Abstract
Alterations in endothelial cell (EC) signaling could serve as a marker of effective antiangiogenic therapy. We determined the effect of an antiangiogenic tyrosine kinase inhibitor, SU6668, on tumor EC signaling in liver metastases in mice. In vitro immunofluorescence verified that pretreatment of ECs with SU6668 before exposure to VEGF decreased in vitro phosphorylation of Erk and Akt. Using double-fluorescence immunohistochemistry, phosphorylated Erk and Akt were constitutively expressed in ECs in liver metastases in untreated mice, but SU6668 blocked activation of these signaling intermediates. Determining the activation status of the Erk and Akt signaling pathways in tumor ECs may serve as a surrogate marker for the effectiveness of antiangiogenic regimens.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Androstadienes / pharmacology
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Angiogenesis Inhibitors / pharmacology*
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Biomarkers, Tumor / physiology
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Blotting, Western
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Endothelial Growth Factors / pharmacology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiology
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Fluorescent Antibody Technique
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Humans
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Indoles / pharmacology*
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Liver Neoplasms / blood supply*
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Liver Neoplasms / secondary
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Lymphokines / pharmacology
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / physiology
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / enzymology
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Neovascularization, Pathologic / physiopathology*
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Oxindoles
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Propionates
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Pyrroles / pharmacology*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / physiology
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Receptors, Growth Factor / antagonists & inhibitors
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Receptors, Growth Factor / physiology
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Wortmannin
Substances
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Androstadienes
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Angiogenesis Inhibitors
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Biomarkers, Tumor
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Endothelial Growth Factors
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Enzyme Inhibitors
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Flavonoids
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Indoles
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Lymphokines
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Oxindoles
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Phosphoinositide-3 Kinase Inhibitors
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Propionates
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Proto-Oncogene Proteins
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Pyrroles
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Receptors, Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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orantinib
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Wortmannin