Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug

Our plain-English summary of Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug, by J.A. Tamminen, V. Parviainen, M. Rönty, et al (Oncogenesis, 2013).

The study

• Authors: J.A. Tamminen, V. Parviainen, M. Rönty, A.P. Wohl, L. Murray, S. Joenväärä, M. Varjosalo, O. Leppäranta, O. Ritvos, G. Sengle, R. Renkonen, M. Myllärniemi, K. Koli
• Journal: Oncogenesis
• Published: 2013;2(8):e66
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is a form of cancer that is highly resistant to conventional cancer therapy for which no major therapeutic advances have been introduced. Here, we identify gremlin-1, a known bone morphogenetic protein inhibitor crucial for embryonic development, as a potential therapeutic target for mesothelioma. We found high expression levels of gremlin-1 in the mesothelioma tumor tissue, as well as in primary mesothelioma cells cultured from pleural effusion samples. Downregulation of gremlin-1 expression by siRNA-mediated silencing in a mesothelioma cell line inhibited cell proliferation. This was associated with downregulation of the transcription factor slug as well as mesenchymal proteins linked to cancer epithelial-to-mesenchymal transition. Further, resistance to paclitaxel-induced cell death was associated with high gremlin-1 and slug expression. Treatment of gremlin-1-silenced mesothelioma cells with paclitaxel or pemetrexed resulted in efficient loss of cell survival. Finally, our data suggest that concomitant upregulation of fibrillin-2 in mesothelioma provides a mechanism for extracellular localization of gremlin-1 to the tumor microenvironment. This was supported by the demonstration of interactions between gremlin-1, and fibrillin-1 and -2 peptides as well as by colocalization of gremlin-1 to fibrillin microfibrils in cells and tumor tissue samples. Our data suggest that gremlin-1 is also a potential target for overcoming drug resistance in mesothelioma.

In plain English

This was a laboratory study from Helsinki, Finland, of a protein called gremlin-1 in malignant mesothelioma. It did not study asbestos exposure. The authors used tumor biopsies and pleural effusion samples from seven patients later diagnosed with mesothelioma. Control pleural samples came from two male smokers operated on for pneumothorax. They also used established mesothelioma cell lines. Intense gremlin-1 staining was seen in all six mesothelioma tissue samples examined. Laboratory tests showed gremlin-1 binding tightly to pieces of fibrillin-1 and fibrillin-2, structural proteins found outside cells. Cells grown from patients' effusions had high gremlin-1 levels compared with non-tumor-forming mesothelial cells. Switching off gremlin-1 in the H2052 mesothelioma cell line reduced cell numbers without causing apoptosis, a form of cell death. It also lowered a protein called slug. H2052 cells were more resistant to the drug paclitaxel than H2452 cells. Combining gremlin-1 silencing with paclitaxel or pemetrexed led to efficient cell death. The authors concluded that blocking gremlin-1 might help fight mesothelioma's resistance to chemotherapy. They noted that the number of patient tissues was relatively small.

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 using patient tumor tissue, primary cells cultured from pleural effusions, and established cell lines (protein-binding tests, tissue staining, gene silencing, drug treatment of cells)
• Who was studied: Seven patients at Helsinki University Hospital, Finland, who had suspected mesothelioma and were later diagnosed with it (six with pleural and one with peritoneal tumor location per Table 3). Six tumor tissues were stained. Control pleural samples came from two male smokers operated on for pneumothorax. The study also used mesothelioma cell lines 211H, H28, H2452 and H2052, and immortalized non-tumorigenic mesothelial cells (Met5A).
• Exposure: No asbestos exposure was studied. The laboratory treatments were silencing of gremlin-1 with siRNA and the drugs paclitaxel and pemetrexed applied to cultured cells.
• Main results:
  • Gremlin-1 bound N-terminal peptides of fibrillin-1 and fibrillin-2 with affinity constants of about 10 nM (7.55 nM for fibrillin-1 and 9.05 nM for fibrillin-2 in Table 1).
  • Intense gremlin-1 staining was seen in all six mesothelioma tissue samples. Normal mesothelial cells showed low expression.
  • Primary mesothelioma cells cultured from pleural effusions had high gremlin-1 mRNA levels compared with Met5A cells.
  • In H2052 mesothelioma cells, two separate siRNAs against gremlin-1 significantly reduced cell numbers at all time points.
  • Loss of gremlin-1 in H2052 cells impaired proliferation but did not induce apoptosis.
  • Gremlin-1 silencing significantly reduced slug mRNA and protein in H2052 cells.
  • H2052 cells, which have high gremlin-1 and slug levels, were more resistant to paclitaxel than H2452 cells.
  • In H2052 cells, paclitaxel or pemetrexed combined with gremlin-1 siRNA led to efficient cell death.
• The authors' conclusion: The authors concluded that blocking gremlin-1 function in mesothelioma might offer a means to fight the tumor's chemoresistance.
• Limitations the authors state:
  • The authors note that the number of patient tissues analyzed was relatively small (six).

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Effusion, Pemetrexed (Alimta), Tumor Microenvironment.

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