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Matrix Metalloproteinases: Pro- and Anti-Angiogenic Activities

      Matrix metalloproteinases (MMP) are a family of structurally related proteinases most widely recognized for their ability to degrade extracellular matrix, although recent investigations have demonstrated other biologic functions for these enzymes. MMP are typically not constitutively expressed, but are regulated by: (1) cytokines, growth factors, and cell–cell and cell–matrix interactions that control gene expression; (2) activation of their proenzyme form; and (3) the presence of MMP inhibitors [tissue inhibitors of metalloproteinases, (TIMP)]. MMP have important roles in normal processes including development, wound healing, mammary gland, and uterine involution, but are also involved in angiogenesis, tumor growth, and metastasis. Angiogenesis, characteristically defined as the establishment of new vessels from pre-existing vasculature, is required for biologic processes such as wound healing and pathologic processes such as arthritis, tumor growth, and metastasis. Blocking of MMP activity has been studied for potential therapeutic efficacy in controlling such pathologic processes. Synthetic MMP inhibitors, most notably the hydroxymates, have been engineered for this purpose and are presently in clinical trial. These inhibitors may have broad versus specific MMP inhibitory activity. As increased nonmatrix degrading capabilities of MMP are recognized, however, i.e., cytokine activation, processing of proteins to molecules of distinct biologic function, it becomes less clear whether the nonselective inhibition of MMP activity for all pathologic processes involving MMP is appropriate. This review focuses upon the contribution of MMP to the process of tumor invasion and angiogenesis, and discusses the design and use of MMP inhibitors as therapeutic agents in these processes.

      Keywords

      Matrix metalloproteinases (MMP) are a structurally related family of proteinases (Figure 1) that are part of a larger superfamily of zinc-dependent endoproteinases called metsincins (
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      The metzincins-topological and sequential relations between the astacins, adamatysins, serrolysins and matrixins (collagenases) define a superfamily of zinc-peptidases.
      ). MMP are widely recognized for their ability to degrade extracellular matrix, and as a family are capable of degrading all extracellular matrix components. Presently, there are over 20 human MMP described, and although most MMP are secreted extracellularly, certain MMP are membrane associated [membrane-type (MT) MMP]. The collagenases (MMP-1, -3, and -13) cleave native fibrillar collagen types I, II, and III (
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      ). Stromelysin-1 and -2 (MMP-3, MMP-10) have broad substrate specificity. Stromelysin-3 (MMP-11) has a more restricted activity (
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      A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas.
      ) and has been found to function in the release of matrix-bound growth factors (
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      Identification of insulin-like growth factor-binding protien-1 as a potential physiological substrate for human stromelysin-3.
      ). Gelatinase A (MMP-2, 72 kDa) and gelatinase B (MMP-9, 92 kDa) degrade denatured collagens and basement membrane components (
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      SV40-transformed human lung fibroblasts secrete a 92 kDa type IV collagenase which is identical to that secreted by normal human macrophages.
      ). Gelatinase A is typically produced by mesenchymal cells, and gelatinase B is found in neutrophils, other inflammatory cells, and endothelial cells (
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      ;
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      92 kDa gelatinase is actively expressed by eosinophils and secreted by neutrophils in invasive squamous cell carcinoma.
      ;
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      The induction of 72 kDa gelatinase in T cells upon adhesion to endothelial cells is VCAM-1 dependent.
      ;
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      Thrombin induces the activation of progelatinase A in vascular endothelial cells.
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      Deregulation of collagen phagocytosis in aging human fibroblasts: Effects of integrin expression and cell cycle.
      ;
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      Active and tissue inhibitor of matrix metalloproteinase-free gelatinase B accumulates within human microvascular endotehlial cell vesicles.
      ;
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      • Gelatinase B.
      Structure, regulation and function.
      ;
      • Xie B.
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      Autocrine regulation of macrophage differentiation and 92 kDa gelatinase production by tumor necrosis factor-alpha via alpha-5/beta1 integrin in HL-60 cells.
      ;
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      Matrix metalloproteinase 2 (gelatinase A) is related to migration of keratinocytes.
      ). Matrilysin (MMP-7) cleaves types I, III, IV, and V collagens, fibronectin, and procollagenase-1 (
      • Quantin B.
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      • Breathnach R.
      • Pump-1 c D.N.A.
      codes for a protein with characteristics similar to those of classical collagenase family members.
      ). More recently described members of the MMP family are five membrane-type matrix metalloproteinases (MT-MMP), membrane-associated proteases that function not only in matrix remodeling but also in pericellular activation of pro-MMP (
      • Knauper V.
      • Will H.
      • Lopez-Otin C.
      • et al.
      Cellular mechanisms for human pro-gelatinase-3 (MMP-13) activation – evidence that MT1-MMP (MMP-14) and gelatinase A (MMP-2) are able to generate active enzyme.
      ;
      • Knauper V.
      • Murphy G.
      Membrane-type matrix metalloproteinases and cell surface-associated activation cascades for matrix metalloproteinases.
      ). MMP-19 (
      • Pendas A.M.
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      • Puente X.S.
      • Llano E.
      • Mattri M.G.
      • Aple S.
      Identification and characterization of a novel matrix metalloproteinase with unique structural characteristics, chromosomal localization and tissue distribution.
      ) and enmelysin (MMP-20) (
      • Llano E.
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      • Knauper V.
      • Sorsa T.
      • Salo T.
      • Sakido E.
      al e. Identification and characterization of human enamelysin (MMP-20).
      ) are the newest MMP described. MMP-19 has been demonstrated in synovial capillary endothelial cells during acute inflammation, findings that may suggest a role in angiogenesis (
      • Kolb C.
      • Mauch S.
      • Krawinkel U.
      • Sedlacek R.
      Matrix metalloproteinase-19 in capillary endothelial cells: expression in acutely, but not chronically, inflamed synovium.
      ). MMP-20 presently has no known function in angiogenesis. In addition to their matrix degrading capabilities, investigations have also determined that MMP have important roles in other biologic processes; most notably, activation of other MMP (
      • Knauper V.
      • Will H.
      • Lopez-Otin C.
      • et al.
      Cellular mechanisms for human pro-gelatinase-3 (MMP-13) activation – evidence that MT1-MMP (MMP-14) and gelatinase A (MMP-2) are able to generate active enzyme.
      ;
      • Knauper V.
      • Murphy G.
      Membrane-type matrix metalloproteinases and cell surface-associated activation cascades for matrix metalloproteinases.
      ) and certain cytokines (TNFα) (
      • Black R.A.
      • Rauch Kozlosky C.T.
      • Peshon C.J.
      • et al.
      A metalloproteinase disintegrin that releases tumor-necrosis-alpha from cells.
      ), modulation of cell adhesion (
      • Makela M.
      • Larjava H.
      • Pirila E.
      • Salo T.
      • Sorsa T.
      • Uitto V.J.
      Matrix metalloproteinase 2 (gelatinase A) is related to migration of keratinocytes.
      ;
      • Sarkissian M.
