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Mesenchymal stem cells within tumour stroma promote breast cancer metastasis

Nature volume 449, pages 557–563 (2007)Cite this article

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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Figure 1: MSCs promote breast cancer metastasis.
Figure 2: MSC-induced increase in the metastasis of MDA-MB-231 cells involves reversible mechanisms.
Figure 3: The interaction of BCCs with MSCs causes a rise in the levels of CCL5.
Figure 4: CCL5 enhances breast cancer cell migration, invasion and metastasis.
Figure 5: CCL5–CCR5 interaction is essential for the MSC-induced metastasis.
Figure 6: Stromal fibroblastic cells of human invasive ductal carcinomas are rich in MSC markers and overexpress CCL5.

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References

  1. Bissell, M. J. & Radisky, D. Putting tumours in context. Nature Rev. Cancer 1, 46–54 (2001)

    Article  CAS  Google Scholar 

  2. Hall, B., Andreeff, M. & Marini, F. The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles. Handb. Exp. Pharmacol. 180, 263–283 (2007)

    Article  CAS  Google Scholar 

  3. Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999)

    Article  ADS  CAS  Google Scholar 

  4. Young, H. E. et al. Clonogenic analysis reveals reserve stem cells in postnatal mammals: I. Pluripotent mesenchymal stem cells. Anat. Rec. 263, 350–360 (2001)

    Article  CAS  Google Scholar 

  5. Young, H. E. et al. Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. Anat. Rec. 264, 51–62 (2001)

    Article  CAS  Google Scholar 

  6. Fox, J. M., Chamberlain, G., Ashton, B. A. & Middleton, J. Recent advances into the understanding of mesenchymal stem cell trafficking. Br. J. Haematol. 137, 491–502 (2007)

    Article  CAS  Google Scholar 

  7. Gregory, C. A., Prockop, D. J. & Spees, J. L. Non-hematopoietic bone marrow stem cells: molecular control of expansion and differentiation. Exp. Cell Res. 306, 330–335 (2005)

    Article  CAS  Google Scholar 

  8. Park, C. C., Bissell, M. J. & Barcellos-Hoff, M. H. The influence of the microenvironment on the malignant phenotype. Mol. Med. Today 6, 324–329 (2000)

    Article  CAS  Google Scholar 

  9. Nakamura, K. et al. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther. 11, 1155–1164 (2004)

    Article  CAS  Google Scholar 

  10. Nakamizo, A. et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 65, 3307–3318 (2005)

    Article  CAS  Google Scholar 

  11. Hung, S. C. et al. Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging. Clin. Cancer Res. 11, 7749–7756 (2005)

    Article  CAS  Google Scholar 

  12. Menon, L. G. et al. Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells. Stem Cells 25, 520–528 (2007)

    Article  CAS  Google Scholar 

  13. Komarova, S., Kawakami, Y., Stoff-Khalili, M. A., Curiel, D. T. & Pereboeva, L. Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses. Mol. Cancer Ther. 5, 755–766 (2006)

    Article  CAS  Google Scholar 

  14. Khakoo, A. Y. et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. J. Exp. Med. 203, 1235–1247 (2006)

    Article  CAS  Google Scholar 

  15. Studeny, M. et al. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-β delivery into tumors. Cancer Res. 62, 3603–3608 (2002)

    CAS  PubMed  Google Scholar 

  16. Luboshits, G. et al. Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res. 59, 4681–4687 (1999)

    CAS  PubMed  Google Scholar 

  17. Niwa, Y. et al. Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer. Clin. Cancer Res. 7, 285–289 (2001)

    CAS  PubMed  Google Scholar 

  18. Azenshtein, E. et al. The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechanisms of promalignant activity. Cancer Res. 62, 1093–1102 (2002)

    CAS  PubMed  Google Scholar 

  19. Robinson, S. C. et al. A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Res. 63, 8360–8365 (2003)

    CAS  PubMed  Google Scholar 

  20. Hillyer, P. & Male, D. Expression of chemokines on the surface of different human endothelia. Immunol. Cell Biol. 83, 375–382 (2005)

    Article  CAS  Google Scholar 

  21. Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002)

    Article  CAS  Google Scholar 

  22. Toker, A. & Yoeli-Lerner, M. Akt signaling and cancer: surviving but not moving on. Cancer Res. 66, 3963–3966 (2006)

    Article  CAS  Google Scholar 

  23. Tanaka, T. et al. Chemokines in tumor progression and metastasis. Cancer Sci. 96, 317–322 (2005)

    Article  CAS  Google Scholar 

  24. Mira, E. et al. A role for chemokine receptor transactivation in growth factor signaling. EMBO Rep. 2, 151–156 (2001)

    Article  CAS  Google Scholar 

  25. Qin, X. F., An, D. S., Chen, I. S. & Baltimore, D. Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc. Natl Acad. Sci. USA 100, 183–188 (2003)

    Article  ADS  CAS  Google Scholar 

  26. West, R. B. et al. Determination of stromal signatures in breast carcinoma. PLoS Biol. 3, e187 (2005)

    Article  Google Scholar 

  27. Allinen, M. et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6, 17–32 (2004)

    Article  CAS  Google Scholar 

  28. Balkwill, F. Cancer and the chemokine network. Nature Rev. Cancer 4, 540–550 (2004)

    Article  CAS  Google Scholar 

  29. Karnoub, A. E. & Weinberg, R. A. Chemokine networks and breast cancer metastasis. Breast Dis. 26, 75–85 (2006)

    Article  CAS  Google Scholar 

  30. Palani, A. & Tagat, J. R. Discovery and development of small-molecule chemokine coreceptor CCR5 antagonists. J. Med. Chem. 49, 2851–2857 (2006)

    Article  CAS  Google Scholar 

  31. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005)

    Article  CAS  Google Scholar 

  32. Elenbaas, B. et al. Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev. 15, 50–65 (2001)

    Article  CAS  Google Scholar 

  33. Lodie, T. A. et al. Systematic analysis of reportedly distinct populations of multipotent bone marrow-derived stem cells reveals a lack of distinction. Tissue Eng. 8, 739–751 (2002)

    Article  CAS  Google Scholar 

  34. Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999)

    Article  ADS  CAS  Google Scholar 

  35. Kuperwasser, C. et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proc. Natl Acad. Sci. USA 101, 4966–4971 (2004)

    Article  ADS  CAS  Google Scholar 

  36. Richardson, A. L. et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9, 121–132 (2006)

    Article  CAS  Google Scholar 

Download references

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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Authors and 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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  1. Antoine E. Karnoub
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Correspondence to Robert A. Weinberg.

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Karnoub, A., Dash, A., Vo, A. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007). https://doi.org/10.1038/nature06188

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