5:3999–4004.

    PubMed  CAS  Google Scholar 

  167. Naundorf S, Preithner S, Mayer P, Lippold S, Wolf A, Hanakam F, et al. In vitro and in vivo activity of MT201, a fully human monoclonal antibody for pancarcinoma treatment. Int J Cancer. 2002;100:101–10.

    PubMed  CAS  Google Scholar 

  168. Hartung G, Hofheinz RD, Dencausse Y, Sturm J, Kopp-Schneider A, Dietrich G, et al. Adjuvant therapy with edrecolomab versus observation in stage II colon cancer: a multicenter randomized phase III study. Onkologie. 2005;28:347–50.

    PubMed  CAS  Google Scholar 

  169. Schmidt M, Ruttinger D, Sebastian M, Hanusch CA, Marschner N, Baeuerle PA et al. Phase IB study of the EpCAM antibody adecatumumab combined with docetaxel in patients with EpCAM-positive relapsed or refractory advanced-stage breast cancer. Ann Oncol. 2012.

  170. Gallatin WM, Weissman IL, Butcher EC. A cell-surface molecule involved in organ-specific homing of lymphocytes. Nature. 1983;304:30–4.

    PubMed  CAS  Google Scholar 

  171. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principle cell-surface receptor for hyaluronate. Cell. 1990;61:1303–13.

    PubMed  CAS  Google Scholar 

  172. Stamenkovic I, Amiot M, Pesando JM, Seed B. A lymphocyte molecule implicated in lymph-node homing is a member of the cartilage link protein family. Cell. 1989;56:1057–62.

    PubMed  CAS  Google Scholar 

  173. Teriete P, Banerji S, Noble M, Blundell CD, Wright AJ, Pickford AR, et al. Structure of the regulatory hyaluronan binding domain in the inflammatory leukocyte homing receptor CD44. Mol Cell. 2004;13:483–96.

    PubMed  CAS  Google Scholar 

  174. Nagano O, Saya H. Mechanism and biological significance of CD44 cleavage. Cancer Sci. 2004;95:930–5.

    PubMed  CAS  Google Scholar 

  175. Vigetti D, Viola M, Karousou E, Rizzi M, Moretto P, Genasetti A, et al. Hyaluronan-CD44-ERK1/2 regulate human aortic smooth muscle cell motility during aging. J Biol Chem. 2008;283:4448–58.

    PubMed  CAS  Google Scholar 

  176. Cheng CH, Sharp PA. Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion. Mol Cell Biol. 2006;26:362–70.

    PubMed  CAS  Google Scholar 

  177. Peach RJ, Hollenbaugh D, Stamenkovic I, Aruffo A. Identification of hyaluronic-acid binding-sites in the extracellular domain of Cd44. J Cell Biol. 1993;122:257–64.

    PubMed  CAS  Google Scholar 

  178. Ishii S, Ford R, Thomas P, Nachman A, Steele G, Jessup JM. Cd44 participates in the adhesion of human colorectal-carcinoma cells to laminin and type-IV collagen. Surg Oncol. 1993;2:255–64.

    PubMed  CAS  Google Scholar 

  179. Jalkanen S, Jalkanen M. Lymphocyte Cd44 binds the Cooh-terminal heparin-binding domain of fibronectin. J Cell Biol. 1992;116:817–25.

    PubMed  CAS  Google Scholar 

  180. Konstantopoulos K, Thomas SN. Cancer cells in transit: the vascular interactions of tumor cells. Ann Rev Biomed Eng. 2009;11:177–202.

    CAS  Google Scholar 

  181. Toyamasorimachi N, Miyasaka M. A novel ligand for Cd44 is sulfated proteoglycan. Int Immunol. 1994;6:655–60.

    CAS  Google Scholar 

  182. Liu DC, Sy MS. Phorbol myristate acetate stimulates the dimerization of CD44 involving a cysteine in the transmembrane domain. J Immunol. 1997;159:2702–11.

    PubMed  CAS  Google Scholar 

  183. Oliferenko S, Paiha K, Harder T, Gerke V, Schwarzler C, Schwarz H, et al. Analysis of CD44-containing lipid rafts: recruitment of annexin II and stabilization by the actin cytoskeleton. J Cell Biol. 1999;146:843–54.

    PubMed  CAS  Google Scholar 

  184. Fehon RG, McClatchey AI, Bretscher A. Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Bio. 2010;11:276–87.

    CAS  Google Scholar 

  185. Siegelman MH, Stanescu D, Estess P. The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion. J Clin Invest. 2000;105:683–91.

    PubMed  CAS  Google Scholar 

  186. Williams DA, Cancelas JA. Leukaemia—niche retreats for stem cells. Nature. 2006;444:827–8.

    PubMed  CAS  Google Scholar 

  187. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818–29.

    PubMed  CAS  Google Scholar 

  188. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004;4:528–39.

    PubMed  CAS  Google Scholar 

  189. Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Bi. 2007;23:675–99.

