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EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

Oncogene volume 25, pages 7019–7028 (2006)Cite this article

Abstract

Prostaglandin E2 (PGE2), a major cyclooxygenase (COX) metabolite, plays important roles in tumor biology. We studied the role of EP2, a receptor for PGE2, in tumor angiogenesis using EP2 knockout mice. We found that deletion of the EP2 receptor impaired tumor angiogenesis and this finding was confirmed by an in vivo corneal angiogenesis model and an ex vivo aortic ring assay. To further characterize the cellular mechanisms of the EP2 receptor in angiogenesis, we isolated primary pulmonary endothelial cells (ECs) from wild-type (wt) and EP2−/− mice and observed that EP2−/− ECs exhibited defects in vascular branch formation when compared to wt ECs. In addition, EP2−/− ECs showed impaired cell motility on collagen-coated surface and they responded poorly to PGE2-induced cell migration compared to control cells. However, no difference in cell proliferation was observed between the EP2−/− and wt Ecs. In addition, EP2−/− ECs were more susceptible to apoptosis than wt cells under growth factor depletion conditions. Collectively, our data demonstrate that EP2 signaling in endothelium directly regulates tumor angiogenesis by contributing to cell survival and endothelial cell motility. Moreover, our finding suggests that EP2 is a major receptor in PGE2-mediated cell motility in ECs.

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Acknowledgements

This work was supported in part by the following grants (NS45888 and CA108856) from National Institute of Health, and by the Vanderbilt-Ingram Cancer Center (CA68485).We thank Drs Raymond DuBois, Larry Marnett and Dennis Hallahan at Vanderbilt University Medical Center for their critical reading and comments on the manuscript. We thank Vanderbilt Cardiovascular Medicine Histo/Imaging Core for Technique support.

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Authors and Affiliations

  1. Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

    M Kamiyama & P C Lin

  2. Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

    A Pozzi & R M Breyer

  3. Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

    A Pozzi, L Yang, L M DeBusk & P C Lin

  4. Department of Pharmacology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

    R M Breyer

  5. Department of Cell & Development Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

    P C Lin

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  1. M Kamiyama
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Correspondence to P C Lin.

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Kamiyama, M., Pozzi, A., Yang, L. et al. EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival. Oncogene 25, 7019–7028 (2006). https://doi.org/10.1038/sj.onc.1209694

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