Cellular Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) Cleaves C3b, an Essential Component of the Complement System

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. 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. It is well established that the progression of metastatic cancer involves the interplay of the host environment with the malignant cells (1Bissell M.J. Radisky D. Nat. Rev. Cancer. 2001; 1: 46-54Crossref PubMed Scopus (1735) Google Scholar). Neoplasms employ multiple means to sustain themselves and to proliferate in vivo. Evidence has emerged that tumor immunity is an important defense mechanism protecting malignant cells from the host immune surveillance. The host immune system is an apparatus directed against foreign invading organisms and tumor cells (2Morgan B.P. Crit. Rev. Immunol. 1999; 19: 173-198Crossref PubMed Google Scholar, 3Morgan B. Methods Mol. Biol. 2000; 150: 1-13PubMed Google Scholar, 4Liszewski M.K. Farries T.C. Lublin D.M. Rooney I.A. Atkinson J.P. Adv. Immunol. 1996; 61: 201-283Crossref PubMed Google Scholar). Controlled activation of the complement system is a critical component of host immunity. Complement activation products stimulate a localized protective inflammation and are involved in both the inductive and effector phases of an immune response (5Jurianz K. Ziegler S. Garcia-Schuler H. Kraus S. Bohana-Kashtan O. Fishelson Z. Kirschfink M. Mol. Immunol. 1999; 36: 929-939Crossref PubMed Scopus (188) Google Scholar). In many cases malignant cells exhibit antigens that are not typically associated with normal cells. These antigens can be identified by the complement system via antibody recognition and, as a result, the recognized cells are attacked by the immune system (6Dachs G.U. Dougherty G.J. Stratford I.J. Chaplin D.J. Oncol. Res. 1997; 9: 313-325PubMed Google Scholar). The complement system is comprised of soluble proteins that interact in a stepwise manner. Complement can be activated via three different pathways: the classical pathway that is usually antibody-dependent, and the alternative and lectin pathways. In the classical pathway, 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 ultimately the cytolytic C5b-9 membrane attack complex (MAC) 1The abbreviations used are: MAC, membrane attack complex; FBS, fetal bovine serum; HRP, horseradish peroxidase; MMP-2, matrix metalloproteinase-2; MT1-MMP, membrane type-1 matrix metalloproteinase; TIMP-2, tissue inhibitor of metalloproteinases-2; DMEM, Dulbecco's modified Eagle's medium; PMA, phorbol 12-myristate 13-acetate; BSA, bovine serum albumin; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence-activated cell sorter. (7Rus H.G. Niculescu F.I. Shin M.L. Immunol. Rev. 2001; 180: 49-55Crossref PubMed Scopus (108) Google Scholar). In the process of complement propagation, proteolytic cleavage of serum C3 and C4 creates transient soluble C3b and C4b products with an exposed reactive thioester group. Once exposed, 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. Subsequent proteolytic cleavage transforms the cell-bound C3b into the cleavage fragments iC3b, C3dg, and C3d, which remain covalently attached to the cell surface. These C3 fragments serve as ligands for receptors on phagocytic and NK cells. Opsonization of target cells with these C3 fragments promotes and enhances both antibody-dependent and complement-dependent cell cytotoxicity, two additional effector systems that play an important role in the elimination of neoplastic cells (8Delibrias C. Fischer E. Kazachtkine M. Rother K. Till G.O. Haensch G.M. The Complement System. 2nd Ed. Springer-Verlag, Berlin1997: 211-220Google Scholar, 9Cole D.S. Morgan B.P. Clin. Sci. (Lond.). 2003; 104: 455-466Crossref PubMed Scopus (155) Google Scholar). The deposition of C3b and C4b and the follow-up amplification of the complement cascade also results in the generation of soluble bioactive C3a and C5a peptides that may potentiate anti-tumor responses via their chemoattractant and proinflammatory activities. Thus, the inactivation of C3b and C4b and their removal from a cell surface represents an important immune evasion mechanism of tumor cells. 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. These regulatory proteins act at different stages of the complement propagation (10Caragine T.A. Okada N. Frey A.B. Tomlinson S. Cancer Res. 2002; 62: 1110-1115PubMed Google Scholar, 11Gorter A. Meri S. Immunol. Today. 1999; 20: 576-582Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 12Morgan B.P. Harris C.L. Complement Regulatory Proteins. Academic Press, San Diego1999Google Scholar, 13Carroll M.C. Fischer M.B. Curr. Opin. Immunol. 1997; 9: 64-69Crossref PubMed Scopus (83) Google Scholar). In addition to the cell-associated regulatory proteins, some tumor cells bind serum complement inhibitory proteins (14Fedarko N.S. Jain A. Karadag A. Van Eman M.R. Fisher L.W. Clin. Cancer Res. 2001; 7: 4060-4066PubMed Google Scholar, 15Fedarko N.S. Fohr B. Robey P.G. Young M.F. Fisher L.W. J. Biol. Chem. 2000; 275: 16666-16672Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar), express proteases to clear the C3b protein from the cell surface, and inhibit the complement cascade (16Jean D. Hermann J. Rodrigues-Lima F. Barel M. Balbo M. Frade R. Biochem. J. 1995; 312: 961-969Crossref PubMed Scopus (28) Google Scholar, 17Jean D. Bar-Eli M. Huang S. Xie K. Rodrigues-Lima F. Hermann J. Frade R. Cancer Res. 1996; 56: 254-258PubMed Google Scholar, 18Jurianz K. Ziegler S. Donin N. Fishelson Z. Kirschfink M. Mol. Immunol. 1999; 36: 316Crossref Scopus (176) Google Scholar). Membrane type-1 matrix metalloproteinase (MT1-MMP) is the most common protease from the membrane-tethered enzyme subfamily of MMPs (19Egeblad M. Werb Z. Nat. Rev. Cancer. 2002; 2: 161-174Crossref PubMed Scopus (5134) Google Scholar). MT1-MMP plays an important, albeit insufficiently characterized, role in tissue remodeling and cell motility, and especially in tumor progression, metastasis, and angiogenesis (20Hotary K.B. Allen E.D. Brooks P.C. Datta N.S. Long M.W. Weiss S.J. Cell. 2003; 114: 33-45Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar, 21Hotary K. Allen E. Punturieri A. Yana I. Weiss S.J. J. Cell Biol. 2000; 149: 1309-1323Crossref PubMed Scopus (510) Google Scholar). MT1-MMP is a cell surface activator of soluble pro-MMP-2 and pro-MMP-13 and has also been implicated in matrix proteolysis and turnover as well as in the proteolytic processing of cell surface-associated adhesion and signaling receptors (19Egeblad M. Werb Z. Nat. Rev. Cancer. 2002; 2: 161-174Crossref PubMed Scopus (5134) Google Scholar, 22Murphy G. Stanton H. Cowell S. Butler G. Knauper V. Atkinson S. Gavrilovic J. Acta Pathol. Microbiol. Immunol. Scand. 1999; 107: 38-44Crossref PubMed Scopus (391) Google Scholar, 23Sounni N.E. Devy L. Hajitou A. Frankenne F. Munaut C. Gilles C. Deroanne C. Thompson E.W. Foidart J.M. Noel A. FASEB J. 2002; 16: 555-564Crossref PubMed Scopus (241) Google Scholar). Although MT1-MMP is detectable in normal tissue, the expression of protease is strongly associated with aggressive, malignant cells (19Egeblad M. Werb Z. Nat. Rev. Cancer. 2002; 2: 161-174Crossref PubMed Scopus (5134) Google Scholar, H. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). a and of MT1-MMP in the proteolysis of the complement C3b and This proteolysis inhibits complement activation in cell-based We that MT1-MMP is to malignant cells more to complement-mediated in vivo. that of MT1-MMP is involved in the of C3b from the tumor cell surface, and is to to the survival and propagation of malignant cells. We that the proteolysis of the complement by MT1-MMP is a and mechanism by malignant cells to protect themselves against host immune and and from C3b, iC3b, and C3 and C4 normal and serum from antibody against C3b from and from antibody against the of MT1-MMP, the and and inhibitor of from antibody and antibody are as R. V. J. PubMed Scopus Google Scholar, A. S. J. Meri S. J. Pathol. 1996; Google Scholar). antibody from The of MT1-MMP in from the and to as B. E. J. G. D. A. Biochem. 