[Frontiers in Bioscience 16, 1752-1758, January 1, 2011]

Modulation of signaling between TM4SF5 and integrins in tumor microenvironment

Sin-Ae Lee1, Ki Hun Park2, Jung Weon Lee1

1Cell Dynamics Research Center, 1Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, 2Division of Applied Life Science, EB-NCRC, Gyeongsang National University, Jinju 660-701, Korea

TABLE OF CONTENTS

1. Abstract
2. Structure of TM4SF5
3. Functions of TM4SF5
3.1. TM4SF5-mediated actin reorganization
3.2. TM4SF5-mediated epithelial-mesenchymal transition
3.3. TM4SF5-mediated cell proliferation
3.4. TM4SF5-mediated cell migration and invasion
3.5. TM4SF5-mediated angiogenesis
3.6. Cross-talks between TM4SF5 and integrins
3.7. TM4SF5-mediated communication with tumor microenvironment
4. Inhibition of TM4SF5
4.1. TSAHC, an anti-TM4SF5 reagent
4.2. Therapeutic approaches targeting TM4SF5-positive tumor
5. Future perspective
6. Acknowledgements
7. References

1. ABSTRACT

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