The L6 protein TM4SF1 is critical for endothelial cell function and tumor angiogenesis

Cancer Res. 2009 Apr 15;69(8):3272-7. doi: 10.1158/0008-5472.CAN-08-4886. Epub 2009 Apr 7.


Transmembrane-4-L-six-family-1 (TM4SF1) was originally described as a cancer cell protein. Here, we show that it is highly expressed in the vascular endothelium of human cancers and in a banded pattern in the filopodia of cultured endothelial cells (EC). TM4SF1 knockdown prevented filopodia formation, inhibited cell mobility, blocked cytokinesis, and rendered EC senescent. Integrin-alpha5 and integrin-beta1 subunits gave a similar staining pattern and interacted constitutively with TM4SF1, whereas integrin subunits often associated with angiogenesis (alphaV, beta3, beta5) interacted with TM4SF1 only after vascular endothelial growth factor (VEGF)-A or thrombin stimulation. TM4SF1 knockdown substantially inhibited maturation of VEGF-A(164)-induced angiogenesis. Thus, TM4SF1 is a key regulator of EC function in vitro and of pathologic angiogenesis in vivo and is potentially an attractive target for antiangiogenesis therapy.

Publication types

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

MeSH terms

  • Animals
  • Antigens, Surface / biosynthesis*
  • Antigens, Surface / genetics
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology*
  • Humans
  • Integrins / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Neoplasms / blood supply*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • Transfection
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics


  • Antigens, Surface
  • Integrins
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • TM4SF1 protein, human