SV40 infection induces telomerase activity in human mesothelial cells

Our plain-English summary of SV40 infection induces telomerase activity in human mesothelial cells, by R. Foddis, A. De Rienzo, D. Broccoli, et al (Oncogene, 2002).

The study

• Authors: R. Foddis, A. De Rienzo, D. Broccoli, M. Bocchetta, E. Stekala, P. Rizzo, A. Tosolini, J.V. Grobelny, S.C. Jhanwar, H.I. Pass, J.R. Testa, M. Carbone
• Journal: Oncogene
• Published: 2002;21(9):1434-42
• Cited by: 95 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesotheliomas are malignant tumors of the pleural and peritoneal membranes which are often associated with asbestos exposure and with Simian virus 40 (SV40) infection. Telomerase activity is repressed in somatic cells and tissues but is activated in immortal and malignant cells. We evaluated telomerase activity in seven primary malignant mesothelioma biopsies and matched lung specimens and 20 mesothelioma cell lines and eight corresponding primary tumor cultures. All the tumor biopsies, and nearly all primary cell mesothelioma cultures and cell lines were telomerase positive. The findings in cell lines paralleled those observed in primary cultures in cases where paired samples were available. Next, we found that SV40, a DNA tumor virus present in approximately 50% of mesothelioma biopsies in the USA, induced telomerase activity in primary human mesothelial cells, but not in primary fibroblasts. Telomerase activity became detectable as early as 72 h following wild-type (strain 776) SV40 infection, and a clear DNA ladder was detectable 1 week after infection. The amount of telomerase activity increased during passage in cell culture and appeared to parallel increases in the cellular amounts of the SV40 large T-antigen. Thus, SV40 infection leads to telomerase activity before the infected mesothelial cells become transformed and immortalized. SV40 infection of human fibroblasts did not cause detectable telomerase activity. We also determined that the SV40 small t-antigen (tag) plays an important role in inducing telomerase activity because this activity was undetectable or minimal in mesothelial cells infected and/or transformed by SV40 tag mutants. Asbestos alone did not induce telomerase activity, and asbestos did not influence telomerase activity in mesothelial cells infected with SV40. Induction of telomerase activity by SV40 may be related to the very high rate of mesothelial cell immortalization that is characteristically associated with SV40 infection of mesothelial cells.

In plain English

This laboratory study measured telomerase activity in mesothelioma tissue and cells and tested whether SV40 infection induces it. Using the TRAP assay, telomerase activity was found in seven of seven pleural mesothelioma biopsies but not in matched lung tissue; five of the seven biopsies contained SV40 sequences. Activity was detected in 19 of 20 (95%) established mesothelioma cell lines, all SV40 negative, and in all eight primary tumour cultures; the one negative line (Meso 10) had ultra-long telomeres characteristic of the ALT pathway. Telomerase activity was detected in six of six mesothelial cell lines transformed by SV40 and increased with culture passage. After infection of primary human mesothelial cells with wild-type SV40 strain 776, activity appeared by 72 hours, with a clear ladder at 7 days; it was not detectable in SV40-infected fibroblasts, and only barely detectable with the small t-antigen mutant dl 884. Adding asbestos to primary mesothelial cultures or SV40-transformed mesothelial cells did not change their telomerase activity. The authors concluded that SV40 infection of mesothelial cells may be a pre-neoplastic event.

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 tumour biopsies, cell lines and primary cell cultures, with in vitro virus infection experiments
• Who was studied: Seven primary malignant (pleural) mesothelioma biopsies with matched lung specimens, 20 mesothelioma cell lines, eight corresponding primary tumour cultures, four normal mesothelial cell cultures, three primary human mesothelial cell cultures (HM2, HM4, HM5) from patients with pleural fluid due to congestive heart failure, and primary human fibroblast cultures (WI38, MRC-5, CCD1069Sk)
• Exposure: Infection with wild-type SV40 (strain 776) and the SV40 small t-antigen deletion mutant dl 884 at a multiplicity of infection of 30; asbestos added to cell cultures (fibre type and dose not stated)
• Main results:
  • Telomerase activity was present in 7 of 7 mesothelioma biopsies and absent in the matched lung tissue; 5 of the 7 biopsies contained SV40 sequences
  • Telomerase activity was detected in 19 of 20 (95%) established mesothelioma cell lines, all SV40 negative, and in all eight primary cultures
  • The single telomerase-negative cell line, Meso 10, had ultra-long telomeres characteristic of the alternative lengthening of telomeres (ALT) phenotype
  • All six mesothelial cell lines transformed in vitro by SV40 had telomerase activity, which increased with passage in culture
  • In primary human mesothelial cells, telomerase activity appeared 72 hours after wild-type SV40 infection, with a clear ladder at 7 days
  • No telomerase activity was detectable in SV40-infected fibroblasts
  • With the SV40 small t-antigen mutant dl 884, telomerase activity was absent at 72 hours and barely detectable at 7 days in mesothelial cells; three cell lines produced with dl 884 plus asbestos had barely detectable levels
  • Adding asbestos to primary mesothelial cultures or to SV40-transformed mesothelial cells did not change telomerase activity
• The authors' conclusion: The authors concluded that SV40 induces telomerase activity in human mesothelial cells early after infection, before transformation, that small t-antigen contributes to this, and that SV40 infection of mesothelial cells may be regarded as a pre-neoplastic event increasing mesothelioma risk
• Limitations the authors state:
  • The authors state it is unknown whether telomerase is induced in only a fraction of infected cells or in all of them, and whether those cells are the ones that later transform
  • The authors note that telomerase was found in biopsies and cell lines regardless of SV40 status, so the in vitro induction may be independent of SV40 status in actual tumours

Topics

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

Medical terms in this study, explained in our Lexicon: SV40, Mesothelial Cells, Mesothelioma, Asbestos Exposure, Malignant Mesothelioma, Fibroblast.

Related studies

• Telomerase activity in pleural malignant mesotheliomas — A.Y. Au, T. Hackl, et al. (2011)
• Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity — M. Bocchetta, I. Di Resta, et al. (2000)
• Telomerase activity in human pleural mesothelioma — K. Dhaene, R. Hübner, et al. (1998)
• Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters — B. Kroczynska, R. Cutrone, et al. (2006)
• Simian virus 40 infection down-regulates the expression of nitric oxide synthase in human mesothelial cells — E. Aldieri, S. Orecchia, et al. (2004)
• Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells — S. Toyooka, M. Carbone, et al. (2002)

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