Urokinase plasminogen activator and urokinase plasminogen activator receptor mediate human stem cell tropism to malignant solid tumors.
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.
Gutova
Margarita
M
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. mgutova@coh.org
Najbauer
Joseph
J
Frank
Richard T
RT
Kendall
Stephen Edward
SE
Gevorgyan
Anna
A
Metz
Marianne Z
MZ
Guevorkian
Mark
M
Edmiston
Marissa
M
Zhao
Donghong
D
Glackin
Carlotta A
CA
Kim
Seung U
SU
Aboody
Karen S
KS
D001932:Brain Neoplasms / Q000503:physiopathology; D001943:Breast Neoplasms / Q000503:physiopathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000503:physiopathology; D008297:Male; D008636:Mesencephalon / Q000196:embryology / Q000503:physiopathology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D009369:Neoplasms / Q000503:physiopathology*; D009447:Neuroblastoma; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000502:physiology*
C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator