The junctions of the endothelium consist a major barrier for the extravasation of leukocytes during inflammation as well as for the blood-borne metastasis of tumor cells. We have previously identified junctional adhesion molecule-C (JAM-C), and could demonstrate that JAM-C is expressed at the interendothelial junctions, mediating the transendothelial migration of inflammatory cells in vitro and in vivo. We have recently found that JAM-C regulates endothelial paracellular permeability. In contrast to other transmembrane molecules of the endothelial junctions that act as gatekeepers, JAM-C was identified as the first molecule to mediate an increase in paracellular permeability. JAM-C regulates the activity of the small GTPase Rap1 and thereby the integrity of adherens junctions. JAM-C inhibition in vivo blocks vascular hyperpermeability as well as pathologic angiogenesis. Our current investigations include: a) The importance of JAM-C in leukocyte recruitment in vivo is tested with the use of JAM-C -/- mice, and mice with an endothelial-specific deletion of JAM-C by using several acute inflammation models. b) We found that mouse melanoma cells express JAM-C. JAM-C on melanoma cells and JAM-C on the endothelium were found to mediate the migration of melanoma cells through the endothelium in vitro and thereby melanoma metastasis in vivo. In particular, lung metastasis of melanoma cells injected i.v. was reduced in mice with deletion of JAM-C. Moreover, we generated mice with a conditional JAM-C allele. Endothelial-specific deletion of JAM-C resulted in reduced melanoma cell transmigration in vitro and melanoma cell metastasis to the lung in vivo. Thus, JAM-C contributes to blood-borne melanoma cell metastasis.
| Langer, Harald F; Chavakis, Triantafyllos (2009) Leukocyte-endothelial interactions in inflammation. J Cell Mol Med 13:1211-20 |
| Chavakis, Emmanouil; Choi, Eun Young; Chavakis, Triantafyllos (2009) Novel aspects in the regulation of the leukocyte adhesion cascade. Thromb Haemost 102:191-7 |
| Choi, Eun Young; Santoso, Sentot; Chavakis, Triantafyllos (2009) Mechanisms of neutrophil transendothelial migration. Front Biosci (Landmark Ed) 14:1596-605 |
| Immenschuh, Stephan; Naidu, Srivatsava; Chavakis, Triantafyllos et al. (2009) Transcriptional induction of junctional adhesion molecule-C gene expression in activated T cells. J Leukoc Biol 85:796-803 |
