Article | Published:

Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay

Nature Biotechnology volume 31, pages 539544 (2013) | Download Citation

Abstract

It has been hypothesized that carcinoma metastasis is initiated by a subpopulation of circulating tumor cells (CTCs) found in the blood of patients. However, although the presence of CTCs is an indicator of poor prognosis in several carcinoma entities, the existence and phenotype of metastasis-initiating cells (MICs) among CTCs has not been experimentally demonstrated. Here we developed a xenograft assay and used it to show that primary human luminal breast cancer CTCs contain MICs that give rise to bone, lung and liver metastases in mice. These MIC-containing CTC populations expressed EPCAM, CD44, CD47 and MET. In a small cohort of patients with metastases, the number of EPCAM+CD44+CD47+MET+ CTCs, but not of bulk EPCAM+ CTCs, correlated with lower overall survival and increased number of metastasic sites. These data describe functional circulating MICs and associated markers, which may aid the design of better tools to diagnose and treat metastatic breast cancer.

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Acknowledgements

We thank T. Oskarsson, M. Milsom, H. Medyouf and E. Espinet for helpful discussions, and M. Stoupiec and K. Leotta for technical support, members of the DKFZ FACS core facility, S. Schmitt and K. Hexel for excellent cell sorting, and members of the DKFZ animal facility for animal husbandry. This work was supported by the BioRN Spitzencluster “Molecular and Cell Based Medicine” supported by the German Bundesministerium für Bildung und Forschung, the EU FP7 Program “EuroSyStem”, the Sonderforschungsbereich SFB-873 funded by the Deutsche Forschungsgemeinschaft, the “TIME” consortium Project and the Dietmar Hopp Foundation (all to A.T.) and the European Research Council Advanced Investigator Grant DISSECT (269081 to K.P.).

Author information

Author notes

    • Andreas Schneeweiss
    • , Sabine Riethdorf
    • , Klaus Pantel
    •  & Wilko Weichert

    These authors contributed equally to this work.

Affiliations

  1. Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH, Heidelberg, Germany.

    • Irène Baccelli
    • , Anja Schillert
    • , Vanessa Vogel
    • , Corinna Klein
    • , Massimo Saini
    • , Thomas Höfner
    • , Martin Sprick
    •  & Andreas Trumpp
  2. Divison of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.

    • Irène Baccelli
    • , Anja Schillert
    • , Vanessa Vogel
    • , Corinna Klein
    • , Thomas Höfner
    • , Martin Sprick
    •  & Andreas Trumpp
  3. National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.

    • Andreas Schneeweiss
    • , Markus Wallwiener
    • , Martina Scharpff
    •  & Frederik Marmé
  4. Department of Tumor Biology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

    • Sabine Riethdorf
    •  & Klaus Pantel
  5. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

    • Albrecht Stenzinger
    • , Vanessa Vogel
    • , Hans Peter Sinn
    •  & Wilko Weichert
  6. Department of Medical Physics in Radiology, DKFZ, Heidelberg, Germany.

    • Tobias Bäuerle
  7. Department of Biostatistics, DKFZ, Heidelberg, Germany.

    • Tim Holland-Letz
  8. German Cancer Consortium, Heidelberg, Germany.

    • Andreas Trumpp

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Contributions

A.T. and K.P. had the initial idea of the assay. A.T. conceived the project and supervised all research. I.B. and A.T. wrote the manuscript and designed the experiments. I.B. performed the majority of experiments. A. Schillert, C.K., T.H., M. Saini and M. Sprick provided technical help for some experiments. T.H.-L. performed part of the statistical analyses. A. Schneeweiss, M.W., M. Scharpff and F.M. provided patient samples and clinical data. S.R. and K.P. performed CellSearch and fluorescence in situ hybridization analyses. A. Stenzinger, V.V., W.W. and H.P.S. carried out histology analyses. T.B. performed animal imaging.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andreas Trumpp.

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DOI

https://doi.org/10.1038/nbt.2576

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