Identification of cancer stem cells: from leukemia to solid cancers

Abstract

Cancer stem cells (CSCs) are widely considered to be a small cell population in leukemia and many solid cancers with the properties including self-renewal and differentiation to non-tumorigenic cancer cells. Identification and isolation of CSCs significantly depend on the special surface markers of CSCs. Aberrant gene expression and signal transduction contribute to malignancies of CSCs, which result in cancer initiation, progression and recurrence. The inefficient therapy of cancers is mainly attributed to the failure of elimination of the malignant CSCs. However, CSCs have not been detected in all cancers and hierarchical organization of tumors might challenge cancer stem cell models. Additionally, opinions about the validity of the CSC hypothesis, the biological properties of CSCs, and the relevance of CSCs to cancer therapy differ widely. In this review, we discuss the debate of cancer stem cell model, the parameters by which CSCs can or cannot be defined, and the advances in the therapy of CSCs.

Key words： Cancer stem cell; leukemia; solid tumor; signal transduction; therapy

Acknowledgement

This work was supported by National Basic Research Program (973 Project) of China (No. 2009CB918902), Hundreds of Talents Program of Chinese Academy of Sciences 2009-2014, and a grant from Beijing Institutes of Life Science, Chinese Academy of Sciences.

References

1 Abraham B K, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H (2005). Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res, 11(3): 1154–1159

2 Al-Hajj M, Wicha M S, Benito-Hernandez A, Morrison S J, Clarke M F (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A, 100(7): 3983–3988

3 Bissell M J, Labarge M A (2005). Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell, 7(1): 17–23

4 Blair A, Hogge D E, Ailles L E, Lansdorp P M, Sutherland H J (1997). Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood, 89(9): 3104–3112

5 Bonnet D, Dick J E (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med, 3(7): 730–737

6 Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005). Opinion: migrating cancer stem cells- an integrated concept of malignant tumour progression. Nat Rev Cancer, 5(9): 744–749

7 Bruce W R, Van Der Gaag H (1963). A Quantitative Assay for the Number of Murine Lymphoma Cells Capable of Proliferation in Vivo. Nature, 199: 79–80

8 Bui M R, Hodson V, King T, Leopold D, Dai S, Fiolkoski V, Oakes S, Duke R, Apelian D, Franzusoff A, DeGregori J (2010). Mutation-specific control of BCR-ABL T315I positive leukemia with a recombinant yeast-based therapeutic vaccine in a murine model. Vaccine, 28(37): 6028–6035

9 Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T (2008). A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep, 9(6): 582–589

10 Campbell L L, Polyak K (2007). Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle, 6(19): 2332–2338

11 Carpten J D, Faber A L, Horn C, Donoho G P, Briggs S L, Robbins C M, Hostetter G, Boguslawski S, Moses T Y, Savage S, Uhlik M, Lin A, Du J, Qian Y W, Zeckner D J, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai M H, Blanchard K L, Thomas J E (2007). A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature, 448(7152): 439–444

12 Chen J L, Limnander A, Rothman P B (2008). Pim-1 and Pim-2 kinases are required for efficient pre-B-cell transformation by v-Abl oncogene. Blood, 111(3): 1677–1685

13 Clarke M F, Dick J E, Dirks P B, Eaves C J, Jamieson C H, Jones D L, Visvader J, Weissman I L, Wahl G M (2006). Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res, 66, 9339–9344

14 Collins A T, Berry P A, Hyde C, Stower M J, Maitland N J (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res, 65(23): 10946–10951

15 Deininger M W, Goldman J M, Melo J V (2000). The molecular biology of chronic myeloid leukemia. Blood, 96(10): 3343–3356

16 Druker B J, Talpaz M, Resta D J, Peng B, Buchdunger E, Ford J M, Lydon N B, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers C L (2001). Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med, 344(14): 1031–1037

17 Fang D, Nguyen T K, Leishear K, Finko R, Kulp A N, Hotz S, Van Belle P A, Xu X, Elder D E, Herlyn M (2005). A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res, 65(20): 9328–9337

18 Ginestier C, Hur M H, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer C G, Liu S, Schott A, Hayes D, Birnbaum D, Wicha M S, 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(5): 555–567

19 Gregory M A, Phang T L, Neviani P, Alvarez-Calderon F, Eide C A, O’Hare T, Zaberezhnyy V, Williams R T, Druker B J, Perrotti D, Degregori J (2010). Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell, 18(1): 74–87

20 Gregory P A, Bracken C P, Bert A G, Goodall G J (2008). MicroRNAs as regulators of epithelial-mesenchymal transition. Cell Cycle, 7(20): 3112–3118

21 Guo G, Qiu X, Wang S, Chen Y, Rothman P B, Wang Z, Chen Y, Wang G, Chen J L (2010). Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells. Oncogene, 29(26): 3845–3853

