Abstract
Downregulating the leukocyte adhesion molecules expressed by endothelial cells that line tumor blood vessels can limit the entry of immune effector cells into the tumor mass, thereby contributing to tumoral immune escape. Egfl7 (also known as VE-statin) is a secreted protein specifically expressed by endothelial cells in normal tissues and by cancer cells in various human tumors. High levels of Egfl7 correlate with higher tumor grade and poorer prognosis. Here we show that expression of Egfl7 in breast and lung carcinoma cells accelerates tumor growth and metastasis in immunocompetent mice but not in immunodeficient mice. Tumors expressing Egfl7 were infiltrated relatively poorly by immune cells and were characterized by reduced levels of immunostimulatory cytokines [IFN-γ, interleukin-12 (IL-12)] and fewer endothelial adhesion molecules [intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)]. In vitro studies revealed that Egfl7 inhibited the expression of leukocyte adhesion molecules by endothelial cells, preventing lymphocyte adhesion. In contrast, Egfl7 did not exert any effects on immune cell activation. Human breast cancer lesions expressing high levels of Egfl7 also expressed less ICAM-1 and VCAM-1 in their blood vessels, also indicating an inverse correlation between expression levels of Egfl7 and IFN-γ. Thus, Egfl7 expression in tumors promotes tumor progression by reducing the expression of endothelial molecules that mediate immune cell infiltration. Our findings highlight a novel mechanism through which tumors escape immune control.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium-Binding Proteins
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Cell Adhesion / genetics
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Cell Adhesion / immunology
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / immunology
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / immunology
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Cells, Cultured
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Disease Progression
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EGF Family of Proteins
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Endothelial Cells / immunology*
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Endothelial Cells / pathology
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / immunology*
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Endothelium, Vascular / immunology
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Endothelium, Vascular / pathology
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Female
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Human Umbilical Vein Endothelial Cells
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Humans
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / immunology
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-12 / genetics
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Interleukin-12 / immunology
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Interleukin-12 / metabolism
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Jurkat Cells
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, SCID
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Neoplasm Metastasis / genetics
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Neoplasm Metastasis / immunology
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Neoplasm Metastasis / pathology
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Proteins / genetics
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Proteins / immunology*
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Tumor Escape / genetics
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Tumor Escape / immunology*
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Vascular Cell Adhesion Molecule-1 / genetics
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Vascular Cell Adhesion Molecule-1 / immunology
Substances
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Calcium-Binding Proteins
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Cell Adhesion Molecules
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EGF Family of Proteins
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EGFL7 protein, human
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Egfl7 protein, mouse
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Endothelial Growth Factors
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Proteins
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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Interleukin-12
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Interferon-gamma