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EMBO Mol Med. 2017 May;9(5):672-686. doi: 10.15252/emmm.201606978.

NRAS destines tumor cells to the lungs.

Author information

1
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
2
Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Member of the German Center for Lung Research (DZL), University Hospital, Ludwig-Maximilians University and Helmholtz Center Munich, Munich, Germany.
3
Pneumology Unit, Department of Pediatrics, Faculty of Medicine, University of Patras, Rio, Greece.
4
Department of Radiation Oncology and Stereotactic Radiotherapy, Faculty of Medicine, University of Patras, Rio, Greece.
5
Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
6
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece magsp@upatras.gr gstathop@upatras.gr stathopoulos@helmholtz-muenchen.de.

Abstract

The lungs are frequently affected by cancer metastasis. Although NRAS mutations have been associated with metastatic potential, their exact role in lung homing is incompletely understood. We cross-examined the genotype of various tumor cells with their ability for automatic pulmonary dissemination, modulated NRAS expression using RNA interference and NRAS overexpression, identified NRAS signaling partners by microarray, and validated them using Cxcr1- and Cxcr2-deficient mice. Mouse models of spontaneous lung metastasis revealed that mutant or overexpressed NRAS promotes lung colonization by regulating interleukin-8-related chemokine expression, thereby initiating interactions between tumor cells, the pulmonary vasculature, and myeloid cells. Our results support a model where NRAS-mutant, chemokine-expressing circulating tumor cells target the CXCR1-expressing lung vasculature and recruit CXCR2-expressing myeloid cells to initiate metastasis. We further describe a clinically relevant approach to prevent NRAS-driven pulmonary metastasis by inhibiting chemokine signaling. In conclusion, NRAS promotes the colonization of the lungs by various tumor types in mouse models. IL-8-related chemokines, NRAS signaling partners in this process, may constitute an important therapeutic target against pulmonary involvement by cancers of other organs.

KEYWORDS:

inflammation and cancer; interleukin‐8‐related chemokines; lung endothelium; myeloid cells; pulmonary metastasis

Comment in

PMID:
28341702
PMCID:
PMC5697015
DOI:
10.15252/emmm.201606978
[Indexed for MEDLINE]
Free PMC Article

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