Article | Published:

Mesenchymal stem cells within tumour stroma promote breast cancer metastasis

Nature volume 449, pages 557563 (04 October 2007) | Download Citation

Abstract

Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.

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Acknowledgements

We thank F. Reinhardt for assistance in animal studies, A. Lu for technical help, J. Yao for SAGE data analysis and the MIT Comparative Pathology Laboratory for immunohistochemical analyses. We are grateful to A. Bernad, X.-F. Qin, D. Baltimore and W. Hahn for providing constructs. We would also like to thank R. Hynes, T. Jacks and R. Goldsby for discussions. A.E.K. is a fellow of the Susan G. Komen Breast Cancer Foundation. R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor. This research is supported by grants from the Breast Cancer Research Foundation (R.A.W.), the Ludwig Trust (R.A.W.), the Susan G. Komen Breast Cancer Foundation (R.A.W.) and the Dana-Farber/Harvard Cancer Center Specialized Program of Research Excellence (SPORE) in Breast Cancer (A.E.K., R.A.W. and K.P.).

Author Contributions A.E.K. conceived and designed this study, and performed most experiments; R.A.W. supervised research; A.E.K. and R.A.W. wrote the manuscript; A.B.D. and R.T. provided human MSCs; A.B.D. helped in in vivo CCL5 neutralization; A.S. helped in the Luminex screens; A.P.V. and M.W.B. provided technical support in tissue culture, ELISA, western blot, RT–PCR and soft-agar analyses; G.W.B. performed CCL5 analysis on soft tumour expression data; A.L.R. obtained and classified the clinical specimens; K.P. fractionated the clinical samples and performed SAGE analyses; and A.L.R. performed the microarray analysis on sorted stroma.

The clinical microarray data on the sorted stroma is deposited at http://www.ncbi.nlm.nih.gov/geo, GSE8977

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Affiliations

  1. Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA

    • Antoine E. Karnoub
    • , Annie P. Vo
    • , Mary W. Brooks
    • , George W. Bell
    •  & Robert A. Weinberg
  2. Genzyme Corporation, Framingham, Massachusetts 01701, USA

    • Ajeeta B. Dash
    • , Andrew Sullivan
    •  & Ross Tubo
  3. Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • Andrea L. Richardson
  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Kornelia Polyak

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert A. Weinberg.

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https://doi.org/10.1038/nature06188

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