Cellular membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves C3b, an essential component of the complement system.
Neoplasms have developed numerous strategies to protect themselves against the host immune system. Membrane type-1 matrix metalloproteinase (MT1-MMP) is strongly associated with many cancer types and is up-regulated in the aggressive, metastatic neoplasms. During the past few years, there has been an increasing appreciation of the important, albeit incompletely understood, role of MT1-MMP in cancer. We have discovered, using cell-free and cell-based assays in vitro, that MT1-MMP proteolysis specifically targets C3b, an essential component of the complement propagation pathway. MT1-MMP proteolysis liberates the deposited C3 activation fragments from the cell surface. The shedding of these cell-deposited opsonins by MT1-MMP inhibits the complement cascade and protects breast carcinoma MCF7 cells from direct complement-mediated injury in the in vitro tests. The functional link associating MT1-MMP with the host immune system, heretofore unrecognized, may empower tumors with an escape mechanism that contributes to the protection against the host anti-tumor immunity as well as to the survival of invading and metastatic malignant cells in the bloodstream.
Rozanov
Dmitri V
DV
The Burnham Institute, La Jolla, California 92037, USA.
Savinov
Alexei Y
AY
Golubkov
Vladislav S
VS
Postnova
Tatiana I
TI
Remacle
Albert
A
Tomlinson
Stephen
S
Strongin
Alex Y
AY
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D002474:Cell-Free System; D003179:Complement C3b / Q000378:metabolism*; D015935:Complement C4b / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism / Q000502:physiology*; D009895:Opsonin Proteins / Q000378:metabolism; D011485:Protein Binding; D013997:Time Factors; D014162:Transfection
D009895:Opsonin Proteins; D003179:Complement C3b; D015935:Complement C4b; D003165:Complement System Proteins; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2