      • Lafyatis R.
      Integrin engagement regulates proliferation and collagenase expression of rheumatoid synovial fobroblasts.
      ) and the proteolysis of parent molecules to biologic proteins with separate and specific activities (angiostatin from plasminogen) (
      • Dong Z.
      • Kumar R.
      • Yang X.
      • Fidler I.J.
      Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.
      ;
      • Patterson B.C.
      • Sang Q.X.A.
      Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9).
      ;
      • Cornelius L.A.
      • Nehring L.C.
      • Harding E.
      • et al.
      Matrix metalloproteinases generate angiostatin. Effects on neovascularization.
      ).
      Figure thumbnail gr1
      Figure 1MMP family, structural domains, and substrates.
      MMP are expressed in an inactive, or zymogen form, and activity is dependent upon extracellular activation of the enzyme that requires cleavage of the cysteine-containing pro-enzyme region that contacts the zinc atom in the active catalytic site (Figure 1) (
      • Woessner J.F.
      The matrix metalloproteinase family.
      . X-ray crystalographic studies have contributed greatly to our understanding of MMP structure and concomitant activity. Studies of full-length collagenase-1 (MMP-1) (
      • Li J.
      • Brick P.
      • O'Hare M.C.
      • et al.
      Structure of full-length porcine synovial collagenase reveals a C-terminal domain containing a calcium-linked, four-bladed beta-propellar.
      ) reveal that the N-terminal catalytic domain and the C-terminal hemopexin domain are connected by a flexible proline-rich linker, and that the hemopexin domain contains four units of a four-stranded antiparallel beta sheet resulting in a four-bladed propeller-like structure. Physiologic MMP inhibitors, known as tissue inhibitors of metalloproteinases (TIMP 1–4), inhibit MMP by forming noncovalent bimolecular complexes with them to block activation or block the active enzyme site itself (
      • Gomis-Ruth F.X.
      • Maskos K.
      • Betz M.
      • et al.
      Mechanism of inhibition of the human metalloproteinase stromelysin-1 by TIMP-1.
      ). Synthetic MMP inhibitors have also been engineered to bind irreversibly to the Zn++ atom of the enzyme active site (
      • Brown P.D.
      Syntehtic inhibitors of matrix metalloproteinases.
      ). The C-terminal hemopexin domain is responsible for MMP substrate and inhibitor specificity, but the actual inhibition of MMP activity occurs due to binding of both physiologic (TIMP) and synthetic inhibitors (hydroxamates) to the catalytic domain. Based upon their 3-dimensional structures, specificity pocket subsites (designated S) within the MMP are formed that determine binding of the specific inhibitor amino acid segments, and result in inactivity of the enzyme. More specifically, determination of the crystal structure of the TIMP-1-MMP-3 complex reveals that the critical TIMP binding residues surround the TIMP disulfide bond between Cys1 and Cys70, with Cys1 located on top of the MMP-3 catalytic site coordinating the catalytic Zn (
      • Gomis-Ruth F.X.
      • Maskos K.
      • Betz M.
      • et al.
      Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1.
      ).
      Regulation of MMP activity is dependent upon gene expression, enzyme activation, and the presence of inhibitors. With few exceptions (
      • Saarialho-Kere U.K.
      • Crouch E.
      • Parks W.C.
      The matrix metalloproteinase matrilysin is constitutively expressed in adult human exocrine epithelium.
      ), MMP are not constitutively expressed and investigations into gene regulation have found that growth factors, cytokines and cell–matrix interactions are important regulators of MMP gene expression (reviewed by
      • Birkedal-Hansen H.
      • Moore W.G.I.
      • Bodden M.K.
      • Windsor L.J.
      • Birkedal-Hansen B.
      • DeCarlo A.
      • Engler J.A.
      Matrix metalloproteinases. A review.
      ). In fact, the regulatory region of most MMP genes contain an AP-1 binding site and TRE-element, which are classically involved in this regulation (
      • Angel P.
      • Imagawa M.
      • Chiu R.
      • et al.
      Phorbol-ester inducible genes contain a common cis element recognized by a, TPA, -modulated trans-acting factor.
      ,
      • Angel P.I.
      • Baumann B.
      • Stein B.
      • Delius H.
      • Rahmsdorf H.J.
      • Herrlich P.
      12–0-tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene is mediated by an inducible enhancer element located in the 5′ region.
      ;
      • Gaire M.
      • Magbanua Z.
      • McDonnell S.
      • McNeil L.
      • Lovett D.H.
      • Matrisian L.M.
      Structure and expression of the human gene for the matris metalloproteinase matrilysin.
      ;
      • Pierce R.A.
      • Sandefur S.
      • Welgus H.G.
      Monocytic cell-type specific transcriptional induction of collagenase.
      ). Transcription factors that have been implicated in MMP gene regulation via these, and other sites (PEA3/ets) (
      • Gum R.
      • Lengyel E.
      • Juarez J.
      • Chen J.H.
      • Sato H.
      • Seiki M.
      • Boyd D.
      Stimulation of 92 kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase I independent and requires multiple transcription sites including closely spaced PEA3/ets and AP-1 sequences.
      ), and include members of the jun family (
      • Mauviel A.
      • Chung K.-Y.
      • Agarwal A.
      • Tamai K.
      • Uitto J.
      Cell-specific induction of distinct oncogenes of the June family is responsible for differential regulation of collagenase gene expression by transforming growth factor-β in fibroblasts and keratinocytes.
      ;
      • Solis-Herruzo J.A.
      • Rippe R.A.
      • Schrum L.W.
      • et al.
      Interleukin-6 increases rat metalloproteinase-13 gene expression through stimulation of activator protein 1 transcription factor in cultured fibroblasts.
      ), AP-2 and YB-1 (
      • Mertens P.R.
      • Alfonso-Jaume M.A.
      • Steinmann K.
      • Lovett D.H.
      A synergistic interaction of transcription factors AP2 and YB-1 regulates gelatinase A enhancer-dependent transcription.
      ), NF-κB (
      • Bond M.
      • Fabunmi R.P.
      • Baker A.H.
      • Newby A.C.
      Synergitic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement.
      ), and Egr-1 (
      • Haas T.L.
      • Stitelman D.
      • Davis S.J.
      • Apte S.S.
      • Madri J.A.
      Egr-1 mediates extracellular matrix-driven transcription of membrane type 1 matrix metalloproteinase in endothelium.
      ). Tyrosine kinase and protein kinase C signaling pathways have been implicated in the control of MMP expression (
      • Sudbeck B.D.
      • Parks W.
      • Welgus H.G.
      • Pentland A.P.
      Collagen-mediated induction of keratinocyte collagenase is mediated by tyrosine kinase and protein kinase C activities.
      ;
      • Vincenti M.P.
      • Schroen D.J.
      • Coon C.I.
      • Brinckerhoff C.E.
      v-src activation of the collagenase-1 gene (MMP-1) promoter through PEA-3 and STAT. requirement of the extracellular signal-regulated kinases and inhibition by retinoic acid receptors.
      ).