    CAS  Google Scholar 

  190. Tallman MS. New strategies for the treatment of acute myeloid leukemia including antibodies and other novel agents. Hematology Am Soc Hematol Educ Program. 2005:143–50.

  191. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6:93–106.

    PubMed  CAS  Google Scholar 

  192. Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood. 2005;106:1901–10.

    PubMed  CAS  Google Scholar 

  193. Marangoni E, Lecomte N, Durand L, de Pinieux G, Decaudin D, Chomienne C, et al. CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts. Brit J Cancer. 2009;100:918–22.

    PubMed  CAS  Google Scholar 

  194. Ulyanova T, Blasioli J, Woodford-Thomas TA, Thomas ML. The sialoadhesin CD33 is a myeloid-specific inhibitory receptor. Eur J Immunol. 1999;29:3440–9.

    PubMed  CAS  Google Scholar 

  195. Taylor VC, Buckley CD, Douglas M, Cody AJ, Simmons DL, Freeman SD. The myeloid-specific sialic acid-binding receptor, CD33, associates with the protein-tyrosine phosphatases, SHP-1 and SHP-2. J Biol Chem. 1999;274:11505–12.

    PubMed  CAS  Google Scholar 

  196. Vitale C, Romagnani C, Puccetti A, Olive D, Costello R, Chiossone L, et al. Surface expression and function of p75/AIRM-1 or CD33 in acute myeloid leukemias: engagement of CD33 induces apoptosis of leukemic cells. Proc Natl Acad Sci U S A. 2001;98:5764–9.

    PubMed  CAS  Google Scholar 

  197. Schwemmlein M, Peipp M, Barbin K, Saul D, Stockmeyer B, Repp R, et al. A CD33-specific single-chain immunotoxin mediates potent apoptosis of cultured human myeloid leukaemia cells. Br J Haematol. 2006;133:141–51.

    PubMed  CAS  Google Scholar 

  198. Damle NK, Frost P. Antibody-targeted chemotherapy with immunoconjugates of calicheamicin. Curr Opin Pharmacol. 2003;3:386–90.

    PubMed  CAS  Google Scholar 

  199. Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R, et al. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem. 2002;13:47–58.

    PubMed  CAS  Google Scholar 

  200. Hamann PR, Hinman LM, Beyer CF, Lindh D, Upeslacis J, Flowers DA, et al. An anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of linker. Bioconjug Chem. 2002;13:40–6.

    PubMed  CAS  Google Scholar 

  201. Linenberger ML. CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leukemia. 2005;19:176–82.

    PubMed  CAS  Google Scholar 

  202. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm216458.htm.

  203. Walter RB, Appelbaum FR, Estey EH, Bernstein ID. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood. 2012.

  204. Furness SGB, McNagny K. Beyond mere markers—functions for CD34 family of sialomucins in hematopoiesis. Immunol Res. 2006;34:13–32.

    PubMed  CAS  Google Scholar 

  205. Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, Shaper JH. Antigenic analysis of hematopoiesis.3. A hematopoietic progenitor-cell surface-antigen defined by a monoclonal-antibody raised against Kg-1a cells. J Immunol. 1984;133:157–65.

    PubMed  CAS  Google Scholar 

  206. Berenson RJ, Andrews RG, Bensinger WI, Kalamasz D, Knitter G, Buckner CD, et al. Antigen Cd34+ marrow-cells engraft lethally irradiated baboons. J Clin Invest. 1988;81:951–5.

    PubMed  CAS  Google Scholar 

  207. Nielsen JS, McNagny KM. Novel functions of the CD34 family. J Cell Sci. 2008;121:3683–92.

    PubMed  CAS  Google Scholar 

  208. Krause DS, Fackler MJ, Civin CI, May WS. CD34: structure, biology, and clinical utility. Blood. 1996;87:1–13.

    PubMed  CAS  Google Scholar 

  209. Healy L, May G, Gale K, Grosveld F, Greaves M, Enver T. The stem cell antigen CD34 functions as a regulator of hemopoietic cell adhesion. Proc Natl Acad Sci USA. 1995;92:12240–4.

    PubMed  CAS  Google Scholar 

  210. Baumhueter S, Singer MS, Henzel W, Hemmerich S, Renz M, Rosen SD, et al. Binding of l-selectin to the vascular sialomucin CD34. Science. 1993;262:436–8.

    CAS  Google Scholar 

  211. Krause DS, Ito T, Fackler MJ, Smith OM, Collector MI, Sharkis SJ, et al. Characterization of murine CD34, a marker for hematopoietic progenitor and stem-cells. Blood. 1994;84:691–701.

    PubMed  CAS  Google Scholar 

  212. Tan PC, Furness SGB, Merkens H, Lin SJ, McCoy ML, Roskelley CD, et al. Na+/H + exchanger regulatory factor-1 is a hematopoietic ligand for a subset of the CD34 family of stem cell surface proteins. Stem Cells. 2006;24:1150–61.

    PubMed  CAS  Google Scholar 

  213. Fackler MJ, Krause DS, Smith OM, Civin CI, May WS. Full-length but not truncated Cd34 inhibits hematopoietic-cell differentiation of M1 cells. Blood. 1995;85:3040–7.

