Cancer Immunology, Immunotherapy

, Volume 64, Issue 1, pp 91–97 | Cite as

Cancer stem cells: perspectives for therapeutic targeting

  • Cristina Maccalli
  • Ruggero De Maria
Focussed Research Review


Cells with “stemness” and tumor-initiating properties have been isolated from both hematological and solid tumors. These cells denominated as cancer stem cells (CSCs), representing rare populations within tumors, have the ability to metastasize and are resistant to standard therapies and immunotherapy. Heterogeneity and plasticity in the phenotype of CSCs have been described in relation to their tissue origin. Few definitive markers have been isolated for CSCs from human solid tumors, limiting their usage for in vivo identification of these cells. Nevertheless, progress in the emerging CSCs concept has been achieved gaining, at least for some type of tumors, their biological and immunological characterization. The recent identification of molecules and signaling pathways that are up-regulated or aberrantly induced in CSCs allowed the development of small agents for specifically targeting of CSCs. A general low immunogenic profile has been reported for CSCs with, in some cases, the identification of the mechanisms responsible of the impairment of cell-mediated immune responses. These concepts are discussed in the context of this review. Although CSCs still need to be fully characterized, potential candidate markers and/or signaling pathways, to be exploited for the design of novel CSC-targeting therapeutic strategies, are described in this review.


Cancer stem cells Cancer stem cells-associated signaling pathways Immunological profile Immune modulation CSC-targeted therapies NIBIT 2013 



Aldehyde dehydrogenase


Bone morphogenetic protein 4


Colon antigen-1


Colorectal cancer


Cancer stem cells


Delta-like ligand 4


Growth differentiation factor-15


Glioblastoma multiforme




Monoclonal antibody


Multi-drug resistance 1 gene


Programmed death 1


Prostaglandin E2


Phosphatidylinositide 3-kinase


Phosphatase and tensin homolog


Transforming growth factor beta 1


X-linked inhibitor of apoptosis


Conflict of interest

The authors have no conflict of interest.