2000; PubMed Scopus Google Scholar). against the breast carcinoma MCF7 cell by and, used to MCF7 cells to antibody against the of MT1-MMP in Cell breast carcinoma MCF7 cells with the and the MT1-MMP and in J.P. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). which MT1-MMP and from cells in Dulbecco's modified Eagle's with fetal bovine serum and breast carcinoma and cells in with and and by MT1-MMP and pro-MMP-2 from a of cells from an cell with the and I. G. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). and cells cells for in with pro-MMP-2 of cells in indicated to the cells. of by the cells by and and cells in to the cells. for cells with and surface with to the cells with and with in with and protease inhibitor and of and The with The of cell of protein with an MT1-MMP antibody and and at immune by the for in proteins to and J.P. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). MT1-MMP of C3b and C4b in C3b and C4b with at in of to the to MT1-MMP The cleavage by in by with C3 and C4 in with and and the MT1-MMP of the Cell C3b and C4b in MCF7 and cells cells for in in of a The cells by for at in serum The cell in which with serum used as cells for at in or serum to the deposition of the C3b and C4b the cell surface. cells for or at for in to the proteolytic shedding and the of the cell-bound C3b and C4b into the to to The of cell surface-associated C3b and C4b by and the cells by an and for at with the antibody against C3b by for with an in with and removal of cells in with BSA, and cells on a with the cells for cells for at in of and to in and with C3 and C4 in with and and the C3b from the cell surface by proteolytic shedding and into the identified by of the these and cells cells for at with serum to deposition of C3b on cell by cells with of to the cells. for to the cell-bound C3b, the of for a of the with the cells to of the of of a with C3 antibody and with to bind for at with the The C3b with C3 by and the The of the at of the Complement Regulatory used to the cell surface expression of complement regulatory proteins and in and cells. these cells by the and with the antibody by with antibody by using cells with normal on a and cells in in of a MCF7 with the cells for at The cells for at in normal serum to the activation of the complement pathway and of the cells by the membrane attack The with serum in The of the cell by using a in with the The of the complement also by and cells cells in in of an serum with the cells for at The cells for at in normal serum and with for at and cells with using a and the by a with a and of by cells with the from by and using the modified in J. J. Biol. Chem. Full Text PDF PubMed Google with using the and from by the of Cell of cell-bound TIMP-2, cells cells well of a to assays with with and, with with and of to the cells. a at cells with with and BSA, and in the The binding using a of of well of used to the of cells. in used to the and the of and from the cells with a by on a and to a membrane The membrane with the MT1-MMP and with the of breast carcinoma MCF7 cells for the cells are in MT1-MMP and J.P. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). used MCF7 cells with the MT1-MMP as well as cells with the by MT1-MMP and to that the cells exhibit of MT1-MMP, MT1-MMP protease in and cells. cells MT1-MMP and The of the activation of and the of of the into the and into the enzyme used as of the cell surface-associated MT1-MMP to the of MCF7 cells in these assays with pro-MMP-2 in that to by cells. the activation of MMP-2, cells with R. Biochem. J. 2003; PubMed Scopus Google Scholar, S. M. M. R. Cancer Biol. 2002; PubMed Scopus Google Scholar). that the of activation by the cells is to that of cells of cell surface-associated MT1-MMP in these two cell these identified the of cell surface-associated MT1-MMP in and cells. these cells with and cell surface-associated MT1-MMP from cell and by with These that cell MT1-MMP in and cells. In cells exhibit of the forms of the the of the MT1-MMP in cells. The of these and of MT1-MMP is in with J.P. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google and the results by S. M. M. R. Cancer Biol. 2002; PubMed Scopus Google Scholar). these which well with of the activation of the MT1-MMP in and cells. these by the of the MT1-MMP in cells with in breast carcinoma and MCF7 cells In with the of that not the expression of the MT1-MMP protein in cells not detectable of the MT1-MMP in cell In the of the MT1-MMP in cells in cells and with the of the identified in cells. these identified the of the MT1-MMP cell surface in and cells. these the cells with increasing of An of the binding of the inhibitor with the cells. inhibitor of of with the not with and to the cells and the in cell of binding the of binding with and cell cells MT1-MMP and These well with the of the MT1-MMP identified by in and cells The from also are in with results J. A. Mol. Cancer Res. 2003; 1: Google Scholar, S. M. C. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, identified that the of MT1-MMP expression in cells are to in carcinoma breast carcinoma and cells J. A. Mol. Cancer Res. 2003; 1: Google Scholar). We from these and the from the that the of MT1-MMP in the breast carcinoma MCF7 cell are with in cells as well as in numerous cell types breast carcinoma and cells. the of MT1-MMP on the complement system with the MCF7 cells are to many cell systems in which membrane protease is and activated MT1-MMP C3b in and have the of cell C3b to proteases (16Jean D. Hermann J. Rodrigues-Lima F. Barel M. Balbo M. Frade R. Biochem. J. 1995; 312: 961-969Crossref PubMed Scopus (28) Google Scholar, 17Jean D. Bar-Eli M. Huang S. Xie K. Rodrigues-Lima F. Hermann J. Frade R. Cancer Res. 1996; 56: 254-258PubMed Google Scholar, 18Jurianz K. Ziegler S. Donin N. Fishelson Z. Kirschfink M. Mol. Immunol. 1999; 36: 316Crossref Scopus (176) Google Scholar). these and to the complement C3b, iC3b, and C4b are to MT1-MMP these of complement with increasing of the of MT1-MMP and the by C4b and, especially C3b and iC3b, by of cleavage fragments in the cleavage The of both C3 and C4 especially to MT1-MMP proteolysis in vitro inhibitor of MT1-MMP proteolysis of C3b, iC3b, and MT1-MMP the complement deposited on a tumor cell surface, proteolytic assays using complement and cells. activate complement and C3b and C4b on the cell surface, the cells with and for in cell MT1-MMP to the deposited C3b and The of cell-associated C3b and C4b by and that cells not cells the of cell surface-associated C4b and, C3b In the of the cells with an antibody to the C3b by the that the MT1-MMP the of the cell C3b in cells. The of the of soluble C3 fragments in the by cells to of cells. the of C3 by cells of cells with in a of C3 from the cell for also that and which are to by are involved in shedding the of the cell-bound MCF7 cells by with serum or for with serum to stimulate deposition of of cells for the indicated in used to stimulate C3b The of the cell surface-associated C3b identified by FACS, the C3b in the by of the of the cells. to the cells. of the soluble C3b from the surface of MCF7 cells. The as and The results of a in are The results of three additional The a the the MT1-MMP and C3b in more the of deposition of C3b on and cells. these cells with serum for different of and the deposition of C3b by that in the deposition of C3b on cells on These well with the of N. L. D. C. Bar-Eli M. Frade R. Cancer Res. PubMed Scopus Google Scholar, R. Rodrigues-Lima F. Huang S. Xie K. N. Bar-Eli M. Cancer Res. Google the of the protease on the deposition of C3b on cell that MT1-MMP inhibits complement activation by cell C3b and C4b from a tumor cell with the of their soluble forms into the MT1-MMP from the functional role of MT1-MMP in protecting MCF7 cells from the complement-mediated a In complement-mediated by the of the from the cells. results indicated that the of a a of and cells with complement and for an additional The by complement in cells. These well with the a of complement an Shin M.L. J. Immunol. Google Scholar, M.W. R. Cancer Res. Google Scholar). these and cells by that cells not with cells to complement-mediated We also cells with and to the cells with a of cells with In a few of the cells in The of in these cell the of and the by Thus, the in cells to that in cells. of cells with of the cells not the We that in cell MT1-MMP protects tumor cells against complement activation and by the MT1-MMP the of the Complement Regulatory cells are to themselves against the complement by the complement regulatory proteins and (10Caragine T.A. Okada N. Frey A.B. Tomlinson S. Cancer Res. 2002; 62: 1110-1115PubMed Google Scholar, 11Gorter A. Meri S. Immunol. Today. 