22 Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y, Dahlberg S, Neuberg D, Moreau L A, Winter S S, Larson R, Zhang J, Protopopov A, Chin L, Pandolfi P P, Silverman L B, Hunger S P, Sallan S E, Look A T (2009). High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood, 114(3): 647–650

23 Guzman M L, Jordan C T (2004). Considerations for targeting malignant stem cells in leukemia. Cancer Control, 11(2): 97–104

24 Haan S, Wüller S, Kaczor J, Rolvering C, Nöcker T, Behrmann I, Haan C (2009). SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling. Oncogene, 28(34): 3069–3080

25 Hemmati H D, Nakano I, Lazareff J A, Masterman-Smith M, Geschwind D H, Bronner-Fraser M, Kornblum H I (2003). Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A, 100(25): 15178–15183

26 Herman S E, Gordon A L, Wagner A J, Heerema N A, Zhao W, Flynn J M, Jones J, Andritsos L, Puri K D, Lannutti B J, Giese N A, Zhang X, Wei L, Byrd J C, Johnson A J (2010). The phosphatidylinositol 3-kinase-{delta} inhibitor CAL-101 demonstrates promising pre-clinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood, 2010(Jun): 3 (Epub ahead of print)

27 Hermann P C, Huber S L, Herrler T, Aicher A, Ellwart J W, Guba M, Bruns C J, Heeschen C (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell, 1(3): 313–323

28 Hu Z, Pan X F, Wu F Q, Ma L Y, Liu D P, Liu Y, Feng T T, Meng F Y, Liu X L, Jiang Q L, Chen X Q, Liu J L, Liu P, Chen Z, Chen S J, Zhou G B (2009). Synergy between proteasome inhibitors and imatinib mesylate in chronic myeloid leukemia. PLoS One, 4(7): e6257

29 Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan D E, Teruya-Feldstein J, Pandolfi P P (2008). PML targeting eradicates quiescent leukaemia-initiating cells. Nature, 453(7198): 1072–1078

30 Jabbour E, Cortes J, Kantarjian H (2010). Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review. Core Evid, 4: 207–213

31 Jamieson C H, Ailles L E, Dylla S J, Muijtjens M, Jones C, Zehnder J L, Gotlib J, Li K, Manz M G, Keating A, Sawyers C L, Weissman I L (2004). Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med, 351(7): 657–667

32 Jiang X, Forrest D, Nicolini F, Turhan A, Guilhot J, Yip C, Holyoake T, Jorgensen H, Lambie K, Saw K M, Pang E, Vukovic R, Lehn P, Ringrose A, Yu M, Brinkman R R, Smith C, Eaves A, Eaves C (2010). Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate. Blood, 116(12): 2112–2121

33 Jordan C T, Upchurch D, Szilvassy S J, Guzman M L, Howard D S, Pettigrew A L, Meyerrose T, Rossi R, Grimes B, Rizzieri D A, Luger S M, Phillips G L (2000). The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia, 14(10): 1777–1784

34 Jørgensen H G, Holyoake T L (2007). Characterization of cancer stem cells in chronic myeloid leukaemia. Biochem Soc Trans, 35(Pt 5): 1347–1351

35 Karnoub A E, Dash A B, Vo A P, Sullivan A, Brooks M W, Bell G W, Richardson A L, Polyak K, Tubo R, Weinberg R A (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature, 449(7162): 557–563

36 Kelly P N, Dakic A, Adams J M, Nutt S L, Strasser A (2007). Tumor growth need not be driven by rare cancer stem cells. Science, 317(5836): 337

37 Kharas M G, Okabe R, Ganis J J, Gozo M, Khandan T, Paktinat M, Gilliland D G, Gritsman K (2010). Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood, 115(7): 1406–1415

38 Kim C F, Jackson E L, Woolfenden A E, Lawrence S, Babar I, Vogel S, Crowley D, Bronson R T, Jacks T (2005). Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell, 121(6): 823–835

39 Kim K Y, Kim S U, Leung P C, Jeung E B, Choi K C (2010). Influence of the prodrugs 5-fluorocytosine and CPT-11 on ovarian cancer cells using genetically engineered stem cells: tumor-tropic potential and inhibition of ovarian cancer cell growth. Cancer Sci, 101(4): 955–962

40 Krause D S, Lazarides K, von Andrian U H, Van Etten R A (2006). Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat Med, 12(10): 1175–1180

41 Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, Huber M, Hohl D, Cano A, Birchmeier W, Huelsken J (2008). Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature, 452(7187): 650–653

42 Mani S A, Guo W, Liao M J, Eaton E N, Ayyanan A, Zhou A Y, Brooks M, Reinhard F, Zhang C C, Shipitsin M, Campbell L L, Polyak K, Brisken C, Yang J, Weinberg R A (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133(4): 704–715

43 Mantovani A (2009). Cancer: Inflaming metastasis. Nature, 457(7225): 36–37

44 Moshaver B, van Rhenen A, Kelder A, van der Pol M, Terwijn M, Bachas C, Westra A H, Ossenkoppele G J, Zweegman S, Schuurhuis G J (2008). Identification of a small subpopulation of candidate leukemia initiating cells in the side population (sp) of patients with acute myeloid leukemia. Stem Cells.

