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dc.contributor.advisorRonald H. Goldfarb
dc.creatorAl-Atrash, Gheath
dc.date.accessioned2019-08-22T21:07:38Z
dc.date.available2019-08-22T21:07:38Z
dc.date.issued2002-05-01T00:00:00-07:00
dc.date.submitted2013-06-06T07:00:09-07:00
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29090
dc.description.abstractAl-Atrash, Gheath, The Urokinase Plasminogen Activator System in NK Cells: Its Role in Invasion and its Regulation by IL-2. Doctor of Philosophy (Biomedical Sciences), May 2002; 202 pp.; 2 tables; 20 figures; bibliography, 143 titles. Adoptively transferred natural killer (NK) cells can infiltrate tumors and directly kill malignantly transformed cells without prior sensitization. This makes NK cells ideal for cancer immunotherapy, not only for their tumoricidal capacities, but also as drug carriers. This dissertation investigates the role of NK cell urokinase plasminogen activator (uPA) system in NK cell invasion through extracellular matrices (ECMs), its cooperation with matrix metalloproteinases (MMPs), the mechanism by which interleukin-2 (IL-2) upregulates NK cell uPA/uPAR, and the in vivo antitumor therapeutic potential of NK cells as drug delivery vehicles. uPA and its receptor uPAR were detected in human and rat NK cells using RT-PCR, casein plasminogen zymography, western blots, and fluorescence microscopy. In vitro invasion assays showed a role for the uPA system in NK cell invasion, alone and in cooperation with MMPs: this was achieved by using selective plasmin inhibitors in combination with selective MMP inhibitors in ECM/Matrigel invasion assays. uPA’s regulation by the ECM proteins collagen type IV, laminin, and fibronectin was investigated and results show a downregulation of NK cell uPA mRNA by these proteins. IL-2, however, a potent NK cell stimulator, increases both uPA and uPAR, coinciding with an increase in NK cell invasion. This IL-2 upregulation has transcriptional and posttranscriptional components, the latter mediated by uPA and uPAR destabilizing mRNA binding proteins. The use of NK cells as drug delivery vehicles was illustrated by in vivo studies which demonstrated that NK cells linked to doxorubicin were more efficacious in prolonging the survival of tumor bearing mice than either treatment alone. The work presented in this dissertation has substantial impact on the field of adoptive immunotherapy for cancer treatment. Engineering NK cells to transiently express high amounts of uPA and/or uPAR may increase the invasive capacities of NK cells, resulting in greater infiltration of tumors by ex-vivo activated NK cells. Moreover, this enhanced infiltration may allow a greater delivery of anticancer drugs to established metastatic tumors. This can potentially lead to more efficacious and possibly curative NK mediated adoptive immunotherapy, thereby constituting a novel means to overcome current limitations to NK cell-mediated adoptive therapy of cancer metastases.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.subjectBiomechanics and Biotransport
dc.subjectBiomedical Engineering and Bioengineering
dc.subjectCancer Biology
dc.subjectCell and Developmental Biology
dc.subjectCell Biology
dc.subjectCells
dc.subjectDiseases
dc.subjectImmunology and Infectious Disease
dc.subjectImmunoprophylaxis and Therapy
dc.subjectLife Sciences
dc.subjectMedical Cell Biology
dc.subjectMedical Sciences
dc.subjectMedicine and Health Sciences
dc.subjectOncology
dc.subjectPharmaceutics and Drug Design
dc.subjectUrokinase plasminogen activator system
dc.subjectadoptively transferred natural killer cells
dc.subjectNK cells
dc.subjectadoptive immunotherapy
dc.subjectcancer treatment
dc.subjectmetastatic tumors
dc.subjectdrug delivery
dc.titleThe Urokinase Plasminogen Activator System in NK Cells: Its Role in Invasion And Its Regulation by IL-2
dc.typeDissertation
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberRichard P. Kitson
dc.contributor.committeeMemberAndrew P. Mazar
dc.type.materialtext
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