Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesterol-depleting agent β-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies. Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesterol-depleting agent β-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies. The principal molecules that have been identified in the normal brain extracellular matrix (ECM) 1The abbreviations used are: ECM, extracellular matrix; EC, endothelial cell; EGCg, epigallocatechin-(3)-gallate; HA, hyaluronan (hyaluronic acid, hyaluronate); MMP, matrix metalloproteinase; MT1-MMP, membrane type 1 matrix metalloproteinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MAPK, mitogen-activated protein kinase; PBS, phosphate-buffered saline; BSA, bovine serum albumin; FITC, fluorescein isothiocyanate; Wt, wild type; TBST, Tris-buffered saline plus Tween 20; ERK, extracellular signal-regulated kinase; Mes, 4-morpholineethanesulfonic acid. are hyaluronan (HA; also known as hyaluronic acid, hyaluronate) and chondroitin sulfate (1Asher R. Perides G. Vanderhaeghen J.J. Bignami A. J. Neurosci. Res. 1991; 28: 410-421Crossref PubMed Scopus (117) Google Scholar, 2Bertolotto A. Rocca G. Schiffer D. J. Neurol. Sci. 1990; 100: 113-123Abstract Full Text PDF PubMed Scopus (61) Google Scholar). HA is an important glycosaminoglycan constituent believed to be implicated in angiogenesis, the formation of new blood vessels from preexisting vasculature. Although the serum level of HA is already used as an indicator of progressive malignant disease (3Thylen A. Wallin J. Martensson G. Cancer. 1999; 86: 2000-2005Crossref PubMed Scopus (43) Google Scholar), its effects on in vivo angiogenesis and endothelial cell (EC) function are complex and have been reported to depend on HA concentration and molecular size (4Rooney P. Kumar S. Ponting J. Wang M. Int. J. Cancer. 1995; 60: 632-636Crossref PubMed Scopus (262) Google Scholar, 5Savani R.C. Cao G. Pooler P.M. Zaman A. Zhou Z. DeLisser H.M. J. Biol. Chem. 2001; 276: 36770-36778Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar). Accordingly, whereas high molecular weight HA was shown to inhibit EC functions (6West D.C. Kumar S. Ciba Found. Symp. 1989; 143: 187-201PubMed Google Scholar), low molecular weight HA stimulated EC proliferation, tubulogenesis (6West D.C. Kumar S. Ciba Found. Symp. 1989; 143: 187-201PubMed Google Scholar, 7Rahmanian M. Pertoft H. Kanda S. Christofferson R. Claesson-Welsh L. Heldin P. Exp. Cell Res. 1997; 237: 223-230Crossref PubMed Scopus (65) Google Scholar), and neovascularization (8Sattar A. Rooney P. Kumar S. Pye D. West D.C. Scott I. Ledger P. J. Invest. Dermatol. 1998; 103: 576-579Crossref Scopus (158) Google Scholar). Moreover, small HA polymers efficiently regulated CD44 cell surface functional expression and promoted tumor cell migration (9Sugahara K.N. Murai T. Nishinakamura H. Kawashima H. Saya H. Miyasaka M. J. Biol. Chem. 2003; 278: 32259-32265Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar). Astrocytic tumors of the central nervous system express CD44 among other cell adhesion receptors of the integrin or immunoglobulin superfamily. Although HA is the principal ligand of CD44, other CD44 ligands include the ECM components collagen, fibronectin, laminin, and chondroitin sulfate, whereas mucosal addressin, serglycin, osteopontin, and the class II invariant chain represent ECM-unrelated ligands of the molecule. CD44 is also implicated in the promotion of tumor growth, invasiveness, and metastatic potential in experimental and human cancers (10Gunthert U. Schwarzler C. Wittig B. Laman J. Ruiz P. Stauder R. Bloem A. Smadja-Joffe F. Zoller M. Rolink A. Adv. Exp. Med. Biol. 1998; 451: 43-49Crossref PubMed Scopus (28) Google Scholar, 11Naot D. Sionov R.V. Ish-Shalom D. Adv. Cancer Res. 1997; 71: 241-319Crossref PubMed Google Scholar). Recent findings suggest that CD44 provides a docking site for matrix metalloproteinase (MMP)-9 on the surface of melanoma and carcinoma cells and thus can indirectly contribute to pericellular proteolysis of types IV and V but not type I collagen (12Yu Q. Stamenkovic I. Genes Dev. 1999; 13: 35-48Crossref PubMed Scopus (608) Google Scholar). Although several other cell surface receptors for HA have been reported, it has been shown that gliomas express significant levels of CD44 and that CD44 expression could be relevant in determining their highly invasive behavior (13Akiyama Y. Jung S. Salhia B. Lee S. Hubbard S. Taylor M. Mainprize T. Akaishi K. van Furth W. Rutka J.T. J. Neurooncol. 