Melanoma Chondroitin Sulfate Proteoglycan Regulates Matrix Metalloproteinase-dependent Human Melanoma Invasion into Type I Collagen

Tumor cell adhesion and proteolysis of the extracellular matrix proteins surrounding the cells are tightly linked processes in tumor invasion. In this study, we sought to identify components of the cell surface of a vertical growth phase melanoma cell line, WM1341D, that mediate invasive cellular behavior. We determined by antisense inhibition that melanoma chondroitin sulfate proteoglycan (MCSP) and membrane-type 3 matrix metalloproteinase (MT3-MMP) expressed on WM1341D are required for invasion of type I collagen and degradation of type I gelatin. MT3-MMP co-immunoprecipitated with MCSP in WM1341D melanoma cells cultured on type I collagen or laminin. The association between MT3-MMP and MCSP was largely disrupted by removing chondroitin sulfate glycosaminoglycan (CS) from the cell surface, suggesting CS could mediate the association between the two cell surface core proteins. Recombinant MT3-MMP and MT3-MMP from whole cell lysates of WM1341D cells were specifically eluted from CS- conjugated affinity columns. The results indicate that MT3-MMP possesses the potential to promote melanoma invasion and proteolysis and that the formation of a complex between MT3-MMP and MCSP may be a crucial step in activating these processes. Tumor cell adhesion and proteolysis of the extracellular matrix proteins surrounding the cells are tightly linked processes in tumor invasion. In this study, we sought to identify components of the cell surface of a vertical growth phase melanoma cell line, WM1341D, that mediate invasive cellular behavior. We determined by antisense inhibition that melanoma chondroitin sulfate proteoglycan (MCSP) and membrane-type 3 matrix metalloproteinase (MT3-MMP) expressed on WM1341D are required for invasion of type I collagen and degradation of type I gelatin. MT3-MMP co-immunoprecipitated with MCSP in WM1341D melanoma cells cultured on type I collagen or laminin. The association between MT3-MMP and MCSP was largely disrupted by removing chondroitin sulfate glycosaminoglycan (CS) from the cell surface, suggesting CS could mediate the association between the two cell surface core proteins. Recombinant MT3-MMP and MT3-MMP from whole cell lysates of WM1341D cells were specifically eluted from CS- conjugated affinity columns. The results indicate that MT3-MMP possesses the potential to promote melanoma invasion and proteolysis and that the formation of a complex between MT3-MMP and MCSP may be a crucial step in activating these processes. extracellular matrix vertical growth phase matrix metalloproteinase membrane-type matrix metalloproteinase tissue inhibitor of matrix metalloproteinases melanoma chondroitin sulfate proteoglycan chondroitin sulfate glycosaminoglycan βDX, α/β-d-xylopyranoside a disintegrin and metalloprotease fetal calf serum monoclonal antibody base pair(s) fluorescence-activated cell sorting phosphate-buffered saline bovine serum albumin N-ethylmaleimide phenylmethylsulfonyl fluoride horseradish peroxidase N-hydroxysuccinimide Cell adhesion and degradation of ECM1 proteins are tightly linked processes in tumor invasion and metastasis (1Mueller B.M. Attempts to Understand Metastasis Formation. 213 (part 1). Springer, New York1996: 65-80Google Scholar). Melanoma progression from radial growth phase to vertical growth phase (VGP) is characterized in part by enhanced invasion into the surrounding dermis (2Herlyn M Tumor Progression in the Melanocytic System. R. G. Landes Company, Georgetown1993Google Scholar). Invasion requires that tumor cells bind to and degrade ECM components within the dermal/epidermal junction (i.e. basal lamina containing type IV collagen) and the dermis (rich in types I and III collagen). Many studies have documented the importance of adhesion receptors such as integrins and cell surface proteoglycans in melanoma cell invasion through basement membrane or into type I collagen matrices in vitro (3Etoh T. Byers H.R. Mihm Jr., M.C. J. Dermatol. 1992; 19: 841-846Crossref PubMed Scopus (34) Google Scholar, 4Faassen A.E. Schrager J.A. Klein D.J. Oegema T.R. Couchman J.R. McCarthy J.B. J. Cell Biol. 1992; 116: 521-531Crossref PubMed Scopus (237) Google Scholar, 5Knutson J.R. Iida J. Fields G.B. McCarthy J.B. Mol. Biol. Cell. 1996; 7: 383-396Crossref PubMed Scopus (128) Google Scholar, 6Yoshinaga I.G. Vink J. Dekker S.K. Mihm M.C.J. Byers H.R. Melanoma Res. 1993; 3: 435-441Crossref PubMed Scopus (53) Google Scholar, 7Schon M. Schon M.P. Kuhrber A. Schirmbeck R. Kaufmann R. Klein C.E. J. Invest Dermatol. 1996; 106: 1175-1181Abstract Full Text PDF PubMed Scopus (13) Google Scholar). Furthermore, it has also been demonstrated that certain cell adhesion receptors (e.g.αvβ3 integrin and CD44) interact with proteolytic enzymes on cell surfaces, and these interactions facilitate proteolysis of ECM proteins and cell migration and/or invasion (8Wei Y. Lukashev M. Simon D.I. Bodary S.C. Rosenberg S. Doyle M.V. Chapman H.A. Science. 1996; 273: 1551-1555Crossref PubMed Scopus (697) Google Scholar, 9Brooks P.C. Stromblad S. Sanders L.C. von Schalscha T.L. Aimes R.T. Stetler-Stevenson W.G. Quigley J.P. Cheresh D.A. Cell. 1996; 85: 683-693Abstract Full Text Full Text PDF PubMed Scopus (1431) Google Scholar, 10Brooks P.C. Silletti S. von Schalscha T.L. Friedlaner M. Cheresh D.A. Cell. 1998; 92: 391-400Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 11Yu Q. Stamenkovic I. Genes Dev. 1999; 13: 35-48Crossref PubMed Scopus (607) Google Scholar). It has been proposed that at least one consequence of integrin/protease interaction on the surface of tumors may be to focus the delivery of extracellular matrix-degrading proteases, allowing for the fine control of ECM degradation and tumor invasion. Melanoma chondroitin sulfate proteoglycan (MCSP) is a cell surface proteoglycan expressed relatively early in melanoma progression (12Reisfeld R.A. Cheresh D.A. Adv. Immunol. 1987; 40: 323-377Crossref PubMed Scopus (103) Google Scholar), and MCSP has been implicated in the malignant properties of advanced melanoma. Melanoma adhesion to endothelial cells and chemotactic responses to fibronectin are inhibited by monoclonal antibodies directed against the MCSP core protein (13De Vries J.E. Keizer G.D. Te Velde A.A. Voordouw A. Ruiter D. Rumke P. Spits H. Figdor C.G. Int. J. Cancer. 1986; 38: 465-473Crossref PubMed Scopus (81) Google Scholar), and MCSP has been associated with melanoma invasion in vitro (14Chattopadhyay P. Starky J. Morrow W.J. Raychaudhuri S. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2684-2688Crossref PubMed Scopus (35) Google Scholar). Furthermore, recent studies demonstrate that mouse melanoma cells transfected with NG2 (the rat homologue of are and control in J. Cell. 1998; PubMed Scopus Google Scholar). the by MCSP may facilitate metastasis are we have demonstrated that MCSP by and MCSP cell by and that MCSP for tumor adhesion and J. McCarthy J.B. J. Cell Biol. 1992; PubMed Scopus Google Scholar, J. Oegema McCarthy J.B. J. Biol. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, McCarthy Iida J. Cell Biol. 1999; PubMed Scopus Google Scholar). MCSP may be at in tumor through to melanoma invasion and matrix metalloproteinases a of metalloproteinases that proteolysis of ECM proteins at the membrane H. Y. M. PubMed Scopus (103) Google Scholar). degrade ECM proteins (i.e. and and on the cell The of within the membrane in to promote tumor invasion H. Y. M. PubMed Scopus (103) Google Scholar). is expressed in with that are or tumors Y. H. H. T. Y. M. M. J. 1998; PubMed Scopus Google Scholar, C.G. M. M. P. Google Scholar, H. H. M. M. H. M. Y. Res. Google Scholar, M. H. J. H. M. Y. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, H. H. T. M. H. M. Y. Res. 1999; Google Scholar). Furthermore, of tumor cell invasion through basement and it has been within adhesion H. T. Y. J. A. M. PubMed Scopus Google H. H. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). has been to degrade type I collagen and to and H. A. H. R. G. