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TRANSLATIONAL AND CLINICAL RESEARCH

Antitumoral Activity and Osteogenic Potential of Mesenchymal Stem Cells Expressing the Urokinase-Type Plasminogen Antagonist Amino-Terminal Fragment in a Murine Model of Osteolytic Tumor

^aInstitut National de la Santé et de la Recherche Médicale U844, Montpellier, France;
^bUniversité Montpellier 1, UFR Médecine, Montpellier, France;
^cInstitut National de la Santé et de la Recherche Médicale U896, Montpellier, France;
^gUnité Clinique d'Immuno-Rhumatologie: Thérapeutique des Maladies Articulaires et Osseuses, CHU Lapeyronie, Montpellier, France;
^eInstitute for Biomedical Engineering, University and ETH of Zürich, Zürich, Switzerland;
^fCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA;
^dUMR8121 Centre National de la Recherche Scientifique Université Paris Sud, Institut Gustave Roussy, Villejuif, France

Key Words. Mesenchymal stem cells • Prostate cancer • Tumor osteolysis • Cell-mediated gene therapy • Angiostatic • Bone repair • Bioluminescence • Microcomputed tomography

Correspondence: Correspondence: Vanessa Fritz, Ph.D., INSERM U896, IRCM, CRLC Val d'Aurelle Paul Lamarque, Parc Euromédecine, 34298 Montpellier Cedex 5, France. Telephone: 33-4-67-61-24-22; Fax: 33-4-67-61-23-33; e-mail: vanessa.fritz{at}inserm.fr

Received on February 13, 2008; accepted for publication on August 12, 2008.

First published online in STEM CELLS EXPRESS  August 28, 2008.

Prostate cancer metastasis to bone results in mixed osteolytic and osteoblastic lesions associated with high morbidity, and there is mounting evidence that the urokinase-type plasminogen system is causatively involved in the progression of prostate cancer. Adult mesenchymal stem cells (MSCs) are promising tools for cell-mediated gene therapy with the advantage of osteogenic potential, a critical issue in the case of osteolytic metastases. In this study, we evaluated the therapeutic use of engineered murine MSCs for in vivo delivery of the urokinase-type plasminogen antagonist amino-terminal fragment (hATF) to impair osteolytic prostate cancer cell progression in bone and to repair bone lesions. Bioluminescence imaging revealed that both primary MSCs and the MSC line C3H10T1/2 (C3) expressing hATF (MSC-hATF) significantly inhibited intratibial PC-3 Luciferase (Luc) growth following coinjection in SCID mice. Furthermore, microcomputed tomography imaging of vascular network clearly demonstrated a significant decrease in tumor-associated angiogenesis and a protection from tumor-induced osteolysis in MSC-hATF-treated mice. Importantly, the osteogenic potential of MSC-hATF cells was unaffected, and an area of new bone formation was evidenced in 60% of animals. Together, these data support the concept of MSC-based therapy of tumor osteolysis disease, indicating that MSCs may combine properties of vehicle for angiostatic agent with osteogenic potential.

Disclosure of potential conflicts of interest is found at the end of this article.

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