Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.
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.
Karnoub
Antoine E
AE
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Dash
Ajeeta B
AB
Vo
Annie P
AP
Sullivan
Andrew
A
Brooks
Mary W
MW
Bell
George W
GW
Richardson
Andrea L
AL
Polyak
Kornelia
K
Tubo
Ross
R
Weinberg
Robert A
RA
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D019899:Paracrine Communication; D019713:Receptors, CCR5 / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*
C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D019713:Receptors, CCR5