Telomerase activity in pleural malignant mesotheliomas

Our plain-English summary of Telomerase activity in pleural malignant mesotheliomas, by A.Y. Au, T. Hackl, T.R. Yeager, et al (Lung Cancer, 2011).

The study

• Authors: A.Y. Au, T. Hackl, T.R. Yeager, S.B. Cohen, H.I. Pass, C.C. Harris, R.R. Reddel
• Journal: Lung Cancer
• Published: 2011;73(3):283-8
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

New treatments are needed for malignant pleural mesothelioma (MPM), which currently has a poor prognosis. Cellular immortalisation, one of the hallmarks of cancer, depends on the activity of a telomere length maintenance mechanism (TMM) - either telomerase or alternative lengthening of telomeres (ALT). The TMMs are widely regarded as potential targets for cancer therapies and telomerase inhibitors have entered clinical trials. The aim of this study was to determine what proportion of MPMs use ALT and/or telomerase. Forty-three MPMs from 42 patients were examined for telomerase and ALT activity. Telomerase activity was detected by immunoaffinity purification followed by the telomere repeat amplification protocol (TRAP), and ALT activity was determined by the C-circle assay and by assessing telomere lengths using terminal restriction fragment analyses. We found that 43 of 43 MPMs were telomerase-positive[+] and ALT-negative[-]. Therefore, to investigate whether pleural mesothelial cells are unusually susceptible to activation of telomerase, we examined activation of the TMMs in an in vitro model of cellular immortalisation, in which normal pleural mesothelial cells were transduced with simian virus 40 (SV40) oncogenes. We found that normal mesothelial cells were TMM-negative, and that expression of the SV40 oncogenes did not directly activate telomerase or ALT. Immortalisation, which in this experimental system results from additional genetic changes that have not yet been identified, was accompanied by activation of either TMM. Therefore, pleural mesothelial cells are capable of activating either TMM in vitro, and the observation that 100% of MPMs were telomerase[+] suggests that there are factors in vivo that select for telomerase activity during oncogenesis of this tumour type. We conclude that MPM is a tumour that could be considered for anti-telomerase therapy.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

In plain English

This laboratory study examined how malignant pleural mesothelioma tumours keep their telomeres (the protective ends of chromosomes) from wearing down, which cancer cells need in order to keep dividing. The two known mechanisms are an enzyme called telomerase and a process called alternative lengthening of telomeres (ALT). The authors tested 43 surgically removed tumours from 42 patients, collected at the Karmanos Cancer Center in Detroit. All 43 tumours showed telomerase activity (24 high, nine moderate, 10 low), and none showed signs of ALT. The authors also grew normal mesothelial cells in the laboratory and added genes from simian virus 40 (SV40). Before becoming immortalised, these cells showed neither mechanism. Once clones became immortalised, two used telomerase and one used ALT. The authors concluded that mesothelial cells can use either mechanism in the laboratory, that factors in the body appear to favour telomerase in these tumours, and that pleural mesothelioma may be considered for telomerase-targeted therapies. They said a larger set of tumours would be needed to check whether ALT occurs rarely. The study did not report the patients' asbestos exposure.

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 stored tumour tissue, plus an in vitro (cell culture) experiment
• Who was studied: 43 malignant pleural mesothelioma samples from 42 patients, surgically resected and collected at the Karmanos Cancer Center, Detroit, Michigan, USA (one patient gave two samples from different surgeries). No collection dates were given. The cell experiments used normal mesothelial cells from individuals with non-malignant effusions: the MeT-4 clones came from a pleural effusion and the MeT-5A cells from ascites fluid.
• Exposure: No asbestos exposure was studied or reported. The tumours were tested for telomerase and ALT activity. In the laboratory, normal mesothelial cells were transduced with simian virus 40 (SV40) early region genes.
• Main results:
  • All 43 pleural mesothelioma tumours were positive for telomerase activity using the IP-TRAP assay.
  • Telomerase activity levels in the tumours: 24 high, nine moderate and 10 low.
  • Mean telomere (TRF) lengths in the 43 tumours ranged from 7.4 to 17.5 kb. No tumour showed the long, heterogeneous telomeres or raised C-circle levels typical of ALT.
  • The standard TRAP assay could give false negative results because some tumour samples contained inhibitors. For this reason the authors used the immunopurified (IP-TRAP) version.
  • SV40-transformed mesothelial cell clones showed no telomerase activity before crisis. Six clones from four other donors were also telomerase negative.
  • After immortalisation, MeT-4D and MeT-5A cells showed telomerase activity, while MeT-4A cells showed the characteristics of ALT.
• The authors' conclusion: The authors concluded that pleural mesothelial cells can activate either mechanism in vitro, but that all 43 tumours used telomerase. They suggested that factors in the body select for telomerase in this cancer, and that pleural mesothelioma may be considered for telomerase-targeted therapies.
• Limitations the authors state:
  • The authors stated that ALT might still occur rarely in pleural mesotheliomas and that a larger panel of tumours would be needed to confirm this.
  • The authors stated that it remains to be determined whether treating these tumours with anti-telomerase drugs would cause them to activate ALT.

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, Pleural Mesothelioma, Prognosis, Clinical Trial, Mesothelial Cells, SV40, Oncogenesis.

Related studies

• SV40 infection induces telomerase activity in human mesothelial cells — R. Foddis, A. De Rienzo, et al. (2002)
• Telomerase activity in human pleural mesothelioma — K. Dhaene, R. Hübner, et al. (1998)
• Telomerase activity analyzed with TRAP in situ provides additional information in effusions remaining equivocal after immunocytochemistry and hyaluronan analysis — E. Adell, A. Dejmek (2014)
• Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters — B. Kroczynska, R. Cutrone, et al. (2006)
• Outcome prediction based on [18F]FDG PET/CT in patients with pleural mesothelioma treated with ipilimumab and nivolumab +/- UV1 telomerase vaccine — S. Thunold, E. Hernes, et al. (2025)
• Telomeres and telomerase in mesothelioma: Pathophysiology, biomarkers and emerging therapeutic strategies (Review) — D. Andreikos, D.A. Spandidos, et al. (2025)

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