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Carcinogenesis Advance Access originally published online on January 30, 2009
Carcinogenesis 2009 30(4):589-597; doi:10.1093/carcin/bgp036
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tissue-resident stem cells promote breast cancer growth and metastasis

Fabian L. Muehlberg{dagger}, Yao-Hua Song{dagger}, Alexander Krohn, Severin P. Pinilla, Lilly H. Droll, Xiaohong Leng, Max Seidensticker1, Jens Ricke1, Andrew M. Altman, Eswaran Devarajan, Weili Liu, Ralph B. Arlinghaus and Eckhard U. Alt*

Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
1 Clinic for Diagnostic Radiology, University Hospital, Otto-von-Guericke University, Magdeburg 39120, Germany

* To whom correspondence should be addressed. University of Texas M.D. Anderson Cancer Center, SCRB2, Box 951, 7435 Fannin Street, Houston, TX 77054, USA. Tel: +713 834 6117; Fax: +713 834 6083; Email: ealt{at}mdanderson.org

Correspondence may also be addressed to Yao-Hua Song. Email: ysong{at}mdanderson.org

Mesenchymal stem cells derived from bone marrow have recently been described to localize to breast carcinomas and to integrate into the tumor-associated stroma. In the present study, we investigated whether adipose tissue-derived stem cells (ASCs) could play a role in tumor growth and invasion. Compared with bone marrow-derived cells, ASCs as tissue-resident stem cells are locally adjacent to breast cancer cells and may interact with tumor cells directly. Here, we demonstrate that ASCs cause the cancer to grow significantly faster when added to a murine breast cancer 4T1 cell line. We further show that breast cancer cells enhance the secretion of stromal cell-derived factor-1 from ASCs, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. The tumor-promoting effect of ASCs was abolished by knockdown of the chemokine C-X-C receptor4 in 4T1 tumor cells. We demonstrated that ASCs home to tumor site and promote tumor growth not only when co-injected locally but also when injected intravenously. Furthermore, we demonstrated that ASCs incorporate into tumor vessels and differentiate into endothelial cells. The tumor-promoting effect of tissue-resident stem cells was also tested and validated using a human breast cancer line MDA-MB-231 cells and human adipose tissue-derived stem cells. Our findings indicate that the interaction of local tissue-resident stem cells with tumor stem cells plays an important role in tumor growth and metastasis.

Abbreviations: ASC, adipose tissue-derived stem cell; CT, computed tomography; CXCR, chemokine C-X-C receptor; EC, endothelial cell; FBS, fetal bovine serum; GFP, green fluorescent protein; i.v., intravenously; mASC, murine adipose tissue-derived stem cell; RANTES, regulated on activation, normal T-cell expressed and secreted; SDF-1, stromal cell-derived factor-1; SMA, smooth muscle actin; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor

{dagger} These authors contributed equally to this work.

Received November 17, 2008; revised January 21, 2009; accepted January 24, 2009.


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