Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling

Cancer Cell. 2005 Jul;8(1):13-23. doi: 10.1016/j.ccr.2005.06.004.


While significant progress has been made in understanding the induction of tumor vasculature by secreted angiogenic factors, little is known regarding contact-dependent signals that promote tumor angiogenesis. Here, we report that the Notch ligand Jagged1 induced by growth factors via mitogen-activating protein kinase (MAPK) in head and neck squamous cell carcinoma (HNSCC) cells triggered Notch activation in neighboring endothelial cells (ECs) and promoted capillary-like sprout formation. Jagged1-expressing HNSCC cells significantly enhanced neovascularization and tumor growth in vivo. Moreover, the level of Jagged1 was significantly correlated with tumor blood vessel content and associated with HNSCC development. Our results elucidate a novel mechanism by which the direct interplay between tumor cells and ECs promotes angiogenesis through MAPK and Notch signaling pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium-Binding Proteins
  • Carcinoma, Squamous Cell / blood supply
  • Carcinoma, Squamous Cell / pathology*
  • Endothelium, Vascular / metabolism*
  • Enzyme Activation
  • Female
  • Head and Neck Neoplasms / blood supply
  • Head and Neck Neoplasms / pathology*
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Jagged-1 Protein
  • Ligands
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, SCID
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasms / blood supply
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Neovascularization, Pathologic / pathology*
  • RNA, Small Interfering / pharmacology
  • Receptors, Cell Surface / metabolism
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • Signal Transduction


  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Ligands
  • Membrane Proteins
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • Mitogen-Activated Protein Kinases