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

Lihong Xu; Janine Stevens; Mary Beth Hilton; Steven Seaman; Thomas P. Conrads; Timothy D. Veenstra; Daniel Logsdon; Holly Morris; Deborah A. Swing; Nimit L. Patel; Joseph Kalen; Diana C. Haines; Enrique Zudaire; Brad St Croix

doi:10.1126/scitranslmed.3008455

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

Lihong Xu, Janine Stevens, Mary Beth Hilton, Steven Seaman, Thomas P. Conrads, Timothy D. Veenstra, Daniel Logsdon, Holly Morris, Deborah A. Swing, Nimit L. Patel, Joseph Kalen, Diana C. Haines, Enrique Zudaire, Brad St Croix^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › peer-review

175 Scopus citations

Abstract

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 inmediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.

Original language	English
Article number	242ra84
Journal	Science Translational Medicine
Volume	6
Issue number	242
DOIs	https://doi.org/10.1126/scitranslmed.3008455
State	Published - 25 Jun 2014

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Xu, L., Stevens, J., Hilton, M. B., Seaman, S., Conrads, T. P., Veenstra, T. D., Logsdon, D., Morris, H., Swing, D. A., Patel, N. L., Kalen, J., Haines, D. C., Zudaire, E., & St Croix, B. (2014). COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models. Science Translational Medicine, 6(242), Article 242ra84. https://doi.org/10.1126/scitranslmed.3008455

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title = "COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models",

abstract = "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 inmediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.",

author = "Lihong Xu and Janine Stevens and Hilton, {Mary Beth} and Steven Seaman and Conrads, {Thomas P.} and Veenstra, {Timothy D.} and Daniel Logsdon and Holly Morris and Swing, {Deborah A.} and Patel, {Nimit L.} and Joseph Kalen and Haines, {Diana C.} and Enrique Zudaire and {St Croix}, Brad",

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doi = "10.1126/scitranslmed.3008455",

language = "English",

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Xu, L, Stevens, J, Hilton, MB, Seaman, S, Conrads, TP, Veenstra, TD, Logsdon, D, Morris, H, Swing, DA, Patel, NL, Kalen, J, Haines, DC, Zudaire, E & St Croix, B 2014, 'COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models', Science Translational Medicine, vol. 6, no. 242, 242ra84. https://doi.org/10.1126/scitranslmed.3008455

TY - JOUR

T1 - COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models

AU - Xu, Lihong

AU - Stevens, Janine

AU - Hilton, Mary Beth

AU - Seaman, Steven

AU - Conrads, Thomas P.

AU - Veenstra, Timothy D.

AU - Logsdon, Daniel

AU - Morris, Holly

AU - Swing, Deborah A.

AU - Patel, Nimit L.

AU - Kalen, Joseph

AU - Haines, Diana C.

AU - Zudaire, Enrique

AU - St Croix, Brad

PY - 2014/6/25

Y1 - 2014/6/25

N2 - 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 inmediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.

AB - 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 inmediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.

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DO - 10.1126/scitranslmed.3008455

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SN - 1946-6234

VL - 6

JO - Science Translational Medicine

JF - Science Translational Medicine

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M1 - 242ra84

ER -

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

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