Subjects

Abstract

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies1,2 and solid cancers3,4,5,6. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994)

  2. 2.

    & Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997)

  3. 3.

    et al. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003)

  4. 4.

    et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004)

  5. 5.

    , , & A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007)

  6. 6.

    et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115 (2007)

  7. 7.

    et al. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res. 65, 4320–4333 (2005)

  8. 8.

    et al. Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res. 64, 4294–4301 (2004)

  9. 9.

    , & Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev. 20, 2149–2182 (2006)

  10. 10.

    , , & Molecular plasticity of human melanoma cells. Oncogene 22, 3070–3075 (2003)

  11. 11.

    et al. Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nature Med. 12, 925–932 (2006)

  12. 12.

    et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 65, 9328–9337 (2005)

  13. 13.

    et al. Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur. J. Cancer 43, 935–946 (2007)

  14. 14.

    et al. Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J. Biol. Chem. 278, 47156–47165 (2003)

  15. 15.

    et al. Activated leukocyte cell adhesion molecule/CD166, a marker of tumor progression in primary malignant melanoma of the skin. Am. J. Pathol. 156, 769–774 (2000)

  16. 16.

    et al. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell 125, 1269–1281 (2006)

  17. 17.

    et al. Expression of the neuroectodermal intermediate filament nestin in human melanomas. Cancer Res. 54, 354–356 (1994)

  18. 18.

    et al. Increased expression of stem cell markers in malignant melanoma. Mod. Pathol. 20, 102–107 (2007)

  19. 19.

    et al. Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin. J. Cell Biol. 175, 99–110 (2006)

  20. 20.

    et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444, 761–765 (2006)

  21. 21.

    et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006)

  22. 22.

    et al. Murine IgG1 complexes trigger immune effector functions predominantly via FcγRIII (CD16). J. Immunol. 161, 3026–3032 (1998)

  23. 23.

    et al. Therapeutic potential of chimeric anti-(ganglioside GD3) antibody KM871: antitumor activity in xenograft model of melanoma and effector function analysis. Cancer Immunol. Immunother. 49, 253–258 (2000)

  24. 24.

    et al. Direct visualisation and quantification of cellular cytotoxicity using two colour flourescence. J. Immunol. Methods 156, 47–54 (1992)

  25. 25.

    , , & Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001)

  26. 26.

    , & Tumour stem cells and drug resistance. Nature Rev. Cancer 5, 275–284 (2005)

  27. 27.

    et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res. 65, 6207–6219 (2005)

  28. 28.

    et al. A proof-of-principle study of epigenetic therapy added to neoadjuvant Doxorubicin cyclophosphamide for locally advanced breast cancer. PLoS ONE 1, e98 (2006)

  29. 29.

    , & Identification of distinct changes in gene expression after modulation of melanoma tumor antigen p97 (melanotransferrin) in multiple models in vitro and in vivo. Carcinogenesis 28, 2172–2183 (2007)

  30. 30.

    et al. Tumor growth need not be driven by rare cancer stem cells. Science 317, 337 (2007)

Download references

Acknowledgements

We thank D. Herlyn and M. Herlyn for providing fresh melanoma tissue specimen for our studies. The construction of the tissue microarray was possible only through the collaborative assistance of P. Van Belle, D. Elder, V. Prieto and A. Lazar. The tissue microarrays were performed with the technical assistance of R. Kim, K. Lamb and L. Biagini. We thank A. Baldor for technical assistance with tumour xenotransplantation experiments, and M. Grimm for tissue sectioning and immunohistochemistry. We thank D. Scadden for comments on the manuscript. This work was supported by the NCI/NIH (M.H.F.), a NCI/NIH Specialized Program of Research Excellence (SPORE) in Skin Cancer (T.S.K.) and the Department of Defense (M.H.F.).

Author Contributions T.S., N.Y.F., and M.H.F. planned the project. T.S., N.Y.F., K.Y., A.M.W.-G., Q.Z., S.J. and C.W. carried out experimental work. T.S., G.F.M., N.Y.F., A.M.W.-G., R.C.F. T.S.K., M.H.S. and M.H.F. analysed data. G.F.M., Q.Z., A.M.W.-G, M.G. and L.M.D. provided clinical information and human tissues or performed pathological analysis. T.S., G.F.M., N.Y.F. and M.H.F. wrote the paper. All authors discussed the results and commented on the manuscript.

Author information

Affiliations

  1. Transplantation Research Center, Children’s Hospital Boston and Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Tobias Schatton
    • , Natasha Y. Frank
    • , Kazuhiro Yamaura
    • , Stefan Jordan
    • , Mohamed H. Sayegh
    •  & Markus H. Frank
  2. Department of Pathology and,

    • George F. Murphy
    •  & Qian Zhan
  3. Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Natasha Y. Frank
  4. Department of Surgery, University of Würzburg Medical School, 97080 Würzburg, Germany

    • Ana Maria Waaga-Gasser
    •  & Martin Gasser
  5. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Lyn M. Duncan
  6. Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA

    • Carsten Weishaupt
    • , Robert C. Fuhlbrigge
    •  & Thomas S. Kupper

Authors

  1. Search for Tobias Schatton in:

  2. Search for George F. Murphy in:

  3. Search for Natasha Y. Frank in:

  4. Search for Kazuhiro Yamaura in:

  5. Search for Ana Maria Waaga-Gasser in:

  6. Search for Martin Gasser in:

  7. Search for Qian Zhan in:

  8. Search for Stefan Jordan in:

  9. Search for Lyn M. Duncan in:

  10. Search for Carsten Weishaupt in:

  11. Search for Robert C. Fuhlbrigge in:

  12. Search for Thomas S. Kupper in:

  13. Search for Mohamed H. Sayegh in:

  14. Search for Markus H. Frank in:

Competing interests

All financial and material support for this research and work are identified in the manuscript; they include solely the U.S. National Institutes of Health and the U.S. Department of Defense. The authors declare the following potential conflicts of interest: M.H.F. and M.H.S. are co-inventors of the ABCB5-related U.S. patent 6,846,883 (Gene encoding a multidrug resistance human P-glycoprotein homologue on chromosome 7p15-21 and uses thereof) assigned to Brigham and Women’s Hospital, Boston, Massachusetts.

Corresponding author

Correspondence to Markus H. Frank.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1–4 with Legends and Supplementary Table 1.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature06489

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.