    PubMed  CAS  Google Scholar 

  214. Gangenahalli GU, Singh VK, Verma YK, Gupta P, Sharma RK, Chandra R, et al. Hematopoietic stem cell antigen CD34: role in adhesion or homing. Stem Cells Dev. 2006;15:305–13.

    PubMed  CAS  Google Scholar 

  215. Kawanobe T, Kogure S, Nakamura S, Sato M, Katayama K, Mitsuhashi J, et al. Expression of human ABCB5 confers resistance to taxanes and anthracyclines. Biochem Bioph Res Co. 2012;418:736–41.

    CAS  Google Scholar 

  216. Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM, Gasser M, et al. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res. 2005;65:4320–33.

    PubMed  CAS  Google Scholar 

  217. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, et al. Identification of cells initiating human melanomas. Nature. 2008;451:345–9.

    PubMed  CAS  Google Scholar 

  218. Wickstrom M, Larsson R, Nygren P, Gullbo J. Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci. 2011;102:501–8.

    PubMed  Google Scholar 

  219. Luan YP, Xu WF. The structure and main functions of aminopeptidase N. Curr Med Chem. 2007;14:639–47.

    PubMed  CAS  Google Scholar 

  220. Umezawa H, Aoyagi T, Suda H, Hamada M, Takeuchi T. Bestatin, an inhibitor of aminopeptidase-B, produced by actinomycetes. J Antibiot. 1976;29:97–9.

    PubMed  CAS  Google Scholar 

  221. Talmadge JE, Lenz BF, Pennington R, Long C, Phillips H, Schneider M, et al. Immunomodulatory and therapeutic properties of bestatin in mice. Cancer Res. 1986;46:4505–10.

    PubMed  CAS  Google Scholar 

  222. Mathe G. Bestatin, an aminopeptidase inhibitor with a multi-pharmacological function. Biomed Pharmacother. 1991;45:49–54.

    PubMed  CAS  Google Scholar 

  223. Sekine K, Fujii H, Abe F. Induction of apoptosis by bestatin (ubenimex) in human leukemic cell lines. Leukemia. 1999;13:729–34.

    PubMed  CAS  Google Scholar 

  224. Ezawa K, Minato K, Dobashi K. Induction of apoptosis by ubenimex (Bestatin(R)) in human non-small-cell lung cancer cell lines. Biomed Pharmacother. 1996;50:283–9.

    PubMed  CAS  Google Scholar 

  225. Thunnissen MMGM, Nordlund P, Haeggstrom JZ. Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation. Nat Struct Biol. 2001;8:131–5.

    PubMed  CAS  Google Scholar 

  226. Tholander F, Rudberg P, Thunnissen M, Haeggstrom JZ. Leukotriene A4 hydrolase, the gatekeeper of chemotactic leukotriene B4 biosynthesis. Prostag Oth Lipid M. 2006;79:157.

    Google Scholar 

  227. Fromm JR. Flow cytometric analysis of CD123 is useful for immunophenotyping classical Hodgkin lymphoma. Cytom Part B-Clin Cy. 2011;80B:91–9.

    CAS  Google Scholar 

  228. Jin LQ, Lee EM, Ramshaw HS, Busfield SJ, Peoppl AG, Wilkinson L, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell. 2009;5:31–42.

    PubMed  CAS  Google Scholar 

  229. Lindberg FP, Gresham HD, Schwarz E, Brown EJ. Molecular-cloning of integrin-associated protein—an immunoglobulin family member with multiple membrane-spanning domains implicated in alpha-nu-beta-3-dependent ligand-binding. J Cell Biol. 1993;123:485–96.

    PubMed  CAS  Google Scholar 

  230. Brown EJ, Frazier WA. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol. 2001;11:130–5.

    PubMed  CAS  Google Scholar 

  231. Hatherley D, Graham SC, Turner J, Harlos K, Stuart DI, Barclay AN. Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47. Mol Cell. 2008;31:266–77.

    PubMed  CAS  Google Scholar 

  232. Majeti R. Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells. Oncogene. 2011;30:1009–19.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Support from the American Cancer Society (IRG-58-001-52-IRG68), the Danny Thompson Memorial Golf Tournament (UMN) Leukemia Research Fund, and the University of Minnesota is gratefully acknowledged. D.W. thanks the American Heart Association (11PRE7240035) for a predoctoral fellowship.

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, University of Minnesota, 717 Delaware St SE, Minneapolis, MN, 55414, USA

    Timothy E. Andrews, Dan Wang & Daniel A. Harki

Authors
  1. Timothy E. Andrews
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel A. Harki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel A. Harki.

Additional information

Timothy E. Andrews and Dan Wang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Andrews, T.E., Wang, D. & Harki, D.A. Cell surface markers of cancer stem cells: diagnostic macromolecules and targets for drug delivery. Drug Deliv. and Transl. Res. 3, 121–142 (2013). https://doi.org/10.1007/s13346-012-0075-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-012-0075-1

Keywords

Search

Navigation