Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo

Dana M. Brantley, Nikki Cheng, Erin J. Thompson, Qing Lin, Rolf A. Brekken, Philip E. Thorpe, Rebecca S. Muraoka, Douglas Pat Cerretti, Ambra Pozzi, Dowdy Jackson, Charles Lin, Jin Chen

Research output: Contribution to journalArticle

279 Scopus citations

Abstract

The Eph family of receptor tyrosine kinases and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis. The function of these molecules in adult angiogenesis has not been well characterized. Here, we report that blocking Eph A class receptor activation inhibits angiogenesis in two independent tumor types, the RIP-Tag transgenic model of angiogenesis-dependent pancreatic islet cell carcinoma and the 4T1 model of metastatic mammary adenocarcinoma. Ephrin-A1 ligand was expressed in both tumor and endothelial cells, and EphA2 receptor was localized primarily in tumor-associated vascular endothelial cells. Soluble EphA2-Fc or EphA3-Fc receptors inhibited tumor angiogenesis in cutaneous window assays, and tumor growth in vivo. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor vascular density, tumor volume, and cell proliferation, but increased cell apoptosis. However, EphA2-Fc had no direct effect on tumor cell growth or apoptosis in culture, yet inhibited migration of endothelial cells in response to tumor cells, suggesting that the soluble receptor inhibited blood vessel recruitment by the tumor. These data provide the first functional evidence for Eph A class receptor regulation of pathogenic angiogenesis induced by tumors and support the function of A class Eph receptors in tumor progression.

Original languageEnglish (US)
Pages (from-to)7011-7026
Number of pages16
JournalOncogene
Volume21
Issue number46
DOIs
StatePublished - 2002

Keywords

  • Eph receptor tyrosine kinase
  • Ephrin
  • Soluble Eph receptor
  • Tumor angiogenesis
  • Vascular window model

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Brantley, D. M., Cheng, N., Thompson, E. J., Lin, Q., Brekken, R. A., Thorpe, P. E., Muraoka, R. S., Cerretti, D. P., Pozzi, A., Jackson, D., Lin, C., & Chen, J. (2002). Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene, 21(46), 7011-7026. https://doi.org/10.1038/sj.onc.1205679