All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice

Our plain-English summary of All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice, by C. Tabata, R. Tabata, N. Hirayama, et al (The European Respiratory Journal, 2009).

The study

• Authors: C. Tabata, R. Tabata, N. Hirayama, A. Yasumitsu, S. Yamada, A. Murakami, S. Iida, K. Tamura, T. Terada, K. Kuribayashi, K. Fukuoka, T. Nakano
• Journal: The European Respiratory Journal
• Published: 2009;34(5):1159-67
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-beta1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-beta1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-beta mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-beta1, TGF-beta1 receptors and PDGFR-beta, and 2) TGF-beta1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

In plain English

This laboratory study from Hyogo College of Medicine, Japan, tested whether all-trans-retinoic acid (ATRA), a vitamin A derivative, slowed malignant pleural mesothelioma growth. It did not study asbestos exposure. The authors treated four human mesothelioma cell lines in culture, plus MeT-5A, a line the article describes as SV40-transformed normal mesothelial cells. They also grew one mesothelioma line, MSTO-211H, the only line that formed tumours, under the skin of female immune-deficient mice. In culture, ATRA reduced growth of all four mesothelioma lines but had no effect on growth of the MeT-5A cells. In mice, ATRA given three times a week for the whole 28 days reduced tumour growth by 68% compared with control mice given only the oil it was dissolved in. Starting ATRA halfway through reduced tumour growth by 36%. ATRA also lowered the genetic messages (mRNA) for the growth signal TGF-beta1 and for the PDGF-beta receptor, and it reduced cell movement driven by PDGF-BB. The authors concluded their data may lead to ATRA-based strategies for preventing and treating mesothelioma. They noted the precise mechanism was not fully investigated.

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 combining cell-culture experiments with an animal experiment (human mesothelioma cells implanted under the skin of mice, a subcutaneous xenograft model)
• Who was studied: Human malignant pleural mesothelioma cell lines H28 (epithelioid), H2052 (sarcomatoid), H2452 (biphasic) and MSTO-211H (biphasic). The comparison line was the human mesothelial cell line MeT-5A, which the article describes as SV40-transformed normal mesothelial cells. All lines came from the American Type Culture Collection. The animals were 6-week-old female SCID (immune-deficient) mice kept at Hyogo College of Medicine, Japan. The number of mice is not stated.
• Exposure: No asbestos exposure was studied. The exposure was the drug ATRA. Cultured cells received ATRA at up to 10 to the minus 5 molar. Mice received 0.5 mg ATRA in 0.1 mL cottonseed oil injected into the abdominal cavity three times weekly, either throughout the 28 days or only in the latter half. Control mice received cottonseed oil alone.
• Main results:
  • In culture, ATRA reduced growth of all four mesothelioma cell lines, more so at higher concentrations. At 10 to the minus 5 molar, growth fell by 59% in H28, by 33% in the line printed as H2042 (apparently H2052), by 45% in H2452 and by 29% in MSTO-211H.
  • ATRA had no effect on the proliferation of the comparison line MeT-5A.
  • The article describes the comparison line MeT-5A as SV40-transformed normal mesothelial cells, a laboratory-modified line rather than unmodified normal cells.
  • Of the four mesothelioma lines implanted in mice, only MSTO-211H grew.
  • In mice given ATRA throughout the course, tumour growth at 28 days after inoculation was 68% lower than in controls.
  • In mice given ATRA only in the latter half of the period, tumour growth was 36% lower than in the vehicle control group.
  • In tumours grown in ATRA-treated mice, TGF-beta1 mRNA was 32% lower and PDGFR-beta mRNA was 31% lower than in mice without ATRA.
  • In MSTO-211H cells, PDGF-BB increased cell migration 1.3-fold, and ATRA reduced this migration by 19%.
  • ATRA did not change IL-6 or IL-6 receptor mRNA in the mesothelioma cells.
  • Tumour cells in ATRA-treated mice showed no increase in apoptosis (programmed cell death) compared with untreated mice.
  • The ATRA injections for 28 days did not affect the health of the mice.
• The authors' conclusion: The authors concluded that their data may lead to new strategies using ATRA to prevent and treat malignant pleural mesothelioma. They proposed that ATRA works by inhibiting TGF-beta1-dependent growth and PDGF-BB-dependent migration of the cells.
• Limitations the authors state:
  • The authors stated that the precise cellular mechanism had not been fully investigated.
  • The authors stated it is not clear whether the observed effect is specific to retinoic acid signalling.

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, Asbestos Exposure, Chemotherapy, Prognosis, Cytokine, Fibroblast, Platelet-Derived Growth Factor (PDGF).

Related studies

• A novel clinical role for angiopoietin-1 in malignant pleural mesothelioma — C. Tabata, N. Hirayama, et al. (2010)
• Clinical significance of serum vascular endothelial growth factor in malignant pleural mesothelioma — A. Yasumitsu, C. Tabata, et al. (2010)
• The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma — V. Laszlo, Z. Valko, et al. (2019)
• Sialic acid-binding lectin from bullfrog eggs inhibits human malignant mesothelioma cell growth in vitro and in vivo — T. Tatsuta, T. Satoh, et al. (2018)
• Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy — M.A. Hoda, A. Mohamed, et al. (2011)
• Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma — E.K. Sage, K.K. Kolluri, et al. (2014)

Browse more research in The European Respiratory Journal, or return to medical research.