      MMP are expressed by various cell types during processes of development, as well as during certain physiologic and pathologic processes. In cancer, MMP activity has been implicated in tumor invasion and metastasis. The matrix degradative activity of tumor cells themselves, the interstitial cells of the surrounding matrix, tumor-associated inflammatory cells, and endothelial cells of the tumor vasculature has been studied. Work investigating the MMP expression of tumors is based upon the premise that increased protease activity leads to the removal of physical barriers to invasion (
      • Kleiner D.E.
      • Stetler-Stevenson W.G.
      Matrix metalloproteinases and metastasis.
      ) and correlates with tumor growth, tumor cell intravasation into the vasculature, extravasation, and metastasis (
      • Sloane B.F.
      • Moin K.
      • Lah T.T.
      Regulation of lysosomal endopeptidases in malignant neoplasm.
      ). In support of this, increased MMP expression has been found in many malignant tumors (
      • Basset P.J.
      • Bellocq P.
      • Wolf C.
      • et al.
      A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas.
      ,
      • Basset P.
      • Okada A.
      • Chenard M.-P.
      • et al.
      Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutical implications.
      ;
      • Sato H.
      • Takino T.
      • Okada Y.
      • Cao J.
      • Shinagawa A.
      • Yamamoto E.
      • Seiki M.
      A matrix metalloproteinase expressed on the surface of invasive tumor cells.
      ;
      • Tolivia J.
      • Lopez-Otin C.
      Molecular cloning and expression of collagenase-3, a novel matrix metalloproteinase produced by breast carcinomas.
      ). Correspondingly, inhibition of MMP activity through inhibition of multiple regulatory and activating pathways has been investigated (Figure 2). Increased expression of the physiologic inhibitor TIMP has been found to reduce the invasive and metastatic capacity of transformed cells in certain murine tumor models (
      • Montgomery A.M.
      • Mueller B.M.
      • Reisfeld R.A.
      • Taylor S.M.
      • DeClerk Y.A.
      Effect of tissue inhibitor of the matrix metalloproteinase-2 expression on the growth and spontaneous metastasis of a human melanoma cell line.
      ). Regulators of MMP expression that suppress MMP synthesis in certain cancer cell types, such as the retinoids (
      • Li Y.
      • Hashimoto Y.
      • Agadir A.
      • Kagechika H.
      • Xk Z.
      Identification of a novel class of retinoic acid receptor beta-selective retinoid antagonists and their inhibitory effects on AP-1 activity and retinoic acid-induced apoptosis in human breast cancer cells.
      ), have been investigated for their potential antitumor activity (
      • Schoenermark M.P.
      • Mitchell T.A.
      • Rutter J.L.
      • Reczek P.R.
      • Brinckerhoff C.E.
      Retinoid-mediated suppression of tumor invasion and matrix metalloproteinase synthesis.
      ). In seeming contradistinction to these findings, there is some evidence that MMP may function as regulators of cellular apoptosis (
      • Vu T.H.
      • Werb Z.
      • Gelatinase B.
      Structure, regulation and function.
      ).
      Figure thumbnail gr2
      Figure 2Targets for inhibiting MMP expression and activity.
      Reproduced with permission from
      • Westermerck J.
      • Veli-Matti K.
      Regulation of matrix metalloproteinase expression in tumor invasion.
      ).
      Tumors are heterogeneous in their expression of MMP and the MMP expressing cell type (tumor versus stromal) varies. In certain cancers, MMP, such as matrilysin, characteristically localise to tumor cells themselves (
      • Powell W.C.
      • Matrisian L.M.
      Complex roles of matrix metalloproteinases in tumor progression.
      ), whereas induction or activation of stromelysin-1 expression is typically found within the stromal cells (
      • Nagase H.
      Stromelysins 1 and 2.
      ). The gelatinases, however, may be expressed by both tumor cells and cells of the surrounding stroma (
      • Birkedal-Hansen H.
      • Moore W.G.I.
      • Bodden M.K.
      • Windsor L.J.
      • Birkedal-Hansen B.
      • DeCarlo A.
      • Engler J.A.
      Matrix metalloproteinases. A review.
      ). In both basal cell and squamous cell carcinomas, altered MMP-2 and TIMP expression has been demonstrated (
      • Wagner S.N.
      • Ockenfels H.M.
      • Wagner C.
      • Soyer H.P.
      • Goos M.
      Differential expression of tissue inhibitor of metalloproteinases-2 by cutaneous squamous and basal cell carcinomas.
      ). Conflicting results have been reported with respect to the relationship of MMP expression and the invasiveness of melanoma cells both in vitro and in an in vivo murine model (
      • Montgomery A.M.
      • Mueller B.M.
      • Reisfeld R.A.
      • Taylor S.M.
      • DeClerk Y.A.
      Effect of tissue inhibitor of the matrix metalloproteinase-2 expression on the growth and spontaneous metastasis of a human melanoma cell line.
      ;
      • Huijzer J.C.
      • Uhlenkott C.E.
      • Meadows G.G.
      Differences in expression of metalloproteinases and plasminogen activators in murine melanocytes and B16 melanoma variants. Lack of association with in vitro invasion.
      ). Nonetheless, with the increasing recognition of the multiple biologic functions performed by MMP, the simplistic assumption that increased tumor MMP expression correlates with increased tumor growth and metastasis cannot always be supported. In this paper, we will specifically address the role of MMP expression as it contributes to one area important to tumor growth and metastasis – tumor angiogenesis – and the potential implications that inhibiting these enzymes may have on tumor behavior.

      Matrix metalloproteinases and angiogenesis

      The contribution of MMP to angiogenesis has been studied through both in vitro and in vivo investigations, and involves cell–cell and cell–matrix interactions together with proteolysis. Growth factors and cytokines have been identified that promote angiogenesis, and include vascular endothelial cell growth factor (VEGF) (
      • Cao Y.
      • Linden P.
      • Farnebo J.
      • et al.
      Vascular endothelial growth factor C induces angiogenesis in vivo.
      ;
      • Shweiki D.
      • Itin A.
      • Neufeld G.
      • Gitay-Goren H.
      • Keshet E.
      Patterns of expression of vascular endothelial growth factor and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis.
      ;
      • Yamagishi S.
      • Yonekura H.
      • Yamamoto Y.
      • et al.
      Advanced glycation end products-driven angiogenesis in vitro. Induction of the growth and tube formation of human microvascualr endothelial cells through autocrine vascular endothelial growth factor.
      ), basic fibroblast growth factor (bFGF, FGF-2) (
      • Kandel J.
      • Bossy-Wetzel E.
      • Radvani F.
      • Klagsburn M.
      • Folkman J.
      • Hanahan D.
      Neovascularization is associated iwth a switch to the export f bFGF in the multi-step development of fibrosarcoma.
      ) (reviewed by
      • Friesel R.E.
      • Maciag T.
      Molecular mechanisms of angiogenesis: fibroblast growth factor signal transduction.
      ), hepatocyte growth factor (HGF) (
      • Rosen E.M.
