Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 9, Pages 3725-3730Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1100446108
Keywords
metastasis; permeability
Categories
Funding
- Dyax
- AstraZeneca
- MedImmune
- AstraZeneca/MedImmune
- Astellas-Fibrogen
- SynDevRx
- Regeneron
- Genzyme
- Morphosys
- Noxxon Pharma
- National Institutes of Health [R01-CA085140, R01-CA115767, P01-CA080124, R01-CA126642]
- Federal Share/National Cancer Institute
- R01-CA096915
- The Scholarship Fund
- Fulbright Postgraduate Award
- American Society of Clinical Oncology
- Susan G. Komen Postdoctoral Research Fellowship
- Department of Defence [W81XWH-10-1-0016]
- Grants-in-Aid for Scientific Research [21117008] Funding Source: KAKEN
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Primary tumors secrete factors that alter the microenvironment of distant organs, rendering those organs as fertile soil for subsequent metastatic cancer cell colonization. Although the lungs are exposed to these factors ubiquitously, lung metastases usually develop as a series of discrete lesions. The underlining molecular mechanisms of the formation of these discrete lesions are not understood. Here we show that primary tumors induce formation of discrete foci of vascular hyperpermeability in premetastatic lungs. This is mediated by endothelial cell-focal adhesion kinase (FAK), which up-regulates E-selectin, leading to preferential homing of metastatic cancer cells to these foci. Suppression of endothelial-FAK or E-selectin activity attenuates the number of cancer cells homing to these foci. Thus, localized activation of endothelial FAK and E-selectin in the lung vasculature mediates the initial homing of metastatic cancer cells to specific foci in the lungs.
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