Expression profile and function of Wnt signaling mechanisms in malignant mesothelioma cells

Our plain-English summary of Expression profile and function of Wnt signaling mechanisms in malignant mesothelioma cells, by S.A. Fox, A.K. Richards, I. Kusumah, et al (Biochemical and Biophysical Research Communications, 2013).

The study

• Authors: S.A. Fox, A.K. Richards, I. Kusumah, V. Perumal, E.M. Bolitho, S.E. Mutsaers, A.M. Dharmarajan
• Journal: Biochemical and Biophysical Research Communications
• Published: 2013;440(1):82-7
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is an uncommon and particularly aggressive cancer associated with asbestos exposure, which currently presents an intractable clinical challenge. Wnt signaling has been reported to play a role in the neoplastic properties of mesothelioma cells but has not been investigated in detail in this cancer. We surveyed expression of Wnts, their receptors, and other key molecules in this pathway in well established in vitro mesothelioma models in comparison with primary mesothelial cultures. We also tested the biological response of MM cell lines to exogenous Wnt and secreted regulators, as well as targeting β-catenin. We detected frequent expression of Wnt3 and Wnt5a, as well as Fzd 2, 4 and 6. The mRNA of Wnt4, Fzd3, sFRP4, APC and axin2 were downregulated in MM relative to mesothelial cells while LEF1 was overexpressed in MM. Functionally, we observed that Wnt3a stimulated MM proliferation while sFRP4 was inhibitory. Furthermore, directly targeting β-catenin expression could sensitise MM cells to cytotoxic drugs. These results provide evidence for altered expression of a number of Wnt/Fzd signaling molecules in MM. Modulation of Wnt signaling in MM may prove a means of targeting proliferation and drug resistance in this cancer.

Copyright © 2013 Elsevier Inc. All rights reserved.

In plain English

This was a laboratory study of cells, not of people or asbestos exposure. The authors examined Wnt signaling, a cell-signaling pathway involved in cell growth. They used three malignant mesothelioma cell lines (JU77, LO68 and ONE58, originally taken from fluid around the lungs of patients with malignant pleural mesothelioma) and normal mesothelial lining cells from three donors. Messenger RNA (mRNA) from five Wnt genes was detected in all the cell cultures. LEF1 mRNA was detected in the mesothelioma cells but not in the normal cells. sFRP4 mRNA was detected in all normal cultures but in none of the mesothelioma lines. Compared with the normal mesothelial cells, the mesothelioma lines had Wnt4 mRNA levels over 1000-fold lower and axin2 and APC levels over 100-fold lower. Adding Wnt3a increased cell growth, significantly in JU77 and less so in ONE58. sFRP4 reduced growth in JU77 and LO68 but not in ONE58. Reducing beta-catenin in ONE58 cells significantly increased the cell-killing effect of the drug gemcitabine. The authors concluded that targeting Wnt signaling can make mesothelioma cells more sensitive to cytotoxic drugs.

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 (in vitro) study of human cell lines and primary cell cultures, measuring gene expression and the effects of added signaling molecules, gene silencing and drugs
• Who was studied: Three human malignant mesothelioma cell lines (JU77, LO68, ONE58), originally derived from pleural effusions of different patients with malignant pleural mesothelioma, compared with primary mesothelial cell cultures from three different donors
• Exposure: Asbestos exposure was not studied. The laboratory treatments were recombinant Wnt3a (250 ng/ml for 48 h), sFRP4 conditioned media, and siRNA silencing of beta-catenin followed by cisplatin or gemcitabine (0 to 100 micromolar).
• Main results:
  • Expression of Wnt 2b, 3, 4, 5a and 10b was identified in all cells, both the mesothelioma lines and the mesothelial cultures. Wnt 6 was clearly detected only in ONE58 cells.
  • The transcription factor LEF1 was expressed in the mesothelioma cells but was not detected in the mesothelial cultures (RT-PCR mRNA detection)
  • sFRP4 mRNA was expressed in all primary mesothelial cultures but was not detected in any of the mesothelioma cell lines
  • Wnt4 mRNA expression was over 1000-fold lower in the mesothelioma cell lines than in primary mesothelial cells
  • axin2 and APC were over 100-fold downregulated in the mesothelioma cell lines compared with mesothelial cells. c-Myc and cyclin D1 were not differentially expressed, except c-Myc in LO68.
  • sFRP4 conditioned media suppressed proliferation/viability in JU77 and LO68 cells but not in ONE58 cells
  • Added Wnt3a stimulated proliferation of the mesothelioma cells, significantly in JU77 and to a lesser extent in ONE58
  • In ONE58 cells, beta-catenin knockdown was most effective and significantly enhanced the cytotoxicity of gemcitabine. The text gives no numerical drug-sensitivity values.
• The authors' conclusion: The authors concluded that targeting Wnt signaling can make mesothelioma cells more sensitive to cytotoxic drugs. They said further investigation is required to see whether therapies targeting this pathway could lead to new treatments.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Asbestos Exposure, Mesothelioma, Mesothelial Cells.

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