      • Goldberg I.D.
      Regulation of angiogenesis by scatter factor.
      ), tumor necrosis factor alpha (TNFα) (
      • Koolwijk P.
      • van Erck M.G.
      • de Vree W.J.
      • Vermeer M.A.
      • Weich H.A.
      • Hanemaaijer R.
      • van Hinsbergh V.W.
      Cooperative effect of TNF alpha, bFGF, and VEGF on the formation of tubular structures of human microvascular endothelial cells in a fibrin matrix. Role of urokinase activity.
      ;
      • Leibovich S.
      Polverini PJ, Shepard HM, Wiseman DM, Shively V, Nuseir N Macrophage-induced angiogenesis is mediated by tumor necrosis factor-alpha.
      ) and platelet-derived growth factor-beta (PDGF-β) (
      • Battegay E.J.
      • Rupp J.
      • Iruela-Arispe L.
      • Sage E.H.
      • Pech M.
      PDGF-BB modulates endothelial proliferation and angiogenesis in vitro PDGF beta-receptors.
      ). Interestingly, many of these same factors are regulators of MMP gene expression (VEGF, TNFα, bFGF,
      • Cornelius L.A.
      • Nehring L.C.
      • Roby J.D.
      • Parks W.C.
      • Welgus H.G.
      Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration.
      ;
      • Qin H.
      • Moellinger J.D.
      • Wells A.
      • Windsor L.J.
      • Sun Y.
      • Benveniste E.N.
      Transcriptional regulation of matrix metalloproteinase-2 expression in human astroglioma cells by TNF-alpha and IFN-gamma.
      ) in endothelial cells and other cell types, although this regulation may not be directly related to their effect on angiogenesis.
      In vitro work has demonstrated the role of endothelial cell MMP in the degradation of basement membrane matrix proteins (collagen type IV and laminin), endothelial cell migration on proteins of the interstitial and provisional matrix (collagen type I and fibrin), and endothelial cell–matrix interactions that promote endothelial cell ‘‘differentiation’' in vitro (the formation of endothelial cell ‘‘tubes’' or ‘‘chords’') (Table 1 and Table 2). Collagenase is induced in microvascular endothelial cells migrating upon type I collagen in the presence of angiogenic cytokines (
      • Cornelius L.A.
      • Nehring L.C.
      • Roby J.D.
      • Parks W.C.
      • Welgus H.G.
      Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration.
      ), and is required for endothelial cells to invade a collagen type I gel matrix (
      • Fisher C.
      • Gilbertson-Beadling S.
      • Powers E.A.
      • Petzold G.
      • Poorman R.
      • Mitchell M.A.
      Interstitial collagenase is required for angiogenesis in vitro.
      ). Plating endothelial cells on the EHS-derived basement membrane matrix Matrigel (Collaborative Biomedical, Twin Oak Park, Bedford, MA), containing types IV collagen, proteoglycans and laminin, induces the formation of endothelial cell ‘‘tubes’' within 18–24 h (
      • Kubota Y.
      • Kleinman H.K.
      • Martin G.R.
      • Lawley T.J.
      Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures.
      ), and provides one in vitro model of endothelial cell morphogenesis. In this model, both type IV collagenases (MMP-2, -9) (
      • Schnaper H.W.
      • Grant D.S.
      • Stetler-Stevenson W.G.
      • et al.
      Type IV collagenase (s) and TIMPs modulate endothelial cell morphogenesis in vitro.
      ) and serine proteases (urokinase plasminogen activator, uPA) (
      • Schnaper H.W.
      • Barnathan E.S.
      • Mazar A.
      • et al.
      Plasminogen activators augment endothelial cell organization in vitro by two distinct pathways.
      ) are induced, and inhibition of either protease type decreases tube formation, although at distinct stages. Microvascular endothelial cells cultured within three-dimensional collagen gels express the membrane-type MMP, MT1-MMP, the inhibition of which delays their differentiation into tube-like structures (
      • Chan V.T.
      • Zhang D.N.
      • Nagaravapu U.
      • Hultquist K.
      • Romero L.I.
      • Herron G.S.
      Membrane-type matrix metalloproteinases in human dermal microvascular endothelial cells: expression and morphogenetic correlation.
      ). Work by other investigators demonstrated that, in a similar system, MT1-MMP was coordinately expressed with, and involved in, the activation of MMP-2 (
      • Haas T.L.
      • Davis S.J.
      • Madri J.A.
      Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells.
      ). Additionally, endothelial cells plated in a fibrin gel utilize MT1-MMP for fibrinolysis in this system (
      • Hiraoka N.
      • Allen E.
      • Apel I.J.
      • Gyetko M.R.
      • Weiss S.J.
      Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins.
      ), an activity that is characteristically ascribed to the serine proteinases and is required for provisional matrix migration. In some studies, the expression of endothelial cell MMP, specifically MMP-9 (gelatinase B, 92 kDa gelatinase) by microvascular (small vessel) cells, the prototypic cell involved in angiogenesis, and macrovascular (large vessel) cells, differs according to cell type (
      • Cornelius L.A.
      • Nehring L.C.
      • Roby J.D.
      • Parks W.C.
      • Welgus H.G.
      Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration.
      ;
      • Nguyen M.
      • Arkell J.
      • Jackson C.J.
      Active and tissue inhibitor of matrix metalloproteinase-free gelatinase B accumulates within human microvascular endotehlial cell vesicles.
      ).
      Table 1Endothelial cell MMP and TIMP
      collagenase (MMP-1)TIMP-1
      gelatinase A (MMP-2)TIMP-2
      gelatinase B (MMP-9)
      stomelysin (MMP-3)
      MT1-MMP (MMP-14)
      MP-19
      Table 2Endothelial cell MMP in angiogenesis
      In vitro assaysIn vivo assaysKnock outs
      migration assayscorneal pocketMMP-2
      collagen I gelsdorsal air sacMMP-9
      Matrigel gels firbrin gelsChick chorioallantoic membrane
      In separate investigations, Brooks et al. demonstrated that MMP-2 (gelatinase A, 72 kDa gelatinase) is expressed on the surface of invasive cells and endothelial cells involved in active angiogenesis, bound to the cell surface integrin αvβ3 (
      • Brooks P.C.
      • Stromblad S.
      • Sanders L.C.
      • et al.
      Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin avb3.
      ). These investigators had previously shown that αvβ3 is an endothelial cell surface integrin that is required for angiogenesis both in vitro and in vivo (
      • Brooks P.C.
      • Clark R.A.
      • Cheresh D.A.
      Requirement of vascular integrin for αvβ3 for angiogenesis.
      ). This group then demonstrated that the noncatalytic hemopexin fragment of the MMP-2 domain (Figure 1), termed PEX, mediates the MMP-2-αvβ3 binding, and that recombinant PEX could inhibit angiogenesis by competing for this binding (
      • Brooks P.C.
      • Silletti S.
      • von Schalscha T.L.
      • Friedlander M.
      • Cheresh D.A.
      Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity.
