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  • Original Paper
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Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo

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.

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Acknowledgements

We would like to thank Amanda Kizzee for excellent technical support, Nick Gale and George Yancopolous (Regeneron Inc.), Chuan-Huan Li and Mark Dewhirst (Duke University), and Doug Hanahan (UCSF) for providing EphA2-Fc construct, the 4T1-GFP subline, and RIP-Tag transgenic mice, respectively. Special thanks to Laura Debusk for assistance with cutaneous window assays, and to Rick Haselton for the transwell co-culture assay protocol and helpful discussions. We thank Ray Dubois, Brigid LM Hogan, and Lynn M Matrisian for helpful discussions, and give special thanks to Carlos L Arteaga for his ongoing support. This work was supported by National Institutes of Health grants HD36400 and DK47078, American Heart Association grant 97300889N, a JDF grant I-2001-519, and an ACS Institutional Research Grant IN-25-38 to J Chen, Vascular Biology Training Grant T32-HL-07751-06 and American Heart Association Fellowship 0120147B to D Brantley, and Cancer training grant T-32 CA09592 to N Cheng. This work was also supported by a core facilities grant 2P30CA68485 to the Vanderbilt-Ingram Cancer Center.

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Correspondence to Jin Chen.

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Brantley, D., Cheng, N., Thompson, E. et al. Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21, 7011–7026 (2002). https://doi.org/10.1038/sj.onc.1205679

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