Collagenases in cancer

Biochimie 87 (2005) 273–286 www.elsevier.com/locate/biochi

Collagenases in cancer Risto Ala-aho, Veli-Matti Kähäri * Department of Medical Biochemistry and Molecular Biology,Department of Dermatology, and MediCity Research Laboratory, University of Turku, Turku, Finland Received 22 October 2004; accepted 21 December 2004 Available online 12 January 2005

Abstract Three mammalian collagenases (MMP-1, MMP-8, and MMP-13) belong to family of matrix metalloproteinases and are the principal secreted endopeptidases capable of cleaving collagenous extracellular matrix. In addition to fibrillar collagens, collagenases can cleave several other matrix and non-matrix proteins including growth factors, and this way regulate cell growth and survival. Collagenases are important proteolytic tools for extracellular matrix remodeling during organ development and tissue regeneration, but they also apparently play important roles in many pathological situations and tumor progression and metastasis. Because of their potentially destructive characteristics the expression and activity of collagenases are strictly controlled. Synthesis of collagenases is regulated by extracellular signals via cellular signal transduction pathways at transcriptional and post-transcriptional level. Collagenases are synthesized as inactive pro-forms, and once activated, their activity is inhibited by specific tissue inhibitors of metalloproteinases, TIMPs, as well as by non-specific proteinase inhibitors. In this review we discuss the current view on the role of collagenases in tumor growth, invasion, and metastasis, as a basis for their feasibility in diagnosis and prognostication, as well as therapeutic targets in cancer patients. © 2005 Published by Elsevier SAS. Keywords: Collagenase; Matrix metalloproteinase; Cancer; Metastasis

1. Introduction Controlled degradation of extracellular matrix (ECM) is an important feature in a variety of biological processes, such as embryonic development, tissue remodeling and tissue repair. On the other hand, controlled degradation of extracellular matrix (ECM) is an essential part of growth, invasion, and metastasis of malignant tumors. Matrix metalloproteinases (MMPs) are a family of extracellular zinc-dependent neutral endopeptidases collectively capable of degrading essentially all ECM components and they play an important role in ECM remodeling in physiologic situations, such as embryonal development, tissue regeneration, and wound repair. MMPs also play a role in pathological conditions involving untimely and accelerated turnover of ECM, including rheumatoid arthritis, osteoarthritis, atherosclerotic plaque rupture, aortic aneurysms, periodontitis, autoimmune blistering * Corresponding author. Department of Medical Biochemistry and Molecular Biology, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland. FAX:+358-2-3337229. Tel:+358-2-3337349. E-mail address: [email protected] (V.-M. Kähäri). 0300-9084/$ - see front matter © 2005 Published by Elsevier SAS. doi:10.1016/j.biochi.2004.12.009

disorders of the skin, dermal photoaging, and chronic ulcerations. In addition, distinct MMPs play important, and sometimes opposite roles at different steps of tumor growth, invasion, and metastasis, and recent observations suggest that MMPs also play a role in cancer cell survival [1,2].

2. Collagenases Collagenase-1 (MMP-1), collagenase-2 (MMP-8), and collagenase-3 (MMP-13) are principal secreted proteinases capable of cleaving native fibrillar collagens of types I, II, III, V and IX. Type I collagen is cleaved at specific sites between Gly775-Ile776 of the a1 chains and Gly775-Leu776 residues of the a2 chain (Fig. 1). In addition to MMP-1, MMP-8, and MMP-13, gelatinase-A (MMP-2) has a weak catalytic activity towards fibrillar collagens [3]. Furthermore, membranetype-1 MMP (MMP-14) has been shown to cleave fibrillar collagens [4]. Recent studies show, that the ability of MMP-1, MMP-2, and MMP-14 to cleave fibrillar collagens depends on their ability to unwind the triple helical structure of native collagens [5,6]. This selective cleavage reaction generates

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Fig. 1. Degradation of fibrillar collagens. Fibrillar collagens are degraded by collagenases, MMP-1, MMP-8 and MMP-13 at the specific site of the alpha chain resulting in generation of 3/4 N-terminal and 1/4 C-terminal fragments that are denaturated into gelatin at body temperature. Gelatin fragments are further degraded by gelatinases MMP-2 and MMP-9 but also by MMP-13. Furthermore MMP-13 cleaves type I collagen in non-helical telopeptide. Membrane bound MT1-MMP (MMP-14) can also cleave fibrillar collagen and MMP-2 shows weak collagenolytic activity.