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), that it may facilitate tumor invasion by on a could facilitate the degradation of and collagen in the of studies that and are expressed at the at the invasive of T. M. J. U. J. Cancer. 1999; PubMed Scopus Google Scholar), suggesting these enzymes may be linked in melanoma progression and invasion into surrounding a type has been in malignant melanoma cells T. H. A. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google in or cells H. H. M. M. H. M. Y. Res. Google Scholar, H. H. T. M. H. M. Y. Res. 1999; Google Scholar). MT3-MMP ECM it is relatively at type I collagen T. H. Y. Y. H. M. Y. J. 1999; PubMed Scopus Google Scholar). The potential of MT3-MMP in tumor invasion and proteolysis has been In this study, we have antisense inhibition to demonstrate that MCSP and MT3-MMP are for the invasion of WM1341D melanoma cells into type I collagen in was to identify association between MCSP and MT3-MMP through chondroitin sulfate Recombinant MT3-MMP was to bind to CS affinity suggesting that MCSP may specifically MT3-MMP to ECM adhesion on the surface of melanoma of cell surface CS in type I collagen degradation by tumor results that MCSP may facilitate the invasion of tumors within the dermis by the and/or of at of between melanoma cells and the The vertical growth phase (VGP) melanoma cell WM1341D was in with M. Cell Scholar, H. Res. 1993; Google Scholar, M. Metastasis PubMed Scopus Google Scholar). cells were from the and cultured in with type I collagen was from was from was from was from and were from and were from I collagen of was from affinity and a were from monoclonal antibody was by R.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). and were from was by of P.C. J. 1996; Google Scholar). was from antibody and antibody were from antibody was in as T. J. A. D. J. PubMed Scopus Google Scholar). The of and antibodies were determined by and cells transfected with or was from MT3-MMP was in T. J. A. D. J. PubMed Scopus Google Scholar). The was and in antisense into Melanoma cells were transfected with this to were by in the of and characterized for MT3-MMP by antibodies in for MCSP were on G. M. A. T. P. P. R.A. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). MCSP and MCSP were by the of were with melanoma cells as MCSP on melanoma melanoma cells were cultured with or antisense MCSP for with to and were The of antisense MCSP on of the was by of and integrins was by as J.R. Iida J. Fields G.B. McCarthy J.B. Mol. Biol. Cell. 1996; 7: 383-396Crossref PubMed Scopus (128) Google Scholar). of of cell were with for at with of were with the containing and and with of at for The of the and the were these were with the and in of containing were on a were in with as J.R. Iida J. Fields G.B. McCarthy J.B. Mol. Biol. Cell. 1996; 7: 383-396Crossref PubMed Scopus (128) Google Scholar). Melanoma cells were and in at a of of the were with containing of rat type I of were to the with or or in were for at are as of cells cells from one melanoma cell invasion was type I collagen in with type I collagen was in to a of of the was in the of by at for were with WM1341D cells were by with with and in at a of to the of melanoma cells The cell was in the of The were with of containing fibronectin as The were for at melanoma cell or were to the cell and the collagen were with and cells were from the of the cells were and by from one was in and results are expressed as from one Cell adhesion were as with J. McCarthy J.B. J. Cell Biol. 1992; PubMed Scopus Google Scholar). type I collagen was in and were in into The were at and with of containing melanoma cells with were with The cells were two with containing and and to a of in the of of the cell were into the and the cells were at for were by and cells from the determined in a was to the of cells that were a of were with I collagen and with Melanoma cells were by with and in at a of of cell were in and for at Cell were and to cell to type I was in of these of was into by suggesting that a part of type I collagen is as gelatin. We these to be type I degradation or was in the cell We these with Melanoma cells were cultured in on with type I were with and with of in for at were and in containing and Cell lysates were by protein and with antibodies J. Oegema McCarthy J.B. J. Biol. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). were by to membrane and with horseradish peroxidase by enhanced cells were with and in containing Cell lysates were and with monoclonal antibodies against MCSP integrin or integrin The were with antibody by and by Melanoma cells were cultured in containing on with type I Cell lysates as were with were with and proteins were in of containing for at and in of containing proteins were with control or The were with containing and with proteins on the were with for at is with The were with to and in to the proteins from the proteins were with and CS affinity were as J. Oegema McCarthy J.B. J. Biol. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). melanoma cell lysates were as for on a and to a CS affinity The was at and with the proteins were eluted with containing of eluted protein were and as proteins were with antibody and MT3-MMP was as cells were transfected with MT3-MMP as T. J. A. D. J. PubMed Scopus Google Scholar). were in containing and and with affinity at were with and proteins were eluted with containing The eluted MT3-MMP was with of CS or as for at The were in MT3-MMP was in and with and melanoma cells the dermis in as a to this in we the and invasion of WM1341D melanoma cells on type I on the of antibodies in adhesion or migration adhesion and migration to type I collagen was determined to on integrin to a on integrin antibodies on melanoma cell adhesion or migration to type I collagen The invasion of cells through type I collagen was on with of of integrins in WM1341D melanoma and invasion into type by monoclonal cell and invasion of type collagen was in the of monoclonal antibodies and as Melanoma cell and invasion of type collagen was in the of monoclonal antibodies and as in a We that cell surface chondroitin sulfate proteoglycans facilitate melanoma invasion into type I collagen and/or basement membrane matrices in vitro A.E. Schrager J.A. Klein D.J. Oegema T.R. Couchman J.R. McCarthy J.B. J. Cell Biol. 1992; 116: 521-531Crossref PubMed Scopus (237) Google Scholar, 5Knutson J.R. Iida J. Fields G.B. McCarthy J.B. Mol. Biol. Cell. 1996; 7: 383-396Crossref PubMed Scopus (128) Google Scholar). WM1341D melanoma cells two cell surface chondroitin sulfate proteoglycan core proteins and CD44) as by MCSP and have been implicated in melanoma antibodies against of these cell surface proteoglycans invasion J.R. Iida J. Fields G.B. McCarthy J.B. Mol. Biol. Cell. 1996; 7: 383-396Crossref PubMed Scopus (128) Google Scholar, P. Starky J. Morrow W.J. Raychaudhuri S. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2684-2688Crossref PubMed Scopus (35) Google Scholar). the importance of MCSP in the invasion of WM1341D we antisense to specifically of the MCSP core Melanoma cells cultured in the of or antisense MCSP to the of were by for cell surface of MCSP and the integrin of MCSP was inhibited by the antisense by the MCSP and or antisense MCSP a on the of WM1341D melanoma cells in tissue and on type I collagen were as by antisense MCSP of integrin the WM1341D melanoma cell adhesion or migration to type I collagen that integrin is specifically WM1341D melanoma cell invasion into type I WM1341D melanoma cells were cultured for in the or of MCSP antisense or cells were and for to type I migration were in with collagen in the at as a were for in the of WM1341D melanoma cells were for invasive in with type I were at for in the of are as of cells two WM1341D melanoma cells with antisense MCSP were for invasive MCSP invasion of type I collagen as with control or MCSP melanoma cells suggesting that MCSP core is for melanoma invasion into type I Furthermore, MCSP to be specifically in invasive potential of the on adhesion or migration to this the for chondroitin sulfate glycosaminoglycan (CS) in WM1341D melanoma invasion into type I melanoma cells were with or to CS from the cell these the or type of integrins on the cell surface was of CS by with 3 or by to cell surface core proteins with 3 inhibited melanoma invasion into type I collagen to control was the antisense MCSP melanoma CS was required for adhesion or migration on type I collagen as with melanoma results indicate that cell surface chondroitin sulfate proteoglycans a in WM1341D melanoma invasion into type I metalloproteinases have been to mediate melanoma invasion (1Mueller B.M. Attempts to Understand Metastasis Formation. 