title: The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells.
abstract: Malignant pleural mesothelioma (MPM) is a lethal neoplasm for which current therapy is unsatisfactory. The urokinase plasminogen activator receptor (uPAR) is associated with increased virulence of many solid neoplasms, but its role in the pathogenesis of MPM is currently unclear. We found that REN human pleural MPM cells expressed 4- to 10-fold more uPAR than MS-1 or M9K MPM cells or MeT5A human pleural mesothelial cells. In a new orthotopic murine model of MPM, we found that the kinetics of REN cell tumorigenesis is accelerated versus MS-1 or M9K cells, and that REN instillates generated larger tumors expressing increased uPAR, were more invasive, and caused earlier mortality. While REN, MS-1, and M9K tumors were all associated with prominent extravascular fibrin deposition, excised REN tumor homogenates were characterized by markedly increased uPAR at both the mRNA and protein levels. REN cells exhibited increased thymidine incorporation, which was attenuated in uPAR-silenced cells (P < 0.01). REN cells traversed three-dimensional fibrin gels while MS-1, M9K, and MeT5A cells did not. uPAR siRNA or uPAR blocking antibodies decreased REN cell migration and invasion, while uPA and fetal bovine serum augmented the effects. Transfection of relatively low uPAR expressing MS-1 cells with uPAR cDNA increased proliferation and migration in vitro and tumor formation in vivo. These observations link overexpression of uPAR to the pathogenesis of MPM, demonstrate that this receptor contributes to accelerated tumor growth in part through interactions with uPA, and suggest that uPAR may be a promising target for therapeutic intervention.
authors.affiliation: The Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, 11937 US HWY 271, Biomedical Research Building, Lab C-5, Tyler, TX 75708, USA. torry.tucker@uthct.edu
authors.forename: Torry A
authors.initials: TA
authors.lastname: Tucker
authors.forename: Candice
authors.initials: C
authors.lastname: Dean
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Komissarov
authors.forename: Kathy
authors.initials: K
authors.lastname: Koenig
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
authors.forename: Usha
authors.initials: U
authors.lastname: Pendurthi
authors.forename: Timothy
authors.initials: T
authors.lastname: Allen
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005337:Fibrin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; D005337:Fibrin; D014568:Urokinase-Type Plasminogen Activator