  1. 1.
    Clarke MF, Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 124:1111–1115PubMedCrossRefGoogle Scholar
  2. 2.
    Clevers H (2011) The cancer stem cells: premises, promises and challenges. Nat Med 17:313–319PubMedCrossRefGoogle Scholar
  3. 3.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737PubMedCrossRefGoogle Scholar
  4. 4.
    Dick JE (2008) Stem cell concepts renew cancer research. Blood 112:4793–4807PubMedCrossRefGoogle Scholar
  5. 5.
    Maccalli C, Volontè A, Cimminiello C, Parmiani G (2013) Immunology of cancer stem cells in solid tumor. Eur J Cancer 50:649–655PubMedCrossRefGoogle Scholar
  6. 6.
    Hjelmeland AB, Rich JN (2012) The quest for self-identity: not all cancer stem cells are the same. Clin Cancer Res 18:3495–3498PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Kemper K, Presetyanti PR, de Lau W, Rodermond H, Clevers H, Medema JP (2012) Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells. Stem Cells 30:2378–2386PubMedCrossRefGoogle Scholar
  8. 8.
    Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, Apuzzo T, Sperduti I, Volpe S, Cocorullo G, Gulotta G, Dieli F, De Maria R, Stassi G (2014) CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 14:342–356PubMedCrossRefGoogle Scholar
  9. 9.
    Maugeri-Saccà M, Vigneri P, De Maria R (2011) Cancer stem cells and chemosensitivity. Clin Cancer Res 17:4942–4947PubMedCrossRefGoogle Scholar
  10. 10.
    Diehn M, Clarke MF (2006) Cancer stem cells and radiotherapy: new insights into tumor radioresistance. J Natl Cancer Inst 98:1755–1757PubMedCrossRefGoogle Scholar
  11. 11.
    Irvin DK, Jouanneau E, Duvall G, Zhang XXY, Zhai Y, Sarayba D, Seksenyan A, Panwar A, Black KL, Wheeler CJ (2010) T cells enhance stem-like properties and conditional malignancy in gliomas. PLoS One 5:e10974. doi: 10.1371/journal.pone.0010974 PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264PubMedCrossRefGoogle Scholar
  13. 13.
    Postow MA, Harding J, Wolchok JD (2012) Targeting immune checkpoints: releasing the restraints on anti-tumor immunity for patients with melanoma. Cancer J 18:153–159PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    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 100:3983–3988PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115PubMedCrossRefGoogle Scholar
  16. 16.
    Zoller M (2011) CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 11:254–267PubMedCrossRefGoogle Scholar
  17. 17.
    Batlle E, Bacani J, Begthel H, Jonkheer S, Gregorieff A, van de Born M, Malats N, Sancho E, Boon E, Pawson T, Gallinger S, Pals S, Clevers H (2005) EphB receptor activity suppresses colorectal cancer progression. Nature 435:1126–1130PubMedCrossRefGoogle Scholar
  18. 18.
    Binda E, Visioli A, Giani F, Lamorte G, Copetti M, Pitter KL, Huse JT, Cajola L, Zanetti N, DiMeco F, De Filippis L, Mangiola A, Maira G, Anile C, De Bonis P, Reynolds BA, Pasquale EB, Vescovi AL (2012) The EphA2 receptor drives self-renewal and tumorigenicity in stem-like tumor-propagating cells from human glioblastomas. Cancer Cell 22:765–780PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquermier 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 1:555–567PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Todaro M, Iovino F, Eterno V, Cammareri P, Gambara G, Espina V, Gulotta G, Dieli F, Giordano S, De Maria R, Stassi G (2010) Tumorigenic and metastatic activity of human thyroid cancer stem cells. Cancer Res 70:8874–8885PubMedCrossRefGoogle Scholar
  21. 21.
    Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, Macswords J, Wu Q, Vasanji A, McLendon RE, Hjelmeland AB, Rich JN (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6:421–432PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Wang ML, Chiou SH, Wu CW (2013) Targeting cancer stem cells: emerging role of Nanog transcription factor. Onco Targets Ther 6:1207–1220PubMedCentralPubMedGoogle Scholar
  23. 23.
    Signore M, Ricci-Vitiani L, De Maria R (2013) Targeting apoptosis pathways in cancer stem cells. Cancer Lett 332:374–382PubMedCrossRefGoogle Scholar
  24. 24.
    Ricci-Vitiani L, Mollinari C, di Martino S, Biffoni M, Pilozzi E, Pagliuca A, de Stefano MC, Circo R, Merlo D, De Maria R, Garaci E (2010) Thymosin beta4 targeting impairs tumorigenic activity of colon cancer stem cells. FASEB J 24:4291–4301PubMedCrossRefGoogle Scholar
  25. 25.
    Lombardo Y, Scopelliti A, Cammareri P, Todaro M, Iovino F, Ricci-Vitiani L, Gulotta G, Dieli F, de Maria R, Stassi G (2011) Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 140:297–309PubMedCrossRefGoogle Scholar