      ). Recently, a family of angio-inhibitory proteins, called METH-1 and METH-2, which also contain a metalloproteinase domain, has been described (
      • Vazquez F.
      • Hastings G.
      • Ortega M.A.
      • Lane T.F.
      • Oikemus S.
      • Lombardo M.
      • Iruela-Arispe M.L.
      METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-iinhibitory activity.
      ). These proteins also share a disintegrin and thrombospondin domain. Thrombospondin has well-recognized antiangiogenic activity (
      • Good D.J.
      • Polverini P.J.
      • Rastinejad F.
      • Le-Beau M.M.
      • Lemons R.S.
      • Frazier W.A.
      • Bouck N.P.
      A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin.
      ;
      • Iruela-Arispe M.L.
      • Bornstein P.
      • Sage H.
      Thrombospondin exerts an antiangiogenic effect on cord formation by endothelial cells in vitro.
      ;
      • Tolsma S.S.
      • Volpert O.V.
      • Good D.J.
      • Frazier W.A.
      • Polverinin P.J.
      • Bouck N.
      Peptides derived from 2 separate domains of the matrix protein thrombospondin-1 have antiangiogenic activity.
      ;
      • Dameron K.M.
      • Volpert O.V.
      • Tainsky M.A.
      • Bouk N.
      Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1.
      ;
      • Volpert O.V.
      • Stellmach V.
      • Bouk N.
      The modulation of thrombospondin and other naturally occuring inhibitors of angiogenesis during tumor progression.
      ;
      • Grant S.W.
      • Kyshtoobayeva A.S.
      • Kurosaki T.
      • Jakowatz J.
      • Fruehauf J.P.
      Mutnat p53 correlates with reduced expression of thrombospondin-1, increased angiogenesis, and metastatic progression in melanoma.
      ) with some investigators also demonstrating angiogenic properties, dependent upon the specific protein domain expressed (
      • Qian X.
      • Wang T.N.
      • Rothman V.L.
      • Nicosia R.F.
      • Tuszynski G.P.
      Thrombospondin-1 modulates angiogenesis in vitro by up-regulation of matrix metalloproteinase-9 in endothelial cells.
      ).
      It should be noted that for many years, physiologic and pathologic angiogenesis in the postnatal period has been defined as the ‘‘sprouting’' of new vessels from differentiated, pre-existing vessels and has been distinguished from vasculogenisis, or the development of vessels during embryogenesis from progenitor cells. The in vivo role of MMP in blood vessel development has been studied in fetal angiogenesis, and MMP-1 was demonstrated in early microvessels developing from undifferentiated mesoderm (
      • Karelina T.V.
      • Goldberg G.I.
      • Eisen A.Z.
      Matrix metalloproteinases in blood vessel developmetn in human fetal skin and in cutaneous tumors.
      ). Recent investigations have determined that endothelial progenitor cells may also play a role in postnatal neovascularization (
      • Asahara T.
      • Takahashi T.
      • Masuda H.
      • et al.
      VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial cell progenitor cells.
      ). Studies of myocardial and hindlimb ischemia demonstrate vascular endothelial cell growth factor (VEGF)-dependent collateral artery growth (
      • Takeshita S.
      Therapeutic angiogenesis: a single intra-arterial bolus of vascular endothelial groowth factor augments revascularization in a rabbit ischemic hindlimb model.
      ). Further work by these investigators has determined that circulating endothelial cell progenitor cells are mobilized from the bone marrow following ischemia and VEGF induction, and may be incorporated into the neovasculature (
      • Takahashi T.
      Ischemia- and cytokine-induced mobilization of bone marrow-derived endotehlial progenitor cells for neovascularization.
      ). To this author's knowledge, the contribution of MMP to this process has not yet been determined.

      Tumor angiogenesis

      The requirement of a tumor and its metastasis to develop a functional vasculature for its survival and growth has been well established, and specific morphometric parameters have been determined in vitro and in vivo (
      • Folkman J.
      What is the evidence that tumors are angiogenesis dependent?.
      ,
      • Folkman J.
      The role of angiogenesis in tumor growth.
      ). Tumor angiogenesis studies are driven by the need to understand the role of blood vessel development in tumor growth, with the ultimate goal of inhibiting growth and metastasis. Quantitative evidence has shown that in certain nonsmall cell lung carcinoma (
      • Macchiarini P.
      • Fontanini G.
      • Hardin M.J.
      Relation of neovascularization to metastasis of non-small-cell lung cancer.
      ), prostate (
      • Wakui S.
      • Fursato M.
      • Itoh T.
      • et al.
      Tumor angiogenesis in prostatic carcinoma with and without bone marrow metastasis. a morphometric study.
      ), and breast cancers (
      • Weich H.A.
      • Iberg N.
      • Folkman J.
      Transcriptional regulation of basic fibroblast growth factor gene expression in capillary endothelial cells.
      ), intratumoral microvessel density correlates with the development of metastasis, and may be an independent and significant prognostic indicator in certain tumors (
      • Weidner N.
      Tumoral vascularity as a prognostic factor in cancer patients. the evidnece continures to grow.
      ). Folkman has proposed that tumor progression is associated with a switch to an ‘‘angiogenic phenotype’' and develops after abrogation of the normal proliferative controls and tumor suppressor mechanisms (
      • Folkman J.
      The role of angiogenesis in tumor growth.
      ).
      The clinical observation that the removal of the primary tumor in certain cancers led to the apparent increased growth of previously dormant metastasis instigated the search for a circulating tumor ‘‘factor’' that inhibited metastatic growth. The first of these ‘‘factors’' to be identified was from a murine model of Lewis lung carcinoma (LLC) and was a protease-generated product of plasminogen called angiostatin (
      • O'Reilly M.S.
      • Holmgren L.
      • Shing Y.
      • et al.
      Angiostatin. A novel angiogenesis inhibitor that mediates the suppression of metastasis by a Lewis Lung Carcinoma.
      ). This protein was found to have endothelial cell antiproliferative properties in vitro (
      • O'Reilly M.S.
      • Holmgren L.
      • Shing Y.
      • et al.
      Angiostatin. A novel angiogenesis inhibitor that mediates the suppression of metastasis by a Lewis Lung Carcinoma.
      ) and to inhibit angiogenesis of certain murine tumors in vivo (
      • O'Reilly M.S.
      • Holmgren L.
      • Chen C.
      • Folkman J.
      Angiostatin induces and sustains dormancy of human primary tumors in mice.
      ). In this model, it was later determined that a tumor-generated growth factor, GM-CSF, induces the protease that cleaves plasminogen to angiostatin (
      • Dong Z.
      • Kumar R.
      • Yang X.
      • Fidler I.J.
      Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.
      ), and that this protease is a macrophage MMP, MMP-12, or macrophage elastase (
      • Dong Z.
      • Kumar R.
      • Yang X.
      • Fidler I.J.
      Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.
      ;
      • Cornelius L.A.
      • Nehring L.C.
      • Harding E.
      • et al.
      Matrix metalloproteinases generate angiostatin. Effects on neovascularization.
