Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells

Our plain-English summary of Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells, by M.A. Hoda, J. Münzker, B. Ghanim, et al (British Journal of Cancer, 2012).

The study

• Authors: M.A. Hoda, J. Münzker, B. Ghanim, K. Schelch, T. Klikovits, V. Laszlo, E. Sahin, A. Bedeir, A. Lackner, B. Dome, U. Setinek, M. Filipits, M. Eisenbauer, I. Kenessey, S. Török, T. Garay, B. Hegedus, A. Catania, S. Taghavi, W. Klepetko, W. Berger, M. Grusch
• Journal: British Journal of Cancer
• Published: 2012;107(12):1978-86
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Activins control the growth of several tumour types including thoracic malignancies. In the present study, we investigated their expression and function in malignant pleural mesothelioma (MPM).

Methods: The expression of activins and activin receptors was analysed by quantitative PCR in a panel of MPM cell lines. Activin A expression was further analysed by immunohistochemistry in MPM tissue specimens (N=53). Subsequently, MPM cells were treated with activin A, activin receptor inhibitors or activin-targeting siRNA and the impact on cell viability, proliferation, migration and signalling was assessed.

Results: Concomitant expression of activin subunits and receptors was found in all cell lines, and activin A was overexpressed in most cell lines compared with non-malignant mesothelial cells. Similarly, immunohistochemistry demonstrated intense staining of tumour cells for activin A in a subset of patients. Treatment with activin A induced SMAD2 phosphorylation and stimulated clonogenic growth of mesothelioma cells. In contrast, treatment with kinase inhibitors of activin receptors (SB-431542, A-8301) inhibited MPM cell viability, clonogenicity and migration. Silencing of activin A expression by siRNA oligonucleotides further confirmed these results and led to reduced cyclin D1/3 expression.

Conclusion: Our study suggests that activin A contributes to the malignant phenotype of MPM cells via regulation of cyclin D and may represent a valuable candidate for therapeutic interference.

In plain English

This was a laboratory study of activin A, a growth-factor protein, in malignant pleural mesothelioma. It did not study asbestos exposure. The authors measured activin genes in nine mesothelioma cell lines against one non-cancerous mesothelial cell line (Met5a). They also stained tumour tissue from 53 patients operated on in Vienna between 1993 and 2010. All lines had detectable RNA for activins and their receptors. RNA for the activin A building block was over four-fold higher in six of the nine. In the tissue, 6 tumours stained strongly, 20 moderately, 20 weakly and 7 not at all. Staining was linked to epitheloid tumour type but not to survival or stage. Adding activin A increased colony growth by up to 50% and sped cell migration. Two drugs blocking activin receptors (SB-431542, A-8301) reduced cell growth. Because these drugs also block a TGF-beta receptor, the authors also silenced the activin A gene. This cut viability by 30–50% in the lines tested, except one line (P31) in the short-term test. The authors concluded that activin A may contribute to mesothelioma cell growth and may be a treatment target.

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 mesothelioma cell lines, plus immunohistochemical staining of archived tumour tissue
• Who was studied: Nine malignant pleural mesothelioma cell lines and the non-malignant mesothelial cell line Met5a. Also paraffin-embedded tumour tissue from 53 MPM patients operated on between 1993 and 2010 at the Medical University of Vienna: 36 epitheloid, 13 biphasic and 4 sarcomatoid.
• Exposure: No asbestos exposure was studied. The cells were treated with one of three things: recombinant activin A, the activin receptor kinase inhibitors SB-431542 and A-8301, or siRNA that silences the activin A (beta-A) gene.
• Main results:
  • Measured as RNA transcripts by QPCR, all cell lines had detectable activin subunits and activin receptors. The activin beta-A subunit transcript was raised more than four-fold in six of the nine MPM cell lines compared with Met5a.
  • In the 53 tumour specimens, activin A staining was strong in 6 (11.3%), moderate in 20 (37.7%), weak in 20 (37.7%) and absent in 7 (13.2%).
  • Activin A staining was significantly associated with epitheloid versus non-epitheloid histology. It was not associated with patient survival, stage or Ki67 expression.
  • Treating MPM cells with activin A increased phosphorylated SMAD2 in all tested cell lines. It also stimulated clonogenic growth by up to 50% compared with mock-treated controls and enhanced cell migration.
  • The activin receptor inhibitor SB-431542 caused a dose-dependent inhibition of colony formation, and A-8301 had a similar growth-inhibitory effect. SB-431542 also significantly delayed wound closure in scratch assays.
  • Silencing activin A by siRNA (knockdown of around 75%) reduced viability by 30–50% in all cell models tested, except P31 in the short-term assay. P31 and its cisplatin-resistant derivative were both inhibited in the clonogenic assay.
  • After activin A silencing, cyclin D1 and cyclin D3 were reduced in VMC20 cells and, more moderately, in P31 cells.
• The authors' conclusion: The authors concluded that their study suggests activin A contributes to the malignant behaviour of MPM cells through regulation of cyclin D, and that it may be a candidate for therapeutic interference.
• Limitations the authors state:
  • The kinase inhibitors also act on the TGF-beta receptor ALK5, so the authors used siRNA silencing to confirm the results more specifically.
  • The authors suggested that the lack of association between activin A and outcome could be explained by the heterogeneous patient group treated in different ways.

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, Immunohistochemistry, Mesothelial Cells, Mesothelioma.

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