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.