      ) (Figure 3). Further studies have found that both serine proteases (plasmin) (
      • Gately S.
      • Twardowski P.
      • Stack S.
      • et al.
      Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, Angiostatin.
      ;
      • Gately S.G.
      • Twardowski P.
      • Stack M.S.
      • et al.
      The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin.
      ;
      • Stathakis P.
      • Fitzgerald M.
      • Matthias L.J.
      • Chesterman C.N.
      • Hogg P.J.
      Generation of angiostatin by reduction and proteolysis of plasmin: Catalysis by a plasmin reductase secreted by cultured cells.
      ) and other MMP (MMP-2, -3, -7, -9) (
      • Patterson B.C.
      • Sang Q.X.A.
      Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9).
      ;
      • Cornelius L.A.
      • Nehring L.C.
      • Harding E.
      • et al.
      Matrix metalloproteinases generate angiostatin. Effects on neovascularization.
      ) are also capable of generating angiostatin from plasminogen. In the LLC model, it was postulated that the angiogenesis inhibitor angiostatin blocks the development of a functional vasculature in the micrometastasis and consequently inhibits their growth. Other endogenous angiogenesis inhibitors have recently been described, most notably endostatin, a cleavage product of collagen XVIII (
      • O'Reilly M.
      • Boehm T.
      • Shing Y.
      • et al.
      Endostatin. An endogenous inhibitor of angiogenesis and tumor growth.
      ), although the specific protease(s) responsible for the cleavage have not been determined.
      Figure thumbnail gr3
      Figure 3Cleavage of plasminogen by matrix metalloproteinases. (A) Pancreatic elastase (PE) [39 mM] and the MMP [final concentration 5 × 10-7 M] mouse and human macrophage elastase (MMP-12, MME and HME, respectively) were incubated with 4 μM plasminogen (HPg) [final concentration] for 1 or 18 h at 37°C. The reaction mixtures were stopped with SDS sample buffer containing DTT and subjected to electrophoresis on a 10% SDS-polyacrylamide gel. (B) The MMP [final concentration 5 × 10-7 M] stromelysin (MMP-3), 92 kDa gelatinase (MMP-9), collagenase-2 (MMP-8), matrilysin (MMP-7), collagenase-1 (MMP-1) and collagenase-3 (MMP-13) were incubated with 4 μM HPg [final concentration] for the indicated times. (C) MMP-12 was preincubated with either aprotinin (Apr) [100 KIU/ml], a hydroxymate MMP-inhibitor (SC 44463) [25 μM], or TIMP [25 μM] for 1 h prior to the addition of HPg. For all parts, the arrows denote 38 kDa, 35 kDa, and 14 kDa cleavage products. The 38 k Da product was subsequently sequenced and is consistent with angiostatin (kringle regions 1–4).
      Reproduced with permission from
      • Cornelius L.A.
      • Nehring L.C.
      • Harding E.
      • et al.
      Matrix metalloproteinases generate angiostatin. Effects on neovascularization.
      , Copyright 1998, American Association of Immunologists.
      Another intriguing development in the area of tumor metastasis is the finding that, in certain in vivo models of lung metastasis, tumor cells remain within the microvasculature, and form distinct tumor cell colonies (
      • Al-Mehdi A.B.
      • Tozawa K.
      • Fisher A.B.
      • Shientag L.
      • Lee A.
      • Muscheil R.J.
      Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis.
      ). Although not yet investigated, further study of the expansion, perhaps proliferation, and ultimately vascularization of such intravascular tumor colonies could reveal novel mechanisms of tumor angiogenesis, possibly involving MMP.
      Nonetheless, it is indeed interesting that the MMP have been recently implicated in the inhibition of angiogenesis, as suggested by their role in the generation of angiogenesis inhibitors (
      • Dong Z.
      • Kumar R.
      • Yang X.
      • Fidler I.J.
      Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.
      ;
      • Patterson B.C.
      • Sang Q.X.A.
      Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9).
      ;
      • Cornelius L.A.
      • Nehring L.C.
      • Harding E.
      • et al.
      Matrix metalloproteinases generate angiostatin. Effects on neovascularization.
      ) and the antiangiogenic activity of certain specific MMP domains (
      • Brooks P.C.
      • Silletti S.
      • von Schalscha T.L.
      • Friedlander M.
      • Cheresh D.A.
      Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity.
      ;
      • Vazquez F.
      • Hastings G.
      • Ortega M.A.
      • Lane T.F.
      • Oikemus S.
      • Lombardo M.
      • Iruela-Arispe M.L.
      METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-iinhibitory activity.
      ). As reviewed above, investigations have previously demonstrated that both endothelial cell serine proteases [urokinase plasminogen activator (uPA), tissue-type plasminogen activator (tPA) and plasmin] (
      • Pepper M.S.
      • Vassalli J.D.
      • Montesano R.
      • Orci L.
      • Medi P.
      Urokinase-type plasminogen activator is induced in migrating capillary endothelial cells.
      ,
      • Pepper M.S.
      • Ferrara N.
      • Orci L.
      • Montesano R.
      Vascular endothelial growth factor induces plasminogen activators and plasminogen actiovator inhibitor-1 in microvascular endothelial cells.
      ;
      • Blei F.
      • Wilson L.
      • Magnatti P.
      • Rifkin D.
      Mechanism of action of angiostatic steroids: Suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis.
      ;
      • van Hinsbergh V.W.
      • Koolwijk P.
      • Hanemaayer R.
      Role of fibrin and plasminogen activation in repair-associated angiogenesis: in vitor studies with human endothelial cells.
      ) and MMP (
      • Fisher C.
      • Gilbertson-Beadling S.
      • Powers E.A.
      • Petzold G.
      • Poorman R.
      • Mitchell M.A.
      Interstitial collagenase is required for angiogenesis in vitro.
      ;
      • Moscatelli D.
      • Rifkin D.B.
      Membrane and matrix localization of proteinases: a common theme in tumor cell invasion and angiogenesis.
      ;
      • Takigawa M.
      • Nishida Y.
      • Suzuki F.
      • Kishi J.
      • Yamashite K.
      • Hayakiana T.
      Induction of angiogenesis in chick yolk-sac membrane by polyamines and its inhibition by tissue inhibitors of metalloproteinases (TIMP and TIMP-2).
      ;
      • Le Querrec A.
      • Duval D.
      • Tobelem G.
      Tumor angiogenesis.
      ;
      • Ray J.M.
      • Stetler-Stevenson W.G.
      The role of matrix metalloproteinases and their inhibitors in tumour invasion, metastasis and angiogenesis.
      ;
      • Taraboletti G.
      • Garofalo A.
      • Belotti D.
      • et al.
      Inhibition of angiogenesis and murine hemangioma growth by batimastst, a synthetic inhibitor of metalloproteinases.
      ;
      • Stetler-Stevenson W.G.
      Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention.
      ) can contribute to angiogenesis through subendothelial basement membrane degradation, endothelial cell migration, and ultimately, the formation of a newly formed vasculature. Substantiating these findings are studies in MMP-9 deficient mice that have demonstrated decreased ossification and growth plate vascularization (
      • Vu T.H.
