The Journal of Experimental Medicine
Cytokines Montreal 2008
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Published online 24 April 2006 doi:10.1084/jem.20051921
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 5, 1235-1247
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ARTICLE

 Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma

Aarif Y. Khakoo1,9, Shibani Pati6,7, Stasia A. Anderson5, William Reid6,7, Mohamed F. Elshal2, Ilsa I. Rovira1, Ahn T. Nguyen6,7, Daniela Malide3, Christian A. Combs3, Gentzon Hall8, Jianhu Zhang9, Mark Raffeld4, Terry B. Rogers8, William Stetler-Stevenson4, Joseph A. Frank5, Marvin Reitz6,7, and Toren Finkel1

1 Laboratory of Molecular Biology, Cardiovascular Branch, 2 Flow Cytometry Core Facility, and 3 Light Microscopy Core Facility, National Heart, Lung, and Blood Institute; 4 National Cancer Institute; and 5 Experimental Neuroimaging Section, Laboratory of Diagnostic Radiology Research, National Institutes of Health, Bethesda, MD 20892
6 Institute of Human Virology, University of Maryland Biotechnology Institute, 7 Department of Microbiology and Immunology, and 8 Department of Biochemistry, School of Medicine, University of Maryland, Baltimore, MD 21201
9 Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

CORRESPONDENCE Aarif Y. Khakoo: aykhakoo{at}mdanderson.org

Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell–cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently down-regulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt.

Abbreviations used: HUVEC, human umbilical vein endothelial cell; KS, Kaposi's sarcoma; MRI, magnetic resonance imaging; MSC, mesenchymal stem cell; VEGF, vascular endothelial growth factor.

A.Y. Khakoo and S. Pati contributed equally to this paper.


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