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Mutant KRAS promotes malignant pleural effusion formation

Author

Listed:
  • Theodora Agalioti

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Anastasios D. Giannou

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Anthi C. Krontira

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Nikolaos I. Kanellakis

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
    Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Trust)

  • Danai Kati

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Malamati Vreka

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
    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))

  • Mario Pepe

    (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))

  • Magda Spella

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Ioannis Lilis

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Dimitra E. Zazara

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Eirini Nikolouli

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Nikolitsa Spiropoulou

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Andreas Papadakis

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Konstantina Papadia

    (Laboratory for Pharmaceutical Technology, School of Health Sciences, University of Patras, and Foundation for Research and Technology Hellas, Institute of Chemical Engineering, FORTH/ICE-HT)

  • Apostolos Voulgaridis

    (Rio University Hospital, Faculty of Medicine, University of Patras)

  • Vaggelis Harokopos

    (Genomics Facility, Biomedical Sciences Research Center ‘Alexander Fleming’)

  • Panagiota Stamou

    (Faculty of Medicine, University of Patras)

  • Silke Meiners

    (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))

  • Oliver Eickelberg

    (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))

  • Linda A. Snyder

    (Oncology Discovery Research, Janssen R&D LLC)

  • Sophia G. Antimisiaris

    (Laboratory for Pharmaceutical Technology, School of Health Sciences, University of Patras, and Foundation for Research and Technology Hellas, Institute of Chemical Engineering, FORTH/ICE-HT)

  • Dimitrios Kardamakis

    (Faculty of Medicine, University of Patras)

  • Ioannis Psallidas

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
    Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Trust)

  • Antonia Marazioti

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras)

  • Georgios T. Stathopoulos

    (Laboratory for Molecular Respiratory Carcinogenesis, Faculty of Medicine, University of Patras
    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))

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.

Suggested Citation

  • Theodora Agalioti & Anastasios D. Giannou & Anthi C. Krontira & Nikolaos I. Kanellakis & Danai Kati & Malamati Vreka & Mario Pepe & Magda Spella & Ioannis Lilis & Dimitra E. Zazara & Eirini Nikolouli , 2017. "Mutant KRAS promotes malignant pleural effusion formation," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15205
    DOI: 10.1038/ncomms15205
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