      • Werb Z.
      • Gelatinase B.
      Structure, regulation and function.
      ). Tumor models in MMP-2 deficient mice have shown reduced angiogenesis and tumor progression (
      • Itoh T.
      • Tanioka M.
      • Yoshida H.
      • Yoshioka T.
      • Nishimoto H.
      • Itohara S.
      Reduced angiogenesis and tumor progression in gelatinase-A deficient mice.
      ). Additionally, the expression of MMP-2 and MT1-MMP, which are the MMP most frequently implicated in angiogenesis, has been found to correlate with malignant progression in gliomas, a highly vascular tumor (
      • Lampert K.
      Machein U, Conca W, Peter HH, Volk B Expression of matrix metalloproteinases ant their inhibitors in human brain tumors.
      ). Work such as this has led to the experimental and current use of MMP inhibitors in clinical trials in certain types of cancer (
      • Breattie G.J.
      • Smyth J.F.
      Phase I study of intraperitoneal mtalloproteinase inhibitor BB94 in patients with malignant ascites.
      ;
      • Davies B.
      • Brown P.
      • East N.
      A synthetic matrix metalloproteinase inhibitor decreases tumour burden and prolongs survival of mice bearing human ovarian caarcinoma xenografts.
      ;
      • DeClerck Y.A.
      • Perez N.
      • Shimada H.
      • Boone T.C.
      • Langley K.E.
      • Taylor S.M.
      Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases.
      ,
      • DeClerk Y.A.
      • Imren S.
      • Montgomery A.M.
      • Mueller B.M.
      • Reisfeld R.A.
      • Laug W.E.
      Proteases and protease inhibitors in tumor progression.
      ;
      • Tarboletti G.
      • Garofalo A.
      • Belotti D.
      Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases.
      ).

      MMP and anti-angiogenic agents

      Physiologic inhibitors of MMP include the TIMP as well as the more general inhibitor α2 macroglobulin. Proteolytic and biologic activity of MMP is partially regulated by the expression of TIMP. MMP often exist complexed with TIMP, and there is evidence to suggest that this complex forms after their secretion (
      • Nguyen M.
      • Arkell J.
      • Jackson C.J.
      Active and tissue inhibitor of matrix metalloproteinase-free gelatinase B accumulates within human microvascular endotehlial cell vesicles.
      ). In vivo murine tumor models have shown that invasiveness of certain tumors may be inversely related to tumor cell expression of TIMP-1 (
      • Soloway P.
      • Alexander C.M.
      • Werb Z.
      • Jaenisch R.
      Targeted mutagensis of TIMP-1 reveals that lung tumor invasion is influenced by TIMP-1 genotype of the tumor but not by that of the host.
      ) and that overexpression of TIMP-3 by tumor cells reduces tumor growth, possibly by its angiostatic activity (
      • Anand-Apte B.
      • Bao L.
      • Smith R.
      • Iwata K.
      • Olsen B.R.
      • Zetter B.
      • Apte S.S.A.
      review of tissue inhibitor of metalloproteinase-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth.
      ). Other systems have used recombinant TIMP protein(s) to inhibit MMP and in vitro angiogenesis (
      • Takigawa M.
      • Nishida Y.
      • Suzuki F.
      • Kishi J.
      • Yamashite K.
      • Hayakiana T.
      Induction of angiogenesis in chick yolk-sac membrane by polyamines and its inhibition by tissue inhibitors of metalloproteinases (TIMP and TIMP-2).
      ;
      • Schnaper H.W.
      • Grant D.S.
      • Stetler-Stevenson W.G.
      • et al.
      Type IV collagenase (s) and TIMPs modulate endothelial cell morphogenesis in vitro.
      ), murine tumor invasiveness (
      • Bao L.
      • Smith R.
      • Iwata K.
      • Olsen B.R.
      • Zetter B.
      • Apte S.S.A.
      review of tissue inhibitor of metalloproteinase-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth.
      ), and blood vessel development (
      • Valente P.
      • Fassina A.
      • Melchiori L.
      • et al.
      TIMP-2 overexpression reduces invasivelness and nagiogenesis and protects B16F10 melanoma cells from apoptosis.
      ). In seeming contradiction, however, studies have shown that TIMP may promote development of certain tumors (
      • Koop S.
      • Khokha R.
      • Schmidt E.R.
      • MacDonald I.C.
      • Morris V.L.
      • Chambers A.F.
      • Groom A.C.
      Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravasation but reduces tumor growth.
      ) and may perform separate biologic functions other than MMP inhibition, such as being effectors of cell proliferation (
      • Murphy A.N.
      • Unsworth E.J.
      • Stetler-Stevenson W.G.
      Tissue inhibitor of metalloproteinase-2 inhibits bFGF induced human microvascular endothelial cell proliferation.
      ). As with the MMP, evidence exists that, in certain tumors, TIMP also have tumor promoting activity (summarized in
      • Blavier L.
      • Henriet P.
      • Imren S.
      • DeClerk Y.A.
      Tissue inhibitors of matrix metalloproteinases in cancer.
      ). The clinical use of recombinant TIMP proteins as antitumor or antiangiogenic agents may be limited by this potential dual function together with the low plasma half-life of the recombinant protein that necessitates unrealistic dosage regimens and protein concentrations (
      • Blavier L.
      • Henriet P.
      • Imren S.
      • DeClerk Y.A.
      Tissue inhibitors of matrix metalloproteinases in cancer.
      ).
      Synthetic MMP inhibitors (MMPI) have been engineered based upon knowledge of the MMP structure and subsites, combined with the capability to chelate Zn++ at the active catalytic site (
      • Skotnicki J.S.
      • Zask A.
      • Nelson F.C.
      • Albright J.D.
      • Levin J.I.
      Design and Synthetic considerations of matrix metalloproteinase inhibitors.
      ). The most widely used Zn++-chelating compounds contain a hydroxamic acid group (Figure 4) (
      • Brown P.D.
      Syntehtic inhibitors of matrix metalloproteinases.
      ;
      • Skotnicki J.S.
      • Zask A.
      • Nelson F.C.
      • Albright J.D.
      • Levin J.I.
      Design and Synthetic considerations of matrix metalloproteinase inhibitors.
      ). Structural modifications of regions within the inhibitor backbone alter their recognition of MMP enabling development of inhibitors that are more specific to certain MMP (
      • Skotnicki J.S.
      • Zask A.
      • Nelson F.C.
      • Albright J.D.
      • Levin J.I.
      Design and Synthetic considerations of matrix metalloproteinase inhibitors.
      ). As previously described, this work has been greatly aided by determination of the MMP catalytic site and MMP/inhibitor complex structures via X-ray crystallography (see Introduction). Available X-ray structures of MMP-3 and MMP-8 have been used to design synthetic compounds with complimentary composition to their respective MMP specificity pocket(s) (
      • Matter H.
      • Schwab W.
      • Barbier D.
      • et al.
