Matrix metalloproteinase 9 (MMP-9/gelatinase B) proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicity.
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.
Fiore
Emilio
E
Molecular Pathology Unit and MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, MA 02129, USA.
Fusco
Carlo
C
Romero
Pedro
P
Stamenkovic
Ivan
I
D002448:Cell Adhesion; D024141:Collagen Type IV / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D017931:DNA Primers / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D005780:Gelatin / Q000378:metabolism; D018922:HL-60 Cells / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D015473:Leukemia, Promyelocytic, Acute / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D009154:Mutation; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology
D024141:Collagen Type IV; D017931:DNA Primers; D018799:Intercellular Adhesion Molecule-1; D005780:Gelatin; D020780:Matrix Metalloproteinase 9