A Role of Agrin in Maintaining the Stability of Vascular Endothelial Growth Factor Receptor-2 during Tumor Angiogenesis

Cell Rep. 2019 Jul 23;28(4):949-965.e7. doi: 10.1016/j.celrep.2019.06.036.


Endothelial cell (EC) recruitment is central to the vascularization of tumors. Although several proteoglycans have been implicated in cancer and angiogenesis, their roles in EC recruitment and vascularization during tumorigenesis remain poorly understood. Here, we reveal that Agrin, which is secreted in liver cancer, promotes angiogenesis by recruiting ECs within tumors and metastatic lesions and facilitates adhesion of cancer cells to ECs. In ECs, Agrin-induced angiogenesis and adherence to cancer cells are mediated by Integrin-β1, Lrp4-MuSK pathways involving focal adhesion kinase. Mechanistically, we uncover that Agrin regulates VEGFR2 levels that sustain the angiogenic property of ECs and adherence to cancer cells. Agrin attributes an ECM stiffness-based stabilization of VEGFR2 by enhancing interactions with Integrin-β1-Lrp4 and additionally stimulates endothelial nitric-oxide synthase (e-NOS) signaling. Therefore, we propose that cross-talk between Agrin-expressing cancer and ECs favor angiogenesis by sustaining the VEGFR2 pathway.

Keywords: Agrin; ECM stiffness; VEGFR2; angiogenesis; cell adhesion; endothelial-NOS; focal adhesion kinase (FAK); integrins; tumor angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agrin / metabolism*
  • Animals
  • Cell Adhesion
  • Cell Line, Tumor
  • Enzyme Activation
  • Extracellular Matrix / metabolism
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Integrin beta1 / metabolism
  • LDL-Receptor Related Proteins / metabolism
  • Mice
  • Neoplasms / blood supply*
  • Neoplasms / metabolism*
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Physiologic
  • Nitric Oxide Synthase Type III / metabolism
  • Protein Stability
  • Signal Transduction
  • Solubility
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • Agrin
  • Integrin beta1
  • LDL-Receptor Related Proteins
  • LRP4 protein, human
  • Nitric Oxide Synthase Type III
  • Vascular Endothelial Growth Factor Receptor-2
  • Focal Adhesion Protein-Tyrosine Kinases