The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells

Our plain-English summary of The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells, by T.A. Tucker, C. Dean, A.A. Komissarov, et al (American Journal of Respiratory Cell and Molecular Biology, 2010).

The study

• Authors: T.A. Tucker, C. Dean, A.A. Komissarov, K. Koenig, A.P. Mazar, U. Pendurthi, T. Allen, S. Idell
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2010;42(6):685-96
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study asked whether the urokinase receptor (uPAR), a cell-surface protein, helps human malignant pleural mesothelioma cells grow. It did not study asbestos exposure. The authors used three mesothelioma cell lines (REN, MS-1, M9K) and one human pleural mesothelial line (MeT5A). They grew all four lines in dishes and injected the three mesothelioma lines into the chest cavity of nude mice. REN cells made more uPAR protein than MS-1, M9K or MeT5A cells (5-, 4- and 10-fold, respectively). REN cells produced more tumors in mice than M9K cells (risk ratio 3.62; 95% CI 2.39–5.50) or MS-1 cells (risk ratio 3.53; 95% CI 2.36–5.30). At 28 days, only REN tumors had invaded nearby tissue. Silencing uPAR reduced REN cell growth, movement and invasion in the dish. REN cells engineered to stably carry a uPAR-silencing construct were tested in only three mice. Their tumors showed a trend toward smaller volume that was not statistically significant (P = 0.052). MS-1 cells given 7-fold more uPAR grew and moved more in the dish and formed more tumors in mice. The authors concluded that uPAR may be a potential treatment target in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human mesothelioma cell lines in culture, plus experiments in a new mouse model in which the cells were injected into the pleural cavity
• Who was studied: Three human malignant pleural mesothelioma cell lines (REN, MS-1, M9K) and MeT5A human pleural mesothelial cells, all studied in culture. Only the three mesothelioma lines were injected into the pleural cavity of nude mice (BALB/c athymic NCr-nu/nu).
• Exposure: No asbestos exposure was studied. The experiments varied uPAR in the cells: it was silenced with siRNA or shRNA, blocked with an antibody (D3036-2), or overexpressed by putting uPAR cDNA into MS-1 cells.
• Main results:
  • In culture, REN cells expressed more uPAR protein than MS-1, M9K and MeT5A cells, by 5-, 4- and 10-fold respectively
  • In mice given equal numbers of cells, REN cells produced more tumors than M9K cells (risk ratio 3.62; 95% CI 2.39–5.50) or MS-1 cells (risk ratio 3.53; 95% CI 2.36–5.30); P less than 0.0001 for each
  • At 28 days, only REN-derived tumors were invasive, in all three REN mice examined
  • Silencing uPAR with siRNA significantly decreased REN cell proliferation and reduced their invasion of Matrigel in culture
  • Only REN cells, not MS-1, M9K or MeT5A cells, crossed three-dimensional fibrin gels
  • REN cells engineered to stably express uPAR shRNA (about 90% less uPAR than control REN cells) showed a trend toward smaller tumor volume in mice: mean 3.5 plus or minus 1.8 cubic mm versus 17.8 plus or minus 4.9 cubic mm in untreated REN controls. There were 3 mice per group, and P = 0.052 was not statistically significant.
  • MS-1 cells engineered to express 7-fold more uPAR showed increased proliferation and migration in culture
  • In mice (7 per group, 49 days), uPAR-overexpressing MS-1 cells produced significantly more tumors than unmodified or empty-vector MS-1 cells (P = 0.043)
• The authors' conclusion: The authors concluded that, as in other cancers, uPAR represents a potential target for treatment in malignant pleural mesothelioma
• Limitations the authors state:
  • The uPAR-silenced REN clone was hard to grow, so only three mice could be injected, and the authors state that interpretation of these data is limited
  • The cell lines also differed in other parts of the fibrinolytic system and likely in other factors, so the authors used separate culture experiments to test uPAR's role
  • Tumors from uPAR-overexpressing MS-1 cells did not invade tissue. The authors say this may be because overexpression was not enough, because invasion might appear later, or because uPAR is not critical to invasion.
  • It is unclear whether mouse uPA interacts with human uPAR in REN tumors in the mice
  • All three mesothelioma cell lines looked epithelioid in culture, possibly because of repeated passaging, although they are described elsewhere as having different cell types

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Pleural Mesothelioma, Neoplasm, Mesothelial Cells, Deposition.

Related studies

• Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma — S. Wang, L. Jiang, et al. (2016)
• Urokinase receptor in human malignant mesothelioma cells: role in tumor cell mitogenesis and proteolysis — S. Shetty, A. Kumar, et al. (1995)
• Asbestos upregulates expression of the urokinase-type plasminogen activator receptor on mesothelial cells — R.C. Perkins, V.C. Broaddus, et al. (1999)
• Expression and activity of urokinase and its receptor in endothelial and pulmonary epithelial cells exposed to asbestos — A. Barchowsky, R.R. Roussel, et al. (1998)
• Podoplanin overexpression in human mesothelioma cell lines enhances the tumorigenic phenotype — E. Yamaki, T. Yajima, et al. (2013)
• Multipotent cancer stem cells derived from human malignant peritoneal mesothelioma promote tumorigenesis — S. Varghese, R. Whipple, et al. (2012)

Browse more research in American Journal of Respiratory Cell and Molecular Biology, or return to medical research.