ADAM12-cleaved ephrin-A1 contributes to lung metastasis

Oncogene. 2014 Apr 24;33(17):2179-90. doi: 10.1038/onc.2013.180. Epub 2013 May 20.


Eph receptor tyrosine kinases and their ephrin ligands have been implicated in neuronal development and neovascularization. Overexpression of ephrin-A1 has been implicated in tumor progression and poor prognosis. However, the mechanisms are not clear. Here, we report a role of the Eph/ephrin system in a cell adhesion mechanism. Clustered erythropoietin-producing hepatocellular receptor A1 (EphA1)/ephrin-A1 complexes on the plasma membrane did not undergo endocytosis, and the cell remained adherent to one another. The cell-cell contacts were maintained in an Eph tyrosine kinase activity-independent manner even in the absence of E-cadherin. EphA1 and ephrin-A1 co-localized in pulmonary endothelial cells, and regulated vascular permeability and metastasis in the lungs. We identified ADAM12 (A disintegrin and metalloproteinase 12) as an EphA1-binding partner by yeast two-hybrid screening and found that ADAM12 enhanced ephrin-A1 cleavage in response to transforming growth factor-β1 in primary tumors. Released soluble ephrin-A1 in the serum deteriorated the EphA1/ephrin-A1-mediated cell adhesion in the lungs in an endocrine manner, causing lung hyperpermeability that facilitated tumor cell entry into the lungs. Depletion of soluble ephrin-A1 by its neutralizing antibody significantly inhibited lung metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / physiology*
  • ADAM12 Protein
  • Animals
  • Antibodies / pharmacology
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / enzymology*
  • Carcinoma, Lewis Lung / secondary
  • Cell Adhesion
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Ephrin-A1 / metabolism*
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / secondary
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Targeted Therapy
  • Neoplasm Transplantation
  • Proteolysis
  • Receptor, EphA2 / genetics
  • Receptor, EphA2 / metabolism
  • Transforming Growth Factor beta1 / physiology
  • Tumor Burden / drug effects


  • Antibodies
  • Antineoplastic Agents
  • Ephrin-A1
  • Transforming Growth Factor beta1
  • Receptor, EphA2
  • ADAM Proteins
  • ADAM12 Protein
  • Adam12 protein, mouse