45 Murray P J (2007). The JAK-STAT signaling pathway: input and output integration. J Immunol, 178(5): 2623–2629

46 Nasr R, Guillemin M C, Ferhi O, Soilihi H, Peres L, Berthier C, Rousselot P, Robledo-Sarmiento M, Lallemand-Breitenbach V, Gourmel B, Vitoux D, Pandolfi P P, Rochette-Egly C, Zhu J, de Thé H (2008). Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med, 14(12): 1333–1342

47 Nusse R (2003). Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development, 130(22): 5297–5305

48 O’Brien C A, Pollett A, Gallinger S, Dick J E (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature, 445(7123): 106–110

49 Peng C, Chen Y, Yang Z, Zhang H, Osterby L, Rosmarin A G, Li S (2010). PTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in mice. Blood, 115(3): 626–635

50 Piccirillo S G, Reynolds B A, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi A L (2006). Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature, 444(7120): 761–765

51 Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti M A, Daidone M G (2005). Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res, 65(13): 5506–5511

52 Pradhan A, Lambert Q T, Reuther G W (2007). Transformation of hematopoietic cells and activation of JAK2-V617F by IL-27R, a component of a heterodimeric type I cytokine receptor. Proc Natl Acad Sci U S A, 104(47): 18502–18507

53 Quintana E, Shackleton M, Sabel M S, Fullen D R, Johnson T M, Morrison S J (2008). Efficient tumour formation by single human melanoma cells. Nature, 456(7222): 593–598

54 Reya T, Duncan A W, Ailles L, Domen J, Scherer D C, Willert K, Hintz L, Nusse R, Weissman I L (2003). A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature, 423(6938): 409–414

55 Reya T, Morrison S J, Clarke M F, Weissman I L (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859): 105–111

56 Savona M, Talpaz M (2008). Getting to the stem of chronic myeloid leukaemia. Nat Rev Cancer, 8(5): 341–350

57 Singh S K, Hawkins C, Clarke I D, Squire J A, Bayani J, Hide T, Henkelman R M, Cusimano M D, Dirks P B (2004). Identification of human brain tumour initiating cells. Nature, 432(7015): 396–401

58 Szotek P P, Pieretti-Vanmarcke R, Masiakos P T, Dinulescu D M, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin D T, Donahoe P K (2006). Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci U S A, 103(30): 11154–11159

59 Thiery J P (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2(6): 442–454

60 Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy J D Jr (2003). The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med, 349(26): 2483–2494

61 van der Pol M A, Feller N, Roseboom M, Moshaver B, Westra G, Broxterman H J, Ossenkoppele G J, Schuurhuis G J (2003). Assessment of the normal or leukemic nature of CD34+ cells in acute myeloid leukemia with low percentages of CD34 cells. Haematologica, 88(9): 983–993

62 van Noort M, Meeldijk J, van der Zee R, Destree O, Clevers H (2002). Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem, 277(20): 17901–17905

63 Venturini L, Battmer K, Castoldi M, Schultheis B, Hochhaus A, Muckenthaler M U, Ganser A, Eder M, Scherr M (2007). Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells. Blood, 109(10): 4399–4405

64 Viswanathan S R, Daley G Q, Gregory R I (2008). Selective blockade of microRNA processing by Lin28. Science, 320(5872): 97–100

65 Wang J C, Dick J E (2005). Cancer stem cells: lessons from leukemia. Trends Cell Biol, 15(9): 494–501

66 Wang Y, Krivtsov A V, Sinha A U, North T E, Goessling W, Feng Z, Zon L I, Armstrong S A (2010). The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science, 327(5973): 1650–1653

67 Williams R T, den Besten W, Sherr C J (2007). Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia. Genes Dev, 21(18): 2283–2287

68 Wong D J, Liu H, Ridky T W, Cassarino D, Segal E, Chang H Y (2008). Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell, 2(4): 333–344

69 Wuchter C, Ratei R, Spahn G, Schoch C, Harbott J, Schnittger S, Haferlach T, Creutzig U, Sperling C, Karawajew L, Ludwig W D (2001). Impact of CD133 (AC133) and CD90 expression analysis for acute leukemia immunophenotyping. Haematologica, 86(2): 154–161

70 Yang Y M, Chang J W (2008). Current status and issues in cancer stem cell study. Cancer Invest, 26(7): 741–755

71 Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J, Song E (2007). let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell, 131(6): 1109–1123

72 Zhang B, Strauss A C, Chu S, Li M, Ho Y, Shiang K D, Snyder D S, Huettner C S, Shultz L, Holyoake T, Bhatia R (2010). Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell, 17(5): 427–442

73 Zhao C, Blum J, Chen A, Kwon H Y, Jung S H, Cook J M, Lagoo A, Reya T (2007). Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell, 12(6): 528–541