EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors

Our plain-English summary of EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors, by H. Kothmaier, F. Quehenberger, I. Halbwedl, et al (Thorax, 2008).

The study

• Authors: H. Kothmaier, F. Quehenberger, I. Halbwedl, P. Morbini, F. Demirag, H. Zeren, C.E. Comin, B. Murer, P.T. Cagle, R. Attanoos, A.R. Gibbs, F. Galateau-Salle, H.H. Popper
• Journal: Thorax
• Published: 2008;63(4):345-51
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is an asbestos related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of our study was to assess possible differences within signalling pathways between short term survivors (survival <3 years; STS) and long term survivors (survival >3 years; LTS) of MPM.

Methods: 37 antibodies detecting proteins engaged in cell signalling pathways, enforcing proliferation, antiapoptosis, angiogenesis and other cellular activities were investigated by tissue microarray (TMA) technology.

Results: Epidermal growth factor receptor (EGFR) was expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling was more abundant in STS. Expression of TIE2/Tek, a receptor for tyrosine kinases involved in angiogenesis, was differentially regulated via PDGFR and thus is more important in STS. Antiapoptosis was upregulated in STS by signal transducer and activator of transcription 1 (STAT1)-survivin and related molecules, but not in LTS. Our study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS.

Conclusion: We have demonstrated that small scale proteomics can be carried out by powerful linkage of TMA, immunohistochemistry and statistical methods to identify proteins which might be relevant targets for therapeutic intervention.

In plain English

This laboratory study examined stored tumour tissue from 48 patients with the epithelioid type of malignant pleural mesothelioma. The cases were diagnosed between 1987 and 2003 and collected in the USA, UK, Turkey, Italy, France and Austria. Using 36 months as the cut-off, 26 patients were long term survivors and 22 were short term survivors. Asbestos exposure was confirmed in one-third of patients in both groups; for the rest, no exposure data were available. The authors stained the tissue for 37 proteins involved in cell signalling. Overall protein patterns differed between the groups, and eight proteins, including STAT3 and c-Met, were higher in long term survivors. EGFR and PDGFR levels were similar in both groups, but their links to other proteins differed. In long term survivors, EGFR was correlated with growth-related proteins. In short term survivors, PDGFR was, and STAT1 was correlated with survivin, a protein that blocks cell death. The authors concluded that EGFR signalling was more active in long term survivors and PDGFR signalling in short term survivors. They described their results as a hypothesis needing further laboratory study.

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 archived surgical tumour tissue, using immunohistochemistry (protein staining) on tissue microarrays, comparing short term and long term survivors
• Who was studied: 48 patients with epithelioid malignant pleural mesothelioma (selected from 70 cases), diagnosed 1987 to 2003, collected in the USA, UK, Turkey, Italy, France and Austria; 26 long term survivors (survival over 36 months) and 22 short term survivors (under 36 months)
• Exposure: The study measured expression of 37 signalling proteins in tumour tissue, not asbestos exposure. Asbestos exposure was confirmed in one-third of patients in both groups, with no exposure data for the others. No fiber types are given.
• Main results:
  • Survival in the 26 long term survivors ranged from 36 to 116 months, with a mean of 50.7 months
  • Overall protein expression profiles differed significantly between long term and short term survivors (p less than 0.009, Goeman's global test)
  • Proliferative activity measured by MIB-1 staining differed significantly between long term and short term survivors (p = 0.014)
  • In long term survivors, significantly higher values (p less than 0.05) were found for STAT3, IGF1Ra, pAKT, c-Met, TGFb, c-Jun, IGF1R and paxillin
  • EGFR and PDGFR expression levels were similar in both groups. Correlation analysis showed long term survivors favoured EGFR signalling and short term survivors favoured PDGFR signalling.
  • In long term survivors, EGFR was correlated with STAT3, c-Fos, c-Jun and PCNA
  • Only in short term survivors were PDGFRa and PDGFRb associated with GSK3, TIE2, c-Fos, cyclin D1 and PCNA
  • Only in short term survivors was STAT1 correlated with survivin, p27 and Grb2
  • Survivin was found only in tumour tissue, not in adjacent normal pleura. Expression was lower in long term survivors than in short term survivors.
  • Sex was not significantly correlated with survival
• The authors' conclusion: The authors concluded that EGFR signalling is activated more strongly in long term survivors and PDGFR signalling is more abundant in short term survivors. They also concluded that, in short term survivors only, resistance to cell death is increased through STAT1 and survivin.
• Limitations the authors state:
  • The authors state that their methods were used to generate a hypothesis and that additional in vitro studies are needed
  • Asbestos exposure data were available for only one-third of patients

Topics

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

Medical terms in this study, explained in our Lexicon: EGFR, Epithelioid, Mesothelioma, Pleural Mesothelioma, Apoptosis, Chemotherapy, Angiogenesis, Immunohistochemistry.

Related studies

• EGFR expression: associations with outcome and clinicopathological variables in malignant pleural mesothelioma — J.G. Edwards, D.E. Swinson, et al. (2006)
• Tissue and serum EGFR as prognostic factors in malignant pleural mesothelioma — R. Gaafar, A. Bahnassy, et al. (2010)
• Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma — O.D. Røe, A. Szulkin, et al. (2012)
• Increased epidermal growth factor-receptor protein in a human mesothelial cell line in response to long asbestos fibers — J.C. Pache, Y.M. Janssen, et al. (1998)
• A comparison of epidermal growth factor receptor expression in malignant peritoneal and pleural mesothelioma — Y. Enomoto, T. Kasai, et al. (2012)
• High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma — H. Ollila, J. Paajanen, et al. (2021)

Browse more research in Thorax, or return to medical research.