2001; 53: 115-127Crossref PubMed Scopus (117) Google Scholar, 14Ranuncolo S.M. Ladeda V. Specterman S. Varela M. Lastiri J. Morandi A. Matos E. Bal de Kier Joffe E. Puricelli L. Pallotta M.G. J. Surg. Oncol. 2002; 79: 30-35Crossref PubMed Scopus (60) Google Scholar). Several studies have revealed different molecular and cellular mechanisms regulating CD44-mediated processes. The most recent studies evaluated the role of CD44 in the rolling interaction of lymphoid cells with HA (15Gal I. Lesley J. Ko W. Gonda A. Stoop R. Hyman R. Mikecz K. J. Biol. Chem. 2003; 278: 11150-11158Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar), the role of E-cadherin in CD44-mediated tumor invasion (16Xu Y. Yu Q. J. Biol. Chem. 2003; 278: 8661-8668Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar), and the role of intracellular Rho-mediated signaling leading to cytokine production and breast tumor progression (17Bourguignon L.Y. Singleton P.A. Zhu H. Diedrich F. J. Biol. Chem. 2003; 278: 29420-29434Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). Moreover, molecular paradigms of cell migration that may be involved in tumor invasion and metastasis have also recently been highlighted by the common cell surface localization of CD44 with a membrane type (MT) 1-MMP at the leading edge of motile cells (lamellipodia) (18Okamoto I. Kawano Y. Tsuiki H. Sasaki J. Nakao M. Matsumoto M. Suga M. Ando M. Nakajima M. Saya H. Oncogene. 1999; 18: 1435-1446Crossref PubMed Scopus (218) Google Scholar, 19Kajita M. Itoh Y. Chiba T. Mori H. Okada A. Kinoh H. Seiki M. J. Cell Biol. 2001; 153: 893-904Crossref PubMed Scopus (625) Google Scholar). These studies elegantly demonstrated that CD44 directed MT1-MMP to lamellipodia by associating with its hemopexin-like domain, and that cell surface MT1-MMP-mediated cleavage of CD44 subsequently played a critical role in promoting tumor cell migration. In addition, one other common feature between MT1-MMP and CD44 is that partially Triton X-100-insoluble and membrane B. M. D. R. J. 2001; PubMed Scopus Google Scholar, A. R. M. B. S. Exp. Cell Res. 2001; PubMed Scopus Google Scholar, A. Lesley J. Hyman R. J. Cell Sci. 1995; PubMed Google Scholar, J. 2003; PubMed Scopus Google Scholar). Accordingly, the of MT1-MMP has been to a mechanism of glioma cells by MT1-MMP, from its in cell and activation of also regulates CD44-mediated binding to HA is Moreover, is known the common regulation of ECM protein In the present study, we the mechanisms involved in the regulation of CD44 function in cells from a highly and brain tumor we the of caveolae with to the potential functional regulation of HA at the cell surface of glioma cells. we the of a new cell surface functional between MT1-MMP and CD44 that on the of gliomas to we show that type I collagen an increased cell surface binding to HA in glioma cells, and that the cytoplasmic and of MT1-MMP may in through intracellular our results a new potential MT1-MMP/CD44/caveolin that could the invasive potential of glioma cells through their interaction with the brain ECM environment and that could represent a new potential target for anti-cancer therapies. sulfate bovine serum and Triton from was from was from and from I collagen was from to J. Biol. Chem. Full Text PDF PubMed Google Scholar). The and from The the the and from hyaluronic and hyaluronic from The MEK inhibitor PD98059 was from Cell and U-87 glioma cell was from and in bovine serum and at a The MT1-MMP and by B. A. D. R. J. 