title: Temsirolimus targets multiple hallmarks of cancer to impede mesothelioma growth in vivo.
abstract: OBJECTIVE
  The mechanistic target of rapamycin (mTOR) promotes cancer cell proliferation and survival, transduces pro-angiogenic signals and regulates immune cell differentiation and function. We hypothesized that temsirolimus, an mTOR inhibitor, would curtail experimental mesothelioma progression in vivo by limiting tumour cell growth, abrogating tumour angiogenesis and modulating immune/inflammatory tumour milieu.
  
  
  METHODS
  We produced flank and pleural syngeneic murine mesotheliomas by delivering AE17 and AB1 murine mesothelioma cells into the right flank or the pleural space of C57BL/6 and BALB/c mice, respectively. Animals were given five times/week intraperitoneal injections of 20 mg/kg temsirolimus or vehicle and were sacrificed on day 26 (flank) or on day 15 (pleural) post-tumour cell propagation.
  
  
  RESULTS
  Temsirolimus limited mesothelioma growth in vivo by stimulating tumour cell apoptosis, inhibiting tumour angiogenesis, enhancing tumour lymphocyte abundance and blocking pro-tumour myeloid cell recruitment. Pleural fluid accumulation was significantly mitigated in AE17 but not in AB1 mesotheliomas. In vitro, temsirolimus hindered mesothelioma cell growth, NF-kappaB activation and macrophage migration.
  
  
  CONCLUSIONS
  In conclusion, temsirolimus apart from inducing tumour cell apoptosis, targets tumour angiogenesis and influences inflammatory tumour microenvironment to halt experimental mesothelioma growth in vivo.
authors.affiliation: 'Marianthi Simou Laboratory', 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Maria Eleni
authors.initials: ME
authors.lastname: Vazakidou
authors.affiliation: 'Marianthi Simou Laboratory', 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Sophia
authors.initials: S
authors.lastname: Magkouta
authors.affiliation: 'Marianthi Simou Laboratory', 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Moschos
authors.affiliation: 'Marianthi Simou Laboratory', 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.|Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford, UK.|Oxford Respiratory Trials Unit, Churchill Hospital, Oxford, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Psallidas
authors.affiliation: 'Marianthi Simou Laboratory', 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Pappas
authors.affiliation: Department of Immunology-Histocompatibility, Evangelismos Hospital, Athens, Greece.
authors.forename: Katherina
authors.initials: K
authors.lastname: Psarra
authors.affiliation: 'Marianthi Simou Laboratory', 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kalomenidis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy*; D008654:Mesothelioma / Q000188:drug therapy*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010997:Pleural Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; C401859:temsirolimus; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: mechanistic target of rapamycin; mesothelioma; pleural effusion; temsirolimus; tumour