      Quantitiative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field anaysis and x-ray structure analysis.
      ).
      Figure thumbnail gr4
      Figure 4Synthetic MMP inhibitors. Hydroxymate group (CONHOH) binds to active site Zn ion of the MMP. Asterisks denote molecule sites that affect recognition of specific MMP.
      One of the first hydroxymates developed was Batimistat (BB-94, British Biotech). This MMP inhibitor was found to have poor solubility and was not suitable for oral or intravenous administration. It has shown efficacy, however, in early clinical studies when administered intraperitoneally for malignant pleural effusions and ascites (
      • Ngo J.A.G.
      • Castaner J.
      Batimastat.
      ). A second generation hydroxymate MMP inhibitor, Marimistat, another broad spectrum MMPI, has increased bioavailability and is in clinical trial as an antiangiogenic agent in certain cancers, including nonsmall cell lung cancer, metastatic breast cancer, small cell lung cancer and the highly vascular glioblastoma (NCI). Recent reports of completed clinical trials employing marimistat in advanced pancreatic carcinoma have demonstrated no survival advantage over chemotherapy, however (
      • Yip D.
      • Ahmad A.
      • Karapetis C.S.
      • Hawkins C.A.
      • Harper P.G.
      Matrix metalloproteinase inhibitors: applications in oncology.
      ). AG3340 (Agouron Pharmaceuticals, San Diego, CA), also a hydroxymate inhibitor, has selective inhibitory activity for the gelatinases, MT1-MMP and collagenase-3. In murine human tumor models, this agent has demonstrated dose-dependant growth inhibition and decreased tumor angiogenesis in certain colon, lung, and breast tumors (
      • Shalinsky D.R.
      • Brekken J.
      • Zou H.
      • et al.
      Broad antitumor and antiangiogenic activities of AG3340, a potent selective MMP Inhibitor undergoing advanced oncology clinical trials.
      ).
      Other Zn++-chelating groups that have been specifically synthesized to inhibit MMP include the mercaptoalcohols and mercaptoketones (
      • Campbell D.A.
      • Xiao X.-Y.
      • Harris D.
      • et al.
      Malonyl a-mercaptoketones and a-mercaptoalcohols, a new class of matrix metalloproteinase inhibitors.
      ;
      • Levin J.I.
      • Di Joseph J.F.
      • Killar L.M.
      • et al.
      The asymmetric synthesis and in vitro characterization of succinyl mercaptoketone inhibitors of matrix metalloproteinases.
      ). The bisphosphonates, a separate class of drugs that are currently in use for diseases of bone-resorption, have recently been recognized to have MMP inhibitor activity in vitro, possibly due to their cation-chelating ability (
      • teronen O.
      • Heikkila P.
      • Konttinen Y.T.
      • et al.
      MMP. inhibition and downregulation by bisphosponates.
      ). Another known class of drugs, the tetracyclines, have been recognized for their ability to inhibit MMP activity, originally in periodontal disease (
      • Golub J.
      Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action.
      ) in doses less than that exibiting antimicrobial activity. Such findings have provided the basis for the development of a class of tetracycline-based MMP inhibitors without antimicrobial activity, the chemically modified tetracyclines. A separate method used to identify MMP inhibitors is the screening of phage display peptide libraries. One group has screened for gelatinase-specific (MMP-2, -9) inhibitors and identified cyclic peptides containing the sequence HWGF (
      • Koivunen E.
      • Arap W.
      • Valtanen H.
      • et al.
      Tumor targeting with a selective gelatinase inhibitor.
      ), prompting the synthesis of the synthetic peptide CTTHWGFTLV that has been shown to inhibit tumors in murine models that target angiogenic blood vessels (
      • Koivunen E.
      • Arap W.
      • Valtanen H.
      • et al.
      Tumor targeting with a selective gelatinase inhibitor.
      ).
      Musculoskeletal pain and inflammation are a commonly reported side-effect of the hydroxymate MMPI that is characteristically dose-related (
      • Nemunaitis J.
      • Poole C.
      • Primrose J.
      • et al.
      Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marismistat on serum tumor markers in advanced cancers: selection of a biologically active and tolerable dose for longer term studies.
      ). Along these lines, the ability of both the broad spectrum and selective MMPI to exhibit anticancer effects (in a mouse melanoma model) and to induce tendinitis (in a rat tendinitis model) (
      • Drummond A.H.
      • Beckett P.
      • Brown P.D.
      • et al.
      Preclinical and clinical studies of MMP Inhibitors in cancer.
      ) has been investigated. Controlling for systemic dose and inhibitor potency, the MMP-selective (collagense-, gelatinase-) inhibitors caused less tendinitis but were also less effective as anticancer agents. Interestingly, at equivalent dosages, one of the broad spectrum MMPI tested that had less ability to inhibit certain MMP-like enzymes known as membrane protein ‘‘sheddases’' also exhibited less capability to induce tendinitis. ‘‘Sheddases’' are metalloenzymes that release membrane-associated proteins, some of which are growth factors and cytokines such as transforming growth factor (TGF-α) (
      • Arribas J.
      • Coodly L.
      • Vollmer P.
      • Kei Kishimoto T.
      • Rose-John S.
      • Massague J.
      Diverse cell surface protein ectodomains are shed by a system sensitive to metalloproteinase inhibitors.
      ) and tumor necrosis factor (TNF-α), and have previously been shown to be inhibited by certain MMPI (
      • Gearing A.J.H.
      • Beckett M.
      • Christodoulou M.
      • et al.
      Processing of tumor necrosis factor-alpha by metalloproteinases.
      ). In related work, MMPI have also been found to inhibit the release of L-selectin from the T lymphocyte surface, and consequently affect lymphocyte transgression through the vasculature and into the lymph node (
      • Preece G.
      • Murphy G.
      • Ager A.
      Metalloproteinase-mediated regression of L-selectin levels on leucocytes.
      ). As studies with MMPI progress, it is increasingly evident that these agents, like the MMP and sheddases that they inhibit, affect varied biologic processes other than tumor cell invasion and angiogenesis. Additionally, they are not cytotoxic but rather cytostatic, and if their efficacy in human studies is proven, their use as anticancer agents may ultimately be as selective adjuvants to chemotherapeutic agents in certain tumors.

      Conclusions

      The contribution of MMP to tumor growth, invasion, and angiogenesis has been established by multiple in vitro and in vivo investigations. In light of such findings, the inhibition of MMP activity has been investigated as a mechanism of inhibiting tumor growth and metastasis. Although the MMP profile of tumors is not homogenous, the expression of certain MMP, i.e., MMP-2, -9 and MT1-MMP, are implicated in both tumor invasion and angiogenesis. There is disagreement as to whether the application of broad-spectrum inhibitors, such as the early hydroxymate inhibitors, in distinction to the use of inhibitors that target certain MMP (i.e., the gelatinases) is most appropriate. Investigations aimed at improving our knowledge of the heterogeneity of specific tumor types and the host defense mechanism(s) involved will potentially allow more tumor-specific intervention of these therapeutic agents.

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