Eph receptor tyrosine kinases are critical for cell-cell communication during normal and oncogenic tissue patterning and tumor growth. Somatic mutation profiles of several cancer genomes suggest EphA3 as a tumor suppressor, but its oncogenic expression pattern and role in tumorigenesis remain largely undefined. Here, we report unexpected EphA3 overexpression within the microenvironment of a range of human cancers and mouse tumor xenografts where its activation inhibits tumor growth. EphA3 is found on mouse bone marrow-derived cells with mesenchymal and myeloid phenotypes, and activation of EphA3+/CD90+/Sca1+ mesenchymal/stromal cells with an EphA3 agonist leads to cell contraction, cell-cell segregation, and apoptosis. Treatment of mice with an agonistic α-EphA3 antibody inhibits tumor growth by severely disrupting the integrity and function of newly formed tumor stroma and microvasculature. Our data define EphA3 as a novel target for selective ablation of the tumor microenvironment and demonstrate the potential of EphA3 agonists for anticancer therapy. ©2014 AACR.
CITATION STYLE
Vail, M. E., Murone, C., Tan, A., Hii, L., Abebe, D., Janes, P. W., … Lackmann, M. (2014). Targeting EphA3 inhibits cancer growth by disrupting the tumor stromal microenvironment. Cancer Research, 74(16), 4470–4481. https://doi.org/10.1158/0008-5472.CAN-14-0218
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