uPA and uPAR Mediate Human Stem Cell Tropism to Malignant Solid Tumors

¹ Divisions of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, 91010, USA
² Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, 91010, USA
³ Department of Medicine, University of British Columbia Hospital, Vancouver, British Columbia, V6T 2B5, Canada; Gachon University School of Medicine, Inchon, 406-799, Korea
⁴ Divisions of Hematology/Hematopoietic Cell Transplantation, Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, 91010, USA

^* To whom correspondence should be addressed. E-mail: mgutova{at}coh.org.

Correspondence may also be addressed to Karen S. Aboody at kaboody@coh.org.

	Abstract

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 its receptor, uPAR, are involved in chemotaxis and cell guidance during normal development and are up-regulated in invasive tumors. Here we provide 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 (suPAR) in tumor cell-conditioned media. Cytokine expression profiles of these tumor-conditioned media were determined by protein arrays. Among 79 cytokines investigated, interleukin-6 (IL-6), interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) were the most highly expressed cytokines in uPAR-positive tumors. We provide evidence that human recombinant uPA induces stem cell migration, while depletion of uPA from PC-3 prostate cancer cell-conditioned media blocked stem cell migration. Furthermore, retrovirus-mediated over-expression of uPA and uPAR in neuroblastoma (NB1691) cells induced robust migration of stem cells towards NB1691 cell-conditioned media, compared to 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.