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The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues
Published on: June 16, 2018
NRAS destines tumor cells to the lungs
Anastasios D Giannou1, Antonia Marazioti1, Nikolaos I Kanellakis1
1Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
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.
Insights
Mutant NRAS promotes lung metastasis by regulating chemokine expression, guiding tumor cells to the lungs. Inhibiting this chemokine signaling offers a potential strategy to prevent NRAS-driven lung colonization by cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- The lungs are a common site for cancer metastasis.
- The precise mechanisms by which NRAS mutations influence lung homing remain unclear.
Purpose of the Study:
- To elucidate the role of NRAS in promoting pulmonary metastasis.
- To identify NRAS signaling pathways involved in lung colonization.
- To explore therapeutic strategies targeting NRAS-driven metastasis.
Main Methods:
- Genomic analysis of tumor cells and their metastatic potential.
- Modulation of NRAS expression via RNA interference and overexpression.
- Microarray analysis to identify NRAS signaling partners.
- Validation using Cxcr1- and Cxcr2-deficient mouse models.
Main Results:
- Mutant or overexpressed NRAS enhances lung colonization in mouse models.
- NRAS regulates interleukin-8-related chemokine expression, facilitating tumor cell interactions with pulmonary vasculature and myeloid cells.
- A model is proposed where NRAS-mutant cells target CXCR1-expressing lung vasculature and recruit CXCR2-expressing myeloid cells.
Conclusions:
- NRAS promotes lung colonization across various tumor types in preclinical models.
- NRAS signaling partners, specifically IL-8-related chemokines, are crucial for NRAS-driven pulmonary metastasis.
- Inhibiting chemokine signaling presents a potential therapeutic approach to prevent NRAS-driven lung metastasis.
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