Abstract
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.
Highlights
It is well established that the progression of metastatic cancer involves the interplay of the host environment with the malignant cells [1]
We believe that Membrane type-1 matrix metalloproteinase (MT1-MMP) directly contributes to tumor cell immune resistance and is associated with the survival of metastatic cells in the bloodstream
Our in vitro and cell-based data show that MT1-MMP inhibits complement by efficiently releasing the C3b and C4b complement components from tumor cell surfaces
Summary
It is well established that the progression of metastatic cancer involves the interplay of the host environment with the malignant cells [1]. Immunoglobulin-coated targets bind and subsequently activate the complement component C1 This event starts the complement cascade, the propagation of which results in the generation of anaphylatoxins (C3a, C4a, and C5a) and the cytolytic C5b-9 membrane attack complex (MAC)1 [7]. The thioester group forms amide and ester bonds with the target cell surface molecules This binding of C3b and C4b is critical for amplification of the cascade and for MAC formation. An important role for complement resistance of tumor cells is indicated by the fact that many tumor cells overexpress one or more of the cell surface-associated complement regulatory proteins: CD46/MCP, CD55/DAF, and CD59/protectin. MT1-MMP plays an important, albeit insufficiently characterized, role in tissue remodeling and cell motility, and especially in tumor progression, metas-
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