Novel orthotopic implantation model of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor

Our plain-English summary of Novel orthotopic implantation model of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor, by E. Nakataki, S. Yano, Y. Matsumori, et al (Cancer Science, 2006).

The study

• Authors: E. Nakataki, S. Yano, Y. Matsumori, H. Goto, S. Kakiuchi, H. Muguruma, Y. Bando, H. Uehara, H. Hamada, K. Kito, A. Yokoyama, S. Sone
• Journal: Cancer Science
• Published: 2006;97(3):183-91
• Cited by: 43 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is closely related to exposure to asbestos, and a rapid increase in the number of MPM patients in Japan is estimated in the years 2010-2050. The purpose of the present study was to establish a clinically relevant animal model that shows human patient-like progression of MPM. Here, we demonstrate that a human MPM cell line (EHMES-10) inoculated orthotopically (thoracic cavity) into severe combined immunodeficiency (SCID) mice produces highly vascularized thoracic tumors with pleural dissemination and bloody pleural effusions by 5 weeks, suggesting a patient-like progression of this cell line after orthotopic inoculation. EHMES-10 cells overexpressed vascular endothelial growth factor (VEGF), a molecule responsible for malignant effusions, and its receptor. Treatment with cisplatin, but not gemcitabine, significantly inhibited the production of pleural effusions, but it was not effective for thoracic tumors, consistent with chemotherapy refractory characteristics of MPM in patients. Our patient-like orthotopic model using EHMES-10 cells overexpressing VEGF and its receptor may be useful for examining the molecular pathogenesis of MPM and may contribute to the development of novel treatment strategies for MPM.

In plain English

This was a laboratory animal study, not a study of people exposed to asbestos. Asbestos appeared only as background. The authors injected a human malignant pleural mesothelioma cell line, EHMES-10, into the chest cavity of immune-deficient (SCID) mice. The cell line had been grown from the pleural fluid of one patient with biphasic mesothelioma. All seven injected mice examined at 5 weeks had chest tumors and bloody pleural effusions. In a separate survival experiment, mice were killed once they became moribund, a median of 33 days after injection. The cells produced high levels of the blood-vessel growth factor VEGF and expressed only one of its receptors, VEGFR-2. The tumors had many blood vessels. In the mice, cisplatin at 6 mg/kg significantly reduced pleural fluid but not tumor weight. Gemcitabine, at doses that did not cause weight loss, did not significantly reduce either. The authors reported, without showing the data, that the tumors lacked several standard mesothelioma markers, and they suggested these may have been lost. They concluded the model may be useful for studying how mesothelioma develops and for developing new treatments.

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: Animal experiment (orthotopic mouse model using a human mesothelioma cell line), with laboratory cell-culture tests
• Who was studied: Male SCID mice, 6 to 8 weeks old, from CLEA Japan, injected with the human malignant pleural mesothelioma cell line EHMES-10. The cell line was established at Ehime University from the pleural effusion of one patient with biphasic-type mesothelioma diagnosed after autopsy. Group sizes were 4 to 8 mice per experiment.
• Exposure: No asbestos exposure was studied. Mice were injected in the chest cavity with 3 million EHMES-10 cells. Some were then treated with cisplatin (3 or 6 mg/kg) or gemcitabine. Cells were also tested in the laboratory against cisplatin, gemcitabine, docetaxel and vinorelbine.
• Main results:
  • Injected EHMES-10 cells produced tumors in the chest cavity in all 7 of 7 mice, assessed on day 35.
  • Bloody pleural effusions of up to 1 mL developed in all 7 of 7 of those mice.
  • In a separate survival experiment, injected mice were killed when they became moribund, and survival was counted up to that day. Median survival was 33 days (range 21 to 44 days).
  • In the laboratory, EHMES-10 cells produced VEGF at a level as high as the lung adenocarcinoma cell line PC14PE6.
  • Of the VEGF receptors, EHMES-10 cells expressed only VEGFR-2.
  • The chest tumors in the mice expressed VEGF protein and were highly angiogenic (rich in blood vessels) on CD31 staining.
  • In laboratory tests, EHMES-10 cells were less sensitive to cisplatin than PC14PE6 lung adenocarcinoma cells.
  • In laboratory tests, EHMES-10 cells were more sensitive to gemcitabine than PC14PE6 lung adenocarcinoma cells.
  • In mice, cisplatin at 3 mg/kg had no effect on tumor weight or pleural effusions.
  • In mice, cisplatin at 6 mg/kg significantly reduced pleural effusions but was less effective on tumor weight. In the treated group, 2 of 5 mice had effusions (median volume 0 µL, p less than 0.05), against 4 of 5 mice (median 500 µL) in the untreated control group.
  • Higher-dose gemcitabine schedules caused severe body weight loss (7 g over 2 weeks) and were judged not feasible.
  • Gemcitabine at 60 or 300 mg/kg on days 14 and 21 did not cause weight loss. It did not significantly reduce chest tumors or pleural effusions. Median tumor weights were 113 mg (60 mg/kg) and 100 mg (300 mg/kg), against 197 mg in controls. Median effusion volumes were 700 µL and 300 µL, against 450 µL in controls.
• The authors' conclusion: The authors concluded that their mouse model, using EHMES-10 cells that overexpress VEGF and its receptor, shows patient-like disease progression. They wrote that it may be useful for examining how mesothelioma develops and may contribute to new treatment strategies.
• Limitations the authors state:
  • The authors reported (data not shown) that EHMES-10 tumors were negative for several mesothelioma markers, including calretinin, cytokeratin and mesothelin, unlike tumors from MPM patients. They suggested the markers may have been lost, either because the original tumor cells were mixed or during laboratory culture.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pleural Effusion, Cisplatin, Gemcitabine, Chemotherapy.

Related studies

• Restored expression of the MYO18B gene suppresses orthotopic growth and the production of bloody pleural effusion by human malignant pleural mesothelioma cells in SCID mice — N. Edakuni, K. Ikuta, et al. (2006)
• Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma — L. Strizzi, A. Catalano, et al. (2001)
• SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model — T.T. Van, M. Hanibuchi, et al. (2012)
• Clinical significance of serum vascular endothelial growth factor in malignant pleural mesothelioma — A. Yasumitsu, C. Tabata, et al. (2010)
• Vascular endothelial growth factor in pleural fluid for differential diagnosis of benign and malignant origin and its clinical applications — A. Fiorelli, G. Vicidomini, et al. (2011)
• Clinical significance of serum vascular endothelial growth factor in malignant pleural mesothelioma — N. Fujimoto, K. Gemba, et al. (2011)

Browse more research in Cancer Science, or return to medical research.