title: Telomerase activity in pleural malignant mesotheliomas.
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.
authors.affiliation: Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, New South Wales 2145, Australia.
authors.forename: Amy Y M
authors.initials: AY
authors.lastname: Au
authors.forename: Torben
authors.initials: T
authors.lastname: Hackl
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Yeager
authors.forename: Scott B
authors.initials: SB
authors.lastname: Cohen
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
authors.forename: Roger R
authors.initials: RR
authors.lastname: Reddel
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009857:Oncogenes / Q000235:genetics; D010994:Pleura / Q000473:pathology; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013539:Simian virus 40 / Q000235:genetics*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000187:drug effects / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019098:Telomerase