Overexpression of activin-A and -B in malignant mesothelioma - attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth

Our plain-English summary of Overexpression of activin-A and -B in malignant mesothelioma - attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth, by J.A. Tamminen, M. Yin, M. Rönty, et al (Experimental Cell Research, 2015).

The study

• Authors: J.A. Tamminen, M. Yin, M. Rönty, E. Sutinen, A. Pasternack, O. Ritvos, M. Myllärniemi, K. Koli
• Journal: Experimental Cell Research
• Published: 2015;332(1):102-15
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Activin-A and activin-B, members of the TGF-β superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

In plain English

This was a laboratory study from Helsinki of activin-A and activin-B, two growth-factor proteins, in malignant mesothelioma. It did not measure asbestos exposure. The authors stained tumor tissue from patients later diagnosed with mesothelioma. They also tested cells grown from patients' pleural effusion samples and four established mesothelioma cell lines, comparing them with immortalized non-tumorigenic mesothelial cells (Met5A). All ten stained tumor samples contained both activins, and activin-A staining was stronger in 8 of 10. Patient-derived cells made considerably more activin than the comparison cells. In some mesothelioma cells, one signaling route (Smad3) responded only weakly to activins, while another (ERK) was switched on. A soluble activin blocker (sActR2B-Fc) slowed cell movement in a wound-closing test and prevented invasive growth in a gel. A drug blocking the ERK route (PD98059) had similar effects. Some results with patient cells did not reach statistical significance because few experiments were possible. The authors concluded that inhibiting activin or ERK activity, or both, represents a therapeutic approach for invasive mesothelioma. All testing was done on tissue samples and cultured cells.

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 of human tumor tissue (immunohistochemical staining), primary mesothelioma cells grown from patients' pleural effusions, and established mesothelioma cell lines
• Who was studied: 12 patients at Helsinki University Hospital, Finland, later diagnosed with mesothelioma (11 pleural, 1 peritoneal; tumor tissue from 10 patients was scored for staining); primary mesothelioma cells from pleural effusion samples; mesothelioma cell lines 211H, H28, H2452 and H2052; immortalized normal mesothelial cells (Met5A) as controls
• Exposure: No asbestos exposure was studied. Cells were treated in the laboratory with recombinant activin-A or activin-B (25 ng/ml), the soluble activin inhibitor sActR2B-Fc, or the MEK inhibitor PD98059 (30 μM), which blocks ERK activation
• Main results:
  • Both activins were detected in mesothelioma tumor tissue. Of 10 tumor samples, all were positive for both, and activin-A staining was stronger than activin-B staining in 8 of 10
  • All primary mesothelioma cells expressed considerably higher levels of activins than the Met5A control cells
  • In primary mesothelioma cells, receptor ACVR2A was expressed at a 13-fold higher level than ACVR2B on average, the reverse of Met5A cells. ALK7 receptor expression was also increased
  • Activin-induced Smad3 activity rose 80-fold (activin-A) and 60-fold (activin-B) in Met5A cells, but was strongly attenuated in H2052 and 211H cell lines and JP5 primary cells
  • In JP5 primary cells, the activin inhibitor sActR2B-Fc delayed wound closure; at 48 h treated wounds were about half as dense as untreated controls. The figure legend reports p equal to 0.1 (Mann–Whitney test) for this comparison
  • sActR2B-Fc inhibited invasive growth in a three-dimensional gel of 211H and H2052 cell lines and JP5 primary cells. A control soluble receptor (sAMHR2-Fc) had no impact
  • Activins induced ERK phosphorylation in H2052 and JP5 primary cells but not in Met5A cells. Blocking ERK activation with the MEK inhibitor delayed wound closure in JP5, 211H and H2052 cells and inhibited invasive growth of 211H and JP5 cells
• The authors' conclusion: The authors concluded that inhibiting activin or ERK activity, or both, represents a therapeutic approach for inhibiting invasive mesothelioma tumors, and that activins are a plausible target for adjunctive therapy
• Limitations the authors state:
  • Few experiments were possible with early-passage primary cells, so the decrease in ERK phosphorylation in JP5 cells did not reach statistical significance
  • The effect of the MEK inhibitor on H2052 invasive growth was unclear because these cells were sensitive to the DMSO control treatment
  • The exact mechanism of the switch from Smad3 to ERK signaling was not determined
  • Established cell lines were more heterogeneous than primary cells, and H28 may be an unusual mesothelioma cell line

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: Malignant Mesothelioma, Inflammation, Asbestos Exposure, Pleura, Prognosis, Mesothelioma.

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