2001; PubMed Google as the MT1-MMP protein a which the cytoplasmic a secreted form of MT1-MMP, which the and cytoplasmic U-87 cells with the was by and involving cells of U-87 with expression used as and was from of U-87 cells of was used for by with the for from human and that the in the of the for for at for for 1 and for 1 by a at on 1 by to which at with in saline Tween in and with primary in bovine serum in TBST, and by a with in was by that of the MT1-MMP was a to whereas that of the MT1-MMP at to a significant the of functional MT1-MMP expression in U-87 cells, we the activation of a of by as B. M. D. R. J. 2001; PubMed Scopus Google Scholar, E. Z. L. J. R. 1999; PubMed Scopus Google Scholar). an of the was to in a The in Triton and in at for in with and in acid, in was as on a with cells that had been by and HA cells for 1 at a with or ilomastat, and cells for at a with in bovine at a concentration of with plus BSA, and with for 1 on with or type I collagen. with the cells in 1 of and on a with the of cell surface CD44 cells from as and in bovine at a concentration of and for at in serum The cells in plus with CD44 or at for and in plus are as the of from the cells to their and are of of with and was as D. F. S. R. Res. 1998; PubMed Scopus Google Scholar). In cells to in a and in of the of was used to the cells the The was to a and was with a by The was with an of in Mes, The was to a and with a of of in The at in a for at was at the and from to and are of or was and was used to the HA cell surface binding of or cells to or U-87 cells. of and an in HA to U-87 an we evaluated HA binding to U-87 glioma cells could be HA was shown to at we the HA binding at at which no S. 1991; PubMed Scopus Google Scholar, C. S. J. 1998; PubMed Scopus Google Scholar). to the cell surface of glioma cells by as was demonstrated by the in levels of HA binding with cells by with not HA is shown to for cell surface HA binding as the in is diminished Interestingly, an of the cells with ilomastat, a broad MMP inhibitor reported to the activation of MT1-MMP J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), and to the of MT1-MMP D. Cancer Res. Google Scholar, S. R. S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), in an increase in HA binding that a MMP is involved in the regulation of the functional cell surface binding of HA could not be at a regulation of HA binding has recently been shown to CD44 M. Itoh Y. Chiba T. Mori H. Okada A. Kinoh H. Seiki M. J. Cell Biol. 2001; 153: 893-904Crossref PubMed Scopus (625) Google Scholar), we U-87 cells with or a The CD44-mediated cell surface HA but that other cell surface molecules could also be involved was Interestingly, whereas had no on the HA cell surface the that increase in HA binding not the that MMP to CD44 functions in binding mechanisms the of HA cell surface binding in U-87 glioma cells. U-87 glioma cells for 1 at with or β-cyclodextrin to membrane or to the cells in the or of type I collagen. and cells for 1 at with was used to HA cell surface The results are of I HA to the Cell of U-87 the and of several matrix molecules on the binding of HA, we glioma cells in the of several ECM of the cells with type I collagen triggered a increase in cell HA binding whereas had an I collagen of U-87 cells also induced morphological cell was by activation of a form of its MMP-2 as by and which activation was by activation by type I collagen was recently to be through an MT1-MMP in C. L. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). a mechanism could functionally HA cell surface binding in glioma cells was MT1-MMP HA through CD44 Cell from its on MT1-MMP is also to be involved in CD44 regulation at the cell the of MT1-MMP to cellular HA binding are We U-87 cells with to MT1-MMP These the MT1-MMP, the MT1-MMP, and a the MT1-MMP in cell but the was secreted the Moreover, the and MT1-MMP to that the cytoplasmic of MT1-MMP is not for as by B. A. D. R. J. 2001; PubMed Google Scholar, D. S. B. R. 2001; PubMed Scopus Google Scholar). Interestingly, whereas CD44 expression was not by overexpression of of the MT1-MMP the MT1-MMP protein was of the cell surface binding of HA as as the CD44 cell surface protein was by and as the of from the cell Although CD44 protein expression was not in cell expression as demonstrated (18Okamoto I. Kawano Y. Tsuiki H. Sasaki J. Nakao M. Matsumoto M. Suga M. Ando M. Nakajima M. Saya H. Oncogene. 