The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells

Torry A. Tucker, Candice Dean, Andrey A. Komissarov, Kathy Koenig, Andrew P. Mazar, Usha Pendurthi, Timothy Allen, Steven Idell

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)685-696
Number of pages12
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume42
Issue number6
DOIs
StatePublished - Jun 1 2010
Externally publishedYes

Fingerprint

Urokinase Plasminogen Activator Receptors
Urokinase-Type Plasminogen Activator
Carcinogenesis
Tumors
Neoplasms
Fibrin
Malignant Mesothelioma
Blocking Antibodies
Thymidine
Small Interfering RNA
Cell Movement
Transfection
Virulence
Complementary DNA

Keywords

  • Invasion
  • Malignant pleural mesothelioma
  • Proliferation
  • Tumorigenesis
  • Urokinase receptor

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Tucker, T. A., Dean, C., Komissarov, A. A., Koenig, K., Mazar, A. P., Pendurthi, U., ... Idell, S. (2010). The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells. American Journal of Respiratory Cell and Molecular Biology, 42(6), 685-696. https://doi.org/10.1165/rcmb.2008-0433OC

The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells. / Tucker, Torry A.; Dean, Candice; Komissarov, Andrey A.; Koenig, Kathy; Mazar, Andrew P.; Pendurthi, Usha; Allen, Timothy; Idell, Steven.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 42, No. 6, 01.06.2010, p. 685-696.

Research output: Contribution to journalArticle

Tucker, TA, Dean, C, Komissarov, AA, Koenig, K, Mazar, AP, Pendurthi, U, Allen, T & Idell, S 2010, 'The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells', American Journal of Respiratory Cell and Molecular Biology, vol. 42, no. 6, pp. 685-696. https://doi.org/10.1165/rcmb.2008-0433OC
Tucker, Torry A. ; Dean, Candice ; Komissarov, Andrey A. ; Koenig, Kathy ; Mazar, Andrew P. ; Pendurthi, Usha ; Allen, Timothy ; Idell, Steven. / The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells. In: American Journal of Respiratory Cell and Molecular Biology. 2010 ; Vol. 42, No. 6. pp. 685-696.
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