1999; 20: 576-582Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, K. S. Garcia-Schuler H. Fishelson Z. Kirschfink M. 1999; PubMed Scopus Google Scholar). is not by MCF7 cells J. S. Morgan B.P. Frey A.B. Tomlinson S. Clin. Immunol. 1999; PubMed Scopus Google Scholar). We used to the expression of and in and cells. the expression of MT1-MMP and expression of or Thus, the that expression of the complement regulatory proteins the resistance of cells to these the role of MT1-MMP in malignant cells against surface expression of the complement regulatory proteins in breast carcinoma in a We that MT1-MMP contributes to tumor cell immune resistance and is associated with the survival of metastatic cells in the bloodstream. The survival of cells in strongly in vitro and cell-based that MT1-MMP inhibits complement by the C3b and C4b complement from tumor cell Sci. S. A. PubMed Scopus Google has also by using that C3 is a target of MT1-MMP results the and link associating MT1-MMP with and the mechanism and the of the MT1-MMP with the of MT1-MMP is a proteolytic defense The MT1-MMP enzyme plays a of important in with malignant cells. is a of MT1-MMP expression with the of many cancer cell types (19Egeblad M. Werb Z. Nat. Rev. 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In with cells into and metastatic cells N. L. D. C. Bar-Eli M. Frade R. Cancer Res. PubMed Scopus Google Scholar, R. Rodrigues-Lima F. Huang S. Xie K. N. Bar-Eli M. Cancer Res. Google Scholar). In a expression of inhibitor of complement the in deposition of complement C3 fragments and the of MCF7 cells. In the expression of inhibitor of the cytolytic membrane attack on the and of MCF7 tumor in (10Caragine T.A. Okada N. Frey A.B. Tomlinson S. Cancer Res. 2002; 62: 1110-1115PubMed Google Scholar). The of C3b deposition is important in tumor immunity C3b and cleavage fragments on the cell surface serve as receptors for immune effector cells. Thus, in a tumor the deposition of C3b of cells by (8Delibrias C. Fischer E. Kazachtkine M. Rother K. Till G.O. Haensch G.M. The Complement System. 2nd Ed. Springer-Verlag, Berlin1997: 211-220Google Scholar, S. J. Immunol. Google Scholar). well with these and that the of C3b and C4b deposition by MT1-MMP is to malignant cells to host immune and to more as tumors and as are that antibody-dependent by complement is a mechanism to tumor J. Biol. 2002; Google Scholar). proteolysis of C3b and C4b is an important in tumor immunity. It is well established that normal cells a of the complement regulatory proteins to and activation of the complement system. These soluble and proteins are by malignant cells to escape complement attack A. Meri S. Immunol. Today. 1999; 20: 576-582Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 12Morgan B.P. Harris C.L. Complement Regulatory Proteins. Academic Press, San Diego1999Google Scholar). We to MT1-MMP expression with the of the complement regulatory and We that MT1-MMP inhibits This well with the that indicated the of the regulatory that are used by tumor cells to escape immune These are additional to the the and complement regulatory proteins B.P. Harris C.L. Complement Regulatory Proteins. Academic Press, San Diego1999Google Scholar, J. S. Morgan B.P. Frey A.B. Tomlinson S. Clin. Immunol. 1999; PubMed Scopus Google Scholar). We that have identified a mechanism that involves MT1-MMP in tumor immunity and have on the important role that protease plays in with invading metastatic malignant cells. additional The the expression of MT1-MMP in tumor cell by tumor in the role of MT1-MMP in the tumor defense