2. Academic Validation
  3. Mutant KRAS promotes malignant pleural effusion formation

Mutant KRAS promotes malignant pleural effusion formation

  • Nat Commun. 2017 May 16;8:15205. doi: 10.1038/ncomms15205.
Theodora Agalioti 1,  Anastasios D Giannou 1,  Anthi C Krontira 1,  Nikolaos I Kanellakis 1 2,  Danai Kati 1,  Malamati Vreka 1 3,  Mario Pepe 3,  Magda Spella 1,  Ioannis Lilis 1,  Dimitra E Zazara 1,  Eirini Nikolouli 1,  Nikolitsa Spiropoulou 1,  Andreas Papadakis 1,  Konstantina Papadia 4,  Apostolos Voulgaridis 5,  Vaggelis Harokopos 6,  Panagiota Stamou 7,  Silke Meiners 3,  Oliver Eickelberg 3,  Linda A Snyder 8,  Sophia G Antimisiaris 4,  Dimitrios Kardamakis 9,  Ioannis Psallidas 1 2,  Antonia Marazioti 1,  Georgios T Stathopoulos 1 3
Affiliations

Affiliations

  • 1 Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece.
  • 2 Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Trust, Churchill Hospital Old Road, Oxford OX3 7LE, UK.
  • 3 Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), 81377 Munich, Germany.
  • 4 Laboratory for Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, and Foundation for Research and Technology Hellas, Institute of Chemical Engineering, FORTH/ICE-HT, 26504 Rio, Greece.
  • 5 Department of Pulmonary Medicine, Rio University Hospital, Faculty of Medicine, University of Patras, 26504 Rio, Greece.
  • 6 Genomics Facility, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Attica 16672, Greece.
  • 7 Department of Hematology, Faculty of Medicine, University of Patras, Rio, Achaia 26504, Greece.
  • 8 Oncology Discovery Research, Janssen R&D LLC, Spring House, Pennsylvania, 19477 USA.
  • 9 Department of Radiation Oncology and Stereotactic Radiotherapy, Faculty of Medicine, University of Patras, 26504 Rio, Greece.
PMID: 28508873 DOI: 10.1038/ncomms15205
Abstract

Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.

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