Targeting EphA3 inhibits cancer growth by disrupting the tumor stromal microenvironment Academic Article uri icon

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 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.

authors

  • Vail, ME
  • Murone, C
  • Tan, A
  • Hii, L
  • Abebe, D
  • Janes, PW
  • Lee, FT
  • Baer, M
  • Palath, V
  • Bebbington, C
  • Yarranton, G
  • Llerena, C
  • Garic, S
  • Abramson, D
  • Cartwright, G
  • Scott, AM
  • Lackmann, M

publication date

  • 2014

has subject area