Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma

Our plain-English summary of Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma, by S. Wang, L. Jiang, Y. Han, et al (Oncotarget, 2016).

The study

• Authors: S. Wang, L. Jiang, Y. Han, S.H. Chew, Y. Ohara, S. Akatsuka, L. Weng, K. Kawaguchi, T. Fukui, Y. Sekido, K. Yokoi, S. Toyokuni
• Journal: Oncotarget
• Published: 2016;7(43):69565-69578
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a rare neoplasm associated with asbestos exposure. The prognosis of MM is poor because it is aggressive and highly resistant to chemotherapy. Using a rat model of asbestos-induced MM, we found elevated urokinase-type plasminogen activator receptor (uPAR; Plaur) expression in rat tissues, which was associated with poor prognosis. The proliferation, migration and invasion of MM cells were suppressed by uPAR knockdown and increased by overexpression experiments, irrespective of urokinase-type plasminogen activator (uPA; Plau) levels. More importantly, we found that uPAR expression is associated with sensitivity to cisplatin in MM through the PI3K/AKT pathway, which was demonstrated with specific inhibitors, LY294002 and Akti-1/2. uPAR knockdown significantly increased sensitivity to cisplatin whereas its overexpression significantly decreased cisplatin sensitivity. Furthermore, sera and tissues from MM patients showed significantly high uPAR levels, which suggested the pathogenic role of uPAR in the tumor biology of human MM. In conclusion, our findings indicate that uPAR levels are associated with malignant characteristics and cisplatin sensitivity of MM. In addition to the potential use of uPAR as a prognostic marker, the combination of uPAR abrogation and cisplatin may reveal a promising therapeutic approach for MM.

In plain English

This was a laboratory study of uPAR, a protein found on cell surfaces, in malignant mesothelioma. In rats given mesothelioma with asbestos (3 types, not named in the text), tumor tissue showed about 6 to 7 times more uPAR than normal mesothelial cells. Among 20 rat tumors, strong uPAR staining (8 tumors) was associated with significantly shorter survival than mild or moderate staining. Lowering uPAR reduced growth, migration and invasion of rat mesothelioma cells, and raising it in a human mesothelioma cell line increased them. Lowering uPAR also slowed tumor growth in mice (4 per group). It made rat cells more sensitive to the chemotherapy drug cisplatin but made practically no difference for pemetrexed. Raising uPAR made human cells less sensitive to cisplatin. Serum uPAR was significantly higher in 21 mesothelioma patients than in 12 people without malignant disease, but 13 lung cancer patients also had high levels. The authors concluded that uPAR increases AKT signaling, a major regulator of cisplatin-induced cell death. They cautioned that this serum marker is shared by other cancers.

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: rat model of asbestos-induced mesothelioma, rat and human mesothelioma cell lines, mouse xenograft experiments, a purchased human tissue array, and blood serum from patients
• Who was studied: 21 rat mesothelioma tissues (8 epithelioid, 13 sarcomatoid) compared with 2 normal rat mesothelial tissue samples; a tissue array of 20 rat mesothelioma samples; rat and human mesothelioma cell lines; nude mice (4 per group); a human mesothelioma tissue array; serum from 21 mesothelioma patients (15 epithelioid, 6 biphasic), 13 lung cancer patients and 12 people without malignant disease
• Exposure: Rats with mesothelioma induced by 3 different types of asbestos (not named in this text); the cell experiments tested cisplatin and pemetrexed
• Main results:
  • Both epithelioid and sarcomatoid rat mesotheliomas showed approximately a 6 to 7-fold increase in uPAR compared with normal mesothelial cells
  • Of 20 rat mesothelioma samples, 2 showed mild, 10 moderate and 8 strong uPAR staining
  • In rats, strong uPAR expression was associated with significantly shorter survival than mild or moderate expression combined
  • In rat epithelioid and sarcomatoid mesothelioma cells, lowering uPAR significantly suppressed proliferation and also inhibited migration and invasion
  • In rat mesothelioma cells, lowering uPA (the molecule that binds uPAR) did not significantly inhibit proliferation or invasion
  • Raising uPAR in the human mesothelioma cell line Y-Meso-8A increased proliferation, migration and invasion
  • In mesothelioma cells, AKT/mTOR signaling activity was closely associated with uPAR levels; uPAR had no obvious effect on ERK signaling
  • In nude mice (4 per group), lowering uPAR significantly slowed the growth of mesothelioma cell tumors
  • In rat cells, lowering uPAR made practically no difference in sensitivity to pemetrexed
  • In rat cells, lowering uPAR made both epithelioid and sarcomatoid cells more sensitive to cisplatin at 24 hours
  • Keeping AKT continuously active nearly abolished the increased cell death seen in rat cells with lowered uPAR
  • In Y-Meso-8A cells, raising uPAR decreased sensitivity to cisplatin at 24 hours, and the inhibitors LY294002 and Akti-1/2 partially reversed this effect
  • In a human tissue array, eight mesothelioma tissue samples from four patients showed increased uPAR staining compared with benign pleural lesions, with matching changes in activated AKT
  • Serum uPAR was significantly increased in 21 mesothelioma patients compared with 12 participants without malignant disease
  • Serum uPAR was also high in 13 lung cancer patients, with no significant difference between the mesothelioma and lung cancer patients
• The authors' conclusion: The authors concluded that elevated uPAR in mesothelioma increases AKT signaling activity, which they describe as a major regulator of cisplatin-induced cell death. They suggested that combining uPAR blocking with chemotherapy would be a promising treatment approach and that serum uPAR could serve as a marker, used with caution.
• Limitations the authors state:
  • The authors could not determine the relationship between uPAR and histological subtype in human mesothelioma cells because no sarcomatoid human cell lines were available
  • Serum uPAR is common to many cancers, including lung cancer, so the authors said results require ample caution
  • AKT inhibitors only slightly increased cisplatin-induced cell death in uPAR-overexpressing cells, which the authors said suggests that other anti-cell-death pathways are probably involved
  • The authors stated that further studies are needed to fully explain the molecular mechanisms

Topics

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

Medical terms in this study, explained in our Lexicon: Cisplatin, Malignant Mesothelioma, Neoplasm, Asbestos Exposure, Prognosis, Chemotherapy.

Related studies

• The urokinase receptor supports tumorigenesis of human malignant pleural mesothelioma cells — T.A. Tucker, C. Dean, et al. (2010)
• Asbestos upregulates expression of the urokinase-type plasminogen activator receptor on mesothelial cells — R.C. Perkins, V.C. Broaddus, et al. (1999)
• PIM1 knockdown inhibits cell proliferation and invasion of mesothelioma cells — A.S. Mawas, V.J. Amatya, et al. (2017)
• Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma — A. Baldi, M.T. Piccolo, et al. (2011)
• Overexpression of Numb suppresses tumor cell growth and enhances sensitivity to cisplatin in epithelioid malignant pleural mesothelioma — Y. Kang, M. Ding, et al. (2013)
• Downregulation of microRNA-34 induces cell proliferation and invasion of human mesothelial cells — N. Tanaka, S. Toyooka, et al. (2013)

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