COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models

Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway bl...

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Bibliographic Details
Published in:Science translational medicine 2014-06, Vol.6 (242), p.242ra84
Main Authors: Xu, Lihong, Stevens, Janine, Hilton, Mary Beth, Seaman, Steven, Conrads, Thomas P, Veenstra, Timothy D, Logsdon, Daniel, Morris, Holly, Swing, Deborah A, Patel, Nimit L, Kalen, Joseph, Haines, Diana C, Zudaire, Enrique, St Croix, Brad
Format: Article
Language:English
Subjects:
Angiogenesis Inhibitors - pharmacology
Angiogenesis Inhibitors - therapeutic use
Animals
Axitinib
Carcinogenesis - pathology
Cell Line, Tumor
Clone Cells
Cyclooxygenase 2 - metabolism
Cyclooxygenase 2 Inhibitors - pharmacology
Cyclooxygenase 2 Inhibitors - therapeutic use
Dinoprostone - metabolism
Female
Humans
Imidazoles - pharmacology
Indazoles - pharmacology
Liver Neoplasms - blood supply
Liver Neoplasms - drug therapy
Liver Neoplasms - prevention & control
Liver Neoplasms - secondary
Mammary Neoplasms, Experimental - blood supply
Mammary Neoplasms, Experimental - drug therapy
Mammary Neoplasms, Experimental - prevention & control
Mammary Neoplasms, Experimental - secondary
Mice
Neoadjuvant Therapy
Signal Transduction - drug effects
Survival Analysis
Vascular Endothelial Growth Factor A - metabolism
Xenograft Model Antitumor Assays
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Summary:Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. We identified prostaglandin E2 (PGE2) as a soluble tumor-derived angiogenic factor associated with VEGF-independent angiogenesis. PGE2 production in preclinical breast and colon cancer models was tightly controlled by cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition augmented VEGF pathway blockade to suppress angiogenesis and tumor growth, prevent metastasis, and increase overall survival. These results demonstrate the importance of the COX-2/PGE2 pathway in mediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.
ISSN:1946-6234
1946-6242
1946-6242
DOI:10.1126/scitranslmed.3008455