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TRANSLATIONAL AND CLINICAL RESEARCH

Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Mediate Human Stem Cell Tropism to Malignant Solid Tumors

Divisions of ^aHematology/Hematopoietic Cell Transplantation,
^bMolecular Medicine, and
^eNeurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA;
^cDepartment of Medicine, University of British Columbia Hospital, Vancouver, British Columbia, Canada;
^dGachon University School of Medicine, Inchon, Korea

Key Words. CD87 • Hepatocyte growth factor • Interleukin-6 • Interleukin-8 • Monocyte chemoattractant protein-1 • Cell migration • Neural stem cells • Mesenchymal stem cells • Urokinase plasminogen activator • Urokinase plasminogen activator receptor • Tissue inhibitor of metalloproteinase

Correspondence: Margarita Gutova, M.D., Division of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, California 91010-3000, USA. Telephone: 626-359-8111, ext. 63613; Fax: 626-930-5416; e-mail: mgutova{at}coh.org; or Karen S. Aboody, M.D., Division of Hematology/Hematopoietic Cell Transplantation and Neurosciences, City of Hope National Medical Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, California 91010-3000, USA. Telephone: 626-471-7177; Fax: 626-301-8857; e-mail: kaboody{at}coh.org

Received February 18, 2008; accepted for publication April 1, 2008.
First published online in STEM CELLS EXPRESS   April 10, 2008.

Human neural and mesenchymal stem cells have been identified for cell-based therapies in regenerative medicine and as vehicles for delivering therapeutic agents to areas of injury and tumors. However, the signals required for homing and recruitment of stem cells to these sites are not well understood. Urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) are involved in chemotaxis and cell guidance during normal development and are upregulated in invasive tumors. Here we provided evidence that activation of uPA and uPAR in malignant solid tumors (brain, lung, prostate, and breast) augments neural and mesenchymal stem cell tropism. Expression levels of uPAR on human solid tumor cell lines correlated with levels of uPA and soluble uPAR in tumor cell-conditioned media. Cytokine expression profiles of these tumor-conditioned media were determined by protein arrays. Among 79 cytokines investigated, interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 were the most highly expressed cytokines in uPAR-positive tumors. We provided evidence that human recombinant uPA induced stem cell migration, whereas depletion of uPA from PC-3 prostate cancer cell-conditioned medium blocked stem cell migration. Furthermore, retrovirus-mediated overexpression of uPA and uPAR in neuroblastoma (NB1691) cells induced robust migration of stem cells toward NB1691 cell-conditioned media, compared with media derived from wild-type NB1691 cells. We conclude that expression of uPA and uPAR in cancer cells underlies a novel mechanism of stem cell tropism to malignant solid tumors, which may be important for development of optimal stem cell-based therapies.

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