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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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
The file contains Supplementary Figures 1-9 and Supplementary Table 1.