  26. 26.
    Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Malanchi I, Santamaria-Martínez A, Susanto E, Peng H, Lehr HA, Delaloye JF, Huelsken J (2011) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481:85–89PubMedCrossRefGoogle Scholar
  28. 28.
    Peters S, Adjei AA (2012) MET: a promising anticancer therapeutic target. Nat Rev Clin Oncol 9:314–326PubMedCrossRefGoogle Scholar
  29. 29.
    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRefGoogle Scholar
  30. 30.
    Bartucci M, Svensson S, Romania P, Dattilo R, Patrizii M, Signore M, Navarra S, Lotti F, Biffoni M, Pilozzi E, Duranti E, Martinelli S, Rinaldo C, Zeuner A, Maugeri-Saccà M, Eramo A, De Maria R (2012) Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy. Cell Death Differ 19:768–778PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES (2009) Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138:645–659PubMedCrossRefGoogle Scholar
  32. 32.
    Francescangeli F, Patrizii M, Signore M, Federici G, Di Franco S, Pagliuca A, Baiocchi M, Biffoni M, Ricci Vitiani L, Todaro M, De Maria R, Zeuner A (2012) Proliferation state and polo-like kinase 1 dependence of tumorigenic colon cancer cells. Stem Cells 30:1819–1830PubMedCrossRefGoogle Scholar
  33. 33.
    Eramo A, Pallini R, Lotti F, Sette G, Patti M, Bartucci M, Ricci-Vitiani L, Signore M, Stassi G, Larocca LM, Crinò L, Peschle C, De Maria R (2005) Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction. Cancer Res 65:11469–11477PubMedCrossRefGoogle Scholar
  34. 34.
    Londoño-Joshi AI, Oliver PG, Li Y, Lee CH, Forero-Torres A, LoBuglio AF, Buchsbaum DJ (2012) Basal-like breast cancer stem cells are sensitive to anti-DR5 mediated cytotoxicity. Breast Cancer Res Treat 133:437–445PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Li M, Knight DA, Smyth MJ, Stewart TJ (2012) Sensitivity of a novel model of mammary cancer stem cell-like cells to TNF-related death pathways. Cancer Immunol Immunother 61:1255–1268PubMedCrossRefGoogle Scholar
  36. 36.
    Piggott L, Omidvar N, Pérez SM, Eberl M, Clarkson RW (2011) Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Res 13:R88PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Vellanki SH, Grabrucker A, Liebau S, Proepper C, Eramo A, Braun V, Boeckers T, Debatin KM, Fulda S (2009) Small-molecule XIAP inhibitors enhance gamma-irradiation-induced apoptosis in glioblastoma. Neoplasia 11:743–752PubMedCentralPubMedGoogle Scholar
  38. 38.
    Maugeri-Saccà M, Bartucci M, De Maria R (2013) Checkpoint kinase 1 inhibitors for potentiating systemic anticancer therapy. Cancer Treat Rev 39:525–533PubMedCrossRefGoogle Scholar
  39. 39.
    Piccirillo SGM, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761–765PubMedCrossRefGoogle Scholar
  40. 40.
    Ricci-Vitiani L, Pallini R, Larocca LM, Lombardi DG, Signore M, Pierconti F, Petrucci G, Montano N, Maira G, De Maria R (2008) Mesenchymal differentiation of glioblastoma stem cells. Cell Death Differ 15:1491–1498PubMedCrossRefGoogle Scholar
  41. 41.
    Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM, Biondi A, Rossi G, Carlo-Stella C, Selleri C, Martino B, Specchia G, Mandelli F (1999) Therapy of molecular relapse in acute promyelocytic leukemia. Blood 94:2225–2229PubMedGoogle Scholar
  42. 42.
    Tate CM, Pallini R, Ricci-Vitiani L, Dowless M, Shiyanova T, D’Alessandris GQ, Morgante L, Giannetti S, Larocca LM, di Martino S, Rowlinson SW, De Maria R, Stancato L (2012) A BMP7 variant inhibits the tumorigenic potential of glioblastoma stem-like cells. Cell Death Differ 19:1644–1654PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, Fitch-Bruhns M, Lazetic S, Park IK, Sato A, Satyal S, Wang X, Clarke MF, Lewicki J, Gurney A (2009) DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5:168–177PubMedCrossRefGoogle Scholar
  44. 44.
    Michaud NR, Wang Y, McEachern KA, Jordan JJ, Mazzola AM, Hernandez A, Jalla S, Chesebrough JW, Hynes MJ, Belmonte MA, Wang L, Kang JS, Jovanovic J, Laing N, Jenkins DW, Hurt E, Liang M, Frantz C, Hollingsworth RE, Simeone DM, Blakey DC, Bedian V (2014) Novel neutralizing hedgehog antibody MEDI-5304 exhibits antitumor activity by inhibiting paracrine hedgehog signaling. Mol Cancer Ther 13:386–398PubMedCrossRefGoogle Scholar
  45. 45.
    Du YR, Chen Y, Gao Y, Niu XL, Li YJ, Deng WM (2013) Effects and mechanisms of anti-CD44 monoclonal antibody A3D8 on proliferation and apoptosis of sphere-forming cells with stemness from human ovarian cancer. Int J Gynecol Cancer 23:1367–1375PubMedCrossRefGoogle Scholar
