¹Molecular Pathology Unit and MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, MA 02129, USA

²Institut Universitaire de Pathologie, 25 Rue du Bugnon, CH-1011 Lausanne, Switzerland

³Ludwig Institute for Cancer Research, Lausanne Branch, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland

Correspondence to: I Stamenkovic, E-mail: Ivan.Stamenkovic@chuv.hospvd.ch

Shedding of intercellular adhesion molecule 1 (ICAM-1) is believed to play a role in tumor cell resistance to cell-mediated cytotoxicity. However, the mechanism whereby ICAM-1 is shed from the surface of tumor cells remains unclear. In this study, we have addressed the possibility that matrix metalloproteinases are implicated in ICAM-1 shedding. Our observations suggest a functional relationship between ICAM-1 and matrix metalloproteinase 9 (MMP-9) whereby ICAM-1 provides a cell surface docking mechanism for proMMP-9, which, upon activation, proteolytically cleaves the extracellular domain of ICAM-1 leading to its release from the cell surface. MMP-9-dependent shedding of ICAM-1 is found to augment tumor cell resistance to natural killer (NK) cell-mediated cytotoxicity. Taken together, our observations propose a mechanism for ICAM-1 shedding from the cell surface and provide support for MMP involvement in tumor cell evasion of immune surveillance.

Oncogene (2002) 21, 5213-5223. doi:10.1038/sj.onc.1205684

ICAM-1; MMP-9; tumor; proteases; cytotoxicity