1999; 18: 1435-1446Crossref PubMed Scopus (218) Google Scholar, 19Kajita M. Itoh Y. Chiba T. Mori H. Okada A. Kinoh H. Seiki M. J. Cell Biol. 2001; 153: 893-904Crossref PubMed Scopus (625) Google Scholar), CD44 the of U-87 cells not The of that the intracellular of MT1-MMP, not for a role in the intracellular signaling for CD44 cell surface expression and the Cell of HA to U-87 in with I recent that MT1-MMP and CD44 partially membrane B. M. D. R. J. 2001; PubMed Scopus Google Scholar, A. Lesley J. Hyman R. J. Cell Sci. 1995; PubMed Google to the of we that depletion from U-87 cell not cell surface CD44 as by depletion of the cells not the expression of in or U-87 glioma cells, it MT1-MMP in glioma cells cells not express MT1-MMP, and CD44 expression was not by type I collagen or β-cyclodextrin of U-87 cells not or MT1-MMP protein expression was by a β-cyclodextrin depletion triggered a of MT1-MMP and to the associated with low type I collagen of glioma cells in increased cell surface HA binding The I in HA Cell through a Cell MMP evaluated the type I HA cell surface binding in glioma cells of caveolae involved cell MMP cells thus with or EGCg, a for which we have recently several and S. D. R. Cancer Res. 2002; Google Scholar, B. M. D. R. 2002; PubMed Scopus Google Scholar, M. J. B. D. D. J. S. Y. R. Med. Chem. 2002; PubMed Scopus Google Scholar). We demonstrated that HA cell surface binding in glioma cells for 1 with or had no whereas a with type I collagen had no on MT1-MMP expression not the type I HA binding was increased in cells and type I collagen and β-cyclodextrin by and These that protein HA cell surface and that depletion of the membrane that to the of type I collagen. The of MT1-MMP HA through the of the have reported that MT1-MMP triggered cellular leading to cell and that from its cytoplasmic D. S. B. R. 2001; PubMed Scopus Google Scholar). We signaling from the HA cell surface or U-87 cells with a and inhibitor of kinase We show that HA cell surface binding was diminished by in cells and that the regulated HA cell surface binding in cells. U-87 cells HA binding diminished by in and as reported in HA binding partially by the of the MEK inhibitor in and to levels cells but with that of the cells. The overexpression of the cytoplasmic no on HA cell surface which was by PD98059 to the level as the the of the with that of the that MT1-MMP-mediated intracellular signaling regulates HA cell surface These effects in we show that the cytoplasmic of MT1-MMP HA cell surface binding signaling through the is increased by the overexpression of the protein and is by the in HA cell surface In the overexpression of the cytoplasmic protein not and not HA cell surface binding in cells. expression the of the by PD98059 which was to HA cell surface binding to levels to that of cells and MT1-MMP-mediated regulation of the with the effects leading to HA cell surface gliomas are the most common and primary tumors of the central nervous The interaction between glioma and brain ECM components complex and The recent that the expression of CD44 with the highly invasive behavior of gliomas S.M. Ladeda V. Specterman S. Varela M. Lastiri J. Morandi A. Matos E. Bal de Kier Joffe E. Puricelli L. 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These could also be involved in the metastatic through interaction and collagen, most type I membrane collagen. thus provides a new at a mechanism of glioma invasion that a interaction between collagen and HA cell surface of interaction could as a target in the of new

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