  46. 46.
    Wang CH, Chiou SH, Chou CP, Chen YC, Huang YJ, Peng CA (2011) Photothermolysis of glioblastoma stem-like cells targeted by carbon nanotubes conjugated with CD133 monoclonal antibody. Nanomedicine 7:69–79PubMedCrossRefGoogle Scholar
  47. 47.
    Di Tomaso T, Mazzoleni S, Wang E, Sovena G, Clavenna D, Franzin A, Mortini P, Ferrone S, Doglioni C, Marincola FM, Galli R, Parmiani G, Maccalli C (2010) Immuno-biological characterization of cancer stem cells isolated from glioblastoma patients. Clin Cancer Res 16:800–813PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Maccalli C, Scaramuzza S, Parmiani G (2009) TNK cells (NKG2D+ CD8+ or CD4+ T lymphocytes) in the control of human tumors. Cancer Immunol Immunother 58:801–808PubMedCrossRefGoogle Scholar
  49. 49.
    Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391–403PubMedCrossRefGoogle Scholar
  50. 50.
    Wei J, Barr J, Kong L-Y, Wang Y, Wu A, Sharma AK, Gumin J, Henry V, Colman H, Sawaya R, Lang FF, Heimberger AB (2010) Glioma-associated cancer-initiating cells induce immunosuppression. Clin Cancer Res 16:461–473PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Schatton T, Schütte U, Frank NY, Zhan Q, Hoerning A, Robles SC, Zhou J, Hodi FS, Spagnoli GC, Murphy GF, Frank MH (2010) Modulation of T-cell activation by malignant melanoma initiating cells. Cancer Res 70:697–708PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Schatton T, Frank MH (2009) Antitumor immunity and cancer stem cells. Ann NY Acad Sci 1176:154–169PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Roth P, Junker M, Tritschler I, Mittelbronn M, Dombrowski Y, Breit SN (2010) GDF-15 contributes to proliferation and immune escape of malignant gliomas. Clin Cancer Res 16:3851–3859PubMedCrossRefGoogle Scholar
  54. 54.
    Volonté A, Di Tomaso T, Spinelli M, Todaro M, Sanvito F, Albarello L, Bissolati M, Ghirardelli L, Orsenigo E, Ferrone S, Doglioni C, Stassi G, Dellabona P, Staudacher C, Parmiani G, Maccalli C (2014) Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. J Immunol 192:523–532PubMedCrossRefGoogle Scholar
  55. 55.
    Francipane MG, Alea MP, Lombardo Y, Todaro M, Medema JP, Stassi G (2008) Crucial role of interleukin-4 in the survival of colon cancer stem cells. Cancer Res 68:4022–4025PubMedCrossRefGoogle Scholar
  56. 56.
    Hallett MA, Venmar T, Fingleton B (2012) Cytokine stimulation of epithelial cancer cells: the similar and divergent functions of IL-4 and IL-13. Cancer Res 72:6338–6343PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Tallerico R, Todaro M, Di Franco S, Maccalli C, Garofalo C, Sottile R, Palmieri C, Tirinato L, Pangigadde PN, La Rocca R, Mandelboim O, Stassi G, Di Fabrizio E, Parmiani G, Moretta A, Dieli F, Kärre K, Carbone E (2013) Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules. J Immunol 190:2381–2390PubMedCrossRefGoogle Scholar
  58. 58.
    Wolpert F, Roth P, Lamszus K, Tabatabai G, Weller M, Eisele G (2012) HLA-E contributes to an immune-inhibitory phenotype of glioblastoma stem-like cells. J Neuroimmunol 250:27–34PubMedCrossRefGoogle Scholar
  59. 59.
    Jewett A, Tseng HC, Arasteh A, Saadat S, Christensen RE, Cacalano NA (2012) Natural killer cells preferentially target cancer stem cells; role of monocytes in protection against NK cell mediated lysis of cancer stem cells. Curr Drug Deliv 9:5–16PubMedCrossRefGoogle Scholar
  60. 60.
    Koh J, Lee SB, Park H, Lee HJ, Cho NH, Kim J (2012) Susceptibility of CD24(+) ovarian cancer cells to anti-cancer drugs and natural killer cells. Biochem Biophys Res Commun 427:373–378PubMedCrossRefGoogle Scholar
  61. 61.
    Kim S-Y, Cho H-S, Yang S-H, Shin J-Y, Kim J-S, Lee S-T et al (2009) Soluble mediators from human neural stem cells play a critical role in suppression of T-cell activation and proliferation. J Neurosci Res 87:2264–2272PubMedCrossRefGoogle Scholar
  62. 62.
    Ljujic B, Milovanovic M, Volarevic V, Murray B, Bugarski D, Przyborski S, Arsenijevic N, Lukic ML, Stojkovic M (2013) Human mesenchymal stem cells creating an immunosuppressive environment and promote breast cancer in mice. Sci Rep 3:2298–2306PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Unit of Immuno-biotherapy of Melanoma and Solid TumorsSan Raffaele Foundation CentreMilanItaly
  2. 2.NIBIT-Italian Network for Bio-therapy of Tumors, c/o Medical Oncology and ImmunotherapyAzienda Ospedaliera Universitaria SeneseSienaItaly
  3. 3.Regina Elena National Cancer InstituteRomeItaly

Personalised recommendations