Targeting EphA3 inhibits cancer growth by disrupting the tumor stromal microenvironment

Mary E Vail, Carmel Murone, Y L April Tan, Linda L P Hii, Degu B Abebe, Peter W Janes, Fook-Thean Lee, Mark E Baer, Varghese Palath, Christopher R Bebbington, Geoffrey T Yarranton, Carmen O Llerena, Slavisa Garic, David A Abramson, Glenn A Cartwright, Andrew M Scott, Martin Lackmann

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58 Citations (Scopus)

Abstract

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 alpha-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. Cancer Res; 74(16); 4470-81. (c)2014 AACR.
Original languageEnglish
Pages (from-to)4470 - 4481
Number of pages12
JournalCancer Research
Volume74
Issue number16
DOIs
Publication statusPublished - 2014

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