213 (part 1). Springer, New York1996: 65-80Google Scholar), we the potential of in WM1341D collagen invasion by a Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). inhibited invasion of type I collagen by melanoma cells identify potential in this we also tissue inhibitor of and for to invasion A.E. Stetler-Stevenson W.G. Cell Biol. 1996; PubMed Scopus Google Scholar). Melanoma invasion into type I collagen was inhibited by by The of these that the invasion of WM1341D cells into collagen may be by a membrane type expressed on WM1341D melanoma cell We melanoma cells for surface of Melanoma cells were and cell lysates were with antibodies against or The of the antibodies for was by from cells transfected with the in WM1341D cells expressed MT3-MMP on the cell were and or were at by this MT3-MMP is required for melanoma invasion of type I we transfected WM1341D cells with a antisense for and MT3-MMP antisense were and cell lysates were with of the antisense inhibited of MT3-MMP at the cell surface Furthermore, the of MT3-MMP melanoma invasion into type I collagen of MT3-MMP melanoma cell adhesion and migration on type I collagen MT3-MMP expressed on melanoma cells melanoma invasion of type I MT3-MMP has been to degrade ECM type I T. H. Y. Y. H. M. Y. J. 1999; PubMed Scopus Google Scholar). We that MT3-MMP expressed on melanoma cells could be invasion of the cells by or type I (the of collagen). We of WM1341D cells and or antisense MT3-MMP proteolytic control that MT3-MMP is for the of these melanoma cells the that proteolysis of type I collagen is by and were as for degradation of type I gelatin. was for tumor and inhibited melanoma degradation of type I gelatin. results are with for MT3-MMP in proteolysis of type I collagen required for invasion of a MCSP was also required for invasion of type I we of type WM1341D cells in the or of and antisense MCSP MCSP inhibited degradation of type I in this to the that MCSP may be required to mediate MT3-MMP proteolysis of type I CS this we for of type WM1341D cells in the or of and to CS βDX, inhibited of I inhibited MT3-MMP on the melanoma cell surface collagen invasion and proteolysis may by association with MT3-MMP through CS at the melanoma cell identify potential interactions between MT3-MMP and cell surface lysates from WM1341D melanoma cells cultured on type I collagen were with against adhesion MCSP integrins and The proteins were by with MT3-MMP was to with integrin MT3-MMP was co-immunoprecipitated with integrin a cell lysates from melanoma cells cultured on were also with and integrin these MT3-MMP is with and in with with integrin demonstrate the of the interaction between MT3-MMP and we Cell lysates from WM1341D cells cultured on type I collagen were with and were and with or integrin were and with this MCSP was to with MT3-MMP a interaction between MT3-MMP and We the importance of CS for this The inhibition of CS by the association of MCSP with MT3-MMP in that CS on the MCSP core protein is a of MT3-MMP interact with we affinity with CS on J. Oegema McCarthy J.B. J. Biol. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). melanoma cell surface proteins were to a as proteins and were in of the CS affinity in of the antibody specifically a protein from the of the CS The of MT3-MMP is with the T. H. A. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). the protein with this suggesting that the protein is from Recombinant MT3-MMP from transfected cells was also for to interact with protein as a at as by The protein is also by antibody with antibodies in the of was with or was and to to the studies demonstrate that MT3-MMP with CS and this interaction may be required for WM1341D melanoma invasion and proteolysis of type I Cell adhesion and proteolysis are tightly linked processes in the migration and invasion of and Cell surface adhesion receptors bind to proteolytic enzymes in degradation of the extracellular The interaction of with integrin was the such P.C. Stromblad S. Sanders L.C. von Schalscha T.L. Aimes R.T. Stetler-Stevenson W.G. Quigley J.P. Cheresh D.A. Cell. 1996; 85: 683-693Abstract Full Text Full Text PDF PubMed Scopus (1431) Google Scholar, 10Brooks P.C. Silletti S. von Schalscha T.L. Friedlaner M. Cheresh D.A. Cell. 1998; 92: 391-400Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar). of by integrin is to a by tumor cells focus and within adhesion in the of the cell it has been that with to enhanced tumor invasion and Q. Stamenkovic I. Genes Dev. 1999; 13: 35-48Crossref PubMed Scopus (607) Google Scholar). to a cell surface that has also been with integrin to on cells (8Wei Y. Lukashev M. Simon D.I. Bodary S.C. Rosenberg S. Doyle M.V. Chapman H.A. Science. 1996; 273: 1551-1555Crossref PubMed Scopus (697) Google Scholar). proteases, interact with integrins and the of integrins on or cells D. A. G. J. Cell Sci. PubMed Google Scholar, R. A. T. R. J. Cell Biol. PubMed Scopus Google Scholar, D. A. Y. J. Biol. 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The of to cell migration may be studies are required to the for such MCSP interaction with MT3-MMP in WM1341D cells requires the of chondroitin sulfate that with the of the MCSP core protein or with the of CS the core protein invasion and proteolysis of type I collagen in degradation of the core protein or the CS has on the adhesion of these cells to type I collagen is the of MT3-MMP inhibited by these Furthermore, MT3-MMP with columns. these results that the CS on the proteoglycan may the and/or of of the have been documented to bind the glycosaminoglycan and this interaction has been to certain T. J. 1993; PubMed Scopus Google Scholar). results are with for melanoma cell surface CS with to The of the and MCSP is on the on the cells are that the interaction of these two membrane is by the extracellular may be on of the two the within MT3-MMP that interact with CS to the for the interaction of these two and for the importance of this interaction for MT3-MMP In to melanoma cells R.A. Cheresh D.A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), the and invasion of these cells on or within type I collagen is of MT3-MMP and MCSP interactions may melanoma cell invasion by to that for integrin and results that MT3-MMP interaction with MCSP is largely on the of we a from the MCSP core of MT3-MMP are also in of is interaction between and It is the of MT3-MMP in the integrin a interaction between integrin and this We are this with (i.e. It is that the of in the integrin may from integrin on the cell surface, by a to we have for interactions J. Oegema McCarthy J.B. J. Biol. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). results demonstrate that the invasion of this melanoma cell requires the of results the of in melanoma invasion. is invasion of these cells in the of and as has been demonstrated for the invasion of certain A. A. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The of cell surface CS is at invasion in and it is that such be melanoma progression in the between and (2Herlyn M Tumor Progression in the Melanocytic System. R. G. Landes Company, Georgetown1993Google Scholar). are in with through adhesion results in the of growth and invasive In progression to melanoma is by a in the with a in the of the to melanoma growth or of adhesion The of such as MT3-MMP may the of adhesion and to early of tumor melanoma cells from early this and to the importance of in early tumor progression be may or the of for melanoma We Oegema for of the CS affinity We also of for WM1341D melanoma

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