Modulation of signaling between TM4SF5 and integrins in tumor microenvironment

Front Biosci (Landmark Ed). 2011 Jan 1;16:1752-8. doi: 10.2741/3818.


TM4SF5 is a transmembrane glycoprotein of the transmembrane 4 L six family, a branch of the tetraspanin family and highly expressed in many types of cancers. TM4SF5 induces epithelial-mesenchymal transition (EMT) by morphological changes resulting from inactivation of RhoA mediated by stabilized cytosolic p27kip1. TM4SF5-mediated EMT can lead to loss of contact inhibition and enhanced migration/invasion, presumably depending on cross-talks between TM4SF5 and integrins. An anti-TM4SF5 agent appears to target the second extracellular domain of TM4SF5, which is important for cross-talk with integrins, leading to a blockade of TM4SF5-mediated multilayer growth and migration/invasion. In addition, TM4SF5 engages in cross-talk with integrin alpha5 to induce and secrete VEGF, which in turn causes activation of angiogenesis in endothelial cells. Therefore, TM4SF5 plays a central regulatory role in a wide variety of physiological processes through cross-talk with integrins. This review presents current knowledge from in vitro and in vivo observations of the roles of TM4SF5-integrin cooperation in hepatocellular carcinogenesis and discusses important areas for future investigation.

Publication types

  • Review

MeSH terms

  • Actins / metabolism
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chalcone / analogs & derivatives
  • Chalcone / pharmacology
  • Epithelial-Mesenchymal Transition / drug effects
  • Integrins / physiology*
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / drug effects
  • Membrane Proteins / physiology*
  • Neoplasm Invasiveness / physiopathology
  • Neovascularization, Pathologic / chemically induced
  • Sulfonamides / pharmacology
  • Tumor Microenvironment / drug effects


  • 4'-(4-toluenesulfonylamido)-4-hydroxychalcone
  • Actins
  • Integrins
  • Membrane Proteins
  • Sulfonamides
  • TM4SF5 protein, human
  • Chalcone