3/4 N-terminal and 1/4 C-terminal triple-helical fragments, which denature spontaneously into gelatin at body temperature, and can be further degraded by other MMPs [1,2]. The catalytic activities of collagenases towards fibrillar collagens differ to some extent. For example, MMP-1 prefers type III collagen and MMP-8 prefers type I collagen [1,2]. MMP13 cleaves type II collagen more efficiently than other fibrillar collagens, and it also degrades gelatin more efficiently than other collagenases [7]. The genes for human MMP-1, MMP-8, and MMP-13 are localized to the telomeric side of the MMP gene cluster in the long arm of chromosome 11 [8]. The fourth vertebrate collagenase has been found only from Xenopus laevis, and it is relatively different in sequence from other collagenases [9]. Collagenases have a characteristic multidomain MMP structure consisting of a signal peptide, a propeptide, a catalytic domain, a hinge region, and a hemopexin domain (Fig. 2). The N-terminal signal peptide directs the newly synthesized preprocollagenase for secretion and is subsequently removed from the latent enzyme. The propeptide contains a conserved cysteine residue, which forms a covalent bond with the catalytic zinc ion in the catalytic site, called cysteine switch, which maintains the procollagenase in latent state [10]. The catalytic domain contains a highly conserved zinc binding sequence HEXXHXXGXXH, which is essential for the proteolytic activity of MMPs. Glutamate and aspartic acid rich sequences at the N- and C-terminal ends of the catalytic domain are thought to represent calcium binding motifs. Collagenases have a hemopexin domain linked to a catalytic domain via a proline-rich hinge region. The hemopexin domain shows sequence similarity to a heme-binding protein hemopexin, and it is highly conserved among MMPs. Two cysteine residues flanking the hemopexin domain form a disulfide bridge folding the domain into a four bladed propeller structure [1,2]. The hemopexin domain plays a role in regulating both substrate specificity and proteolytic activities. It is also important for the binding of tissue inhibitors of metalloproteinases (TIMPs) [11–14]. Characteristic 9-amino acid

Fig. 2. The domain structures of human MMPs. MMPs are classified into subgroups on the basis of their domain structures and substrate specifities.

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sequence present in the linker region of stromelysins is absent in collagenases. Lack of this peptide in collagenases is essential for their collagen binding characteristics [15]. It has been suggested that the short linker region of collagenases positions the hemopexin domain just over the catalytic domain destabilizing triple helical collagen, unwinding it and allowing the single a-chains of the collagen molecule fit into the active site where each a-chain is hydrolyzed [16].

Table 2 In vivo expression profiles of collagenases Collagenase Collagenase-1 (MMP-1)

2.1. Collagenase-1 (MMP-1) The first member of MMP family was purified from the tail of a tadpole, in which collagenolysis is required to digest the collagen of the tail during amphibian metamorphosis [17]. The first human MMP cDNA cloned and sequenced, i.e. that of MMP-1, was obtained from adult skin fibroblasts [18]. Human MMP-1 is produced as two differently glycosylated proenzymes, a major 52 kDa and a minor 57 kDa form. Cleavage of the propeptide in these generates two active proteinases 42 kDa and 47 kDa in size, respectively [19]. Expression of human MMP-1 is detected in a variety of physiological processes including embryonic development, and wound healing, as well as in a number of pathological processes, including chronic cutaneous ulcers and different types of malignant tumors [20,21]. In cultured cells, MMP-1 is expressed by various normal cells, for example keratinocytes, fibroblasts, endothelial cells, monocytes, macrophages, hepatocytes, chondrocytes, and osteoblasts, as well as by many different types of tumor cells (Table 2) [1,2,22]. MMP-1 cleaves several components of the ECM, including collagen of types I, II, III, VII, VIII, and X, aggrecan, as well as serin proteinase inhibitors, and a2 macroglobulin (Table 1). However, its substrates do not include the main components of basement membranes. Recently, two closely related mouse counterparts to human MMP-1 have been cloned: Mcol-A and Mcol-B, which are expressed during embryo implantation, but only Mcol-A is able to cleave fibrillar collagens [23]. The original mouse interstitial collagenase (MMP-13) shows the highest homology to human MMP-13, indicating that this MMP represents a counterpart to human MMP-13 instead of MMP-1 [24]. However, mouse and rat MMP-13 are also expressed in similar situations as human MMP-1, providing evidence, that they are also functional homologues of human MMP-1.

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Collagenase-2 (MMP-8)

Collagenase-3 (MMP-13)

Expression Physiologic situations Organ development Tissue repair Pathological conditions Chronic cutaneous ulcers Malignant tumors Breast carcinoma Colorectal carcinoma Gastric carcinoma Malignant melanoma Ovarian carcinoma Oesophageal carcinoma Pancreatic adenocarcinoma Physiologic situations Articular cartilage Maturing neutrophils Pathological conditions Rheumatoid synovium Bronchitis Malignant tumors Ovarian carcinoma Physiologic situations Bone development Bone remodeling Fetal wound repair Gingival wound repair Pathological conditions Osteoarthritis Rheumatoid synovium Chronic cutaneous ulcers Intestinal ulcerations Chronic periodontitis Atherosclerosis Aortic aneurysms Malignant tumors BCC of the skin Breast carcinoma Chondrosarcoma Head and neck SCC Malignant melanoma Oesophageal carcinoma Urothelial carcinoma Vulvar SCC

References [20] [21] [52] [165] [104] [105] [108,127] [106] [116] [107] [28] [25] [29] [30] [119] [40,41] [41] [43] [42] [48] [41,46] [52] [51] [50] [49] [47] [122] [24] [67] [110] [127,108] [125] [129] [124]

Table 1 Substrates and activators of human collagenases AAT, a1-antitrypsin; ACT, a1-antichymotrypsin; a2M, a2-macroglobulin; IGFBP, insulin-like growth factor binding protein; IL-1b, interleukin 1b; MBP, myelin basic protein; MCP, monocyte chemoattractant protein; SDF-1, stromal cell-derived factor-1 Collagenase Collagenase-1 (MMP-1)

Collagenase-2 (MMP-8) Collagenase-3 (MMP-13)

Matrix substrates aggrecan, collagens I, II, III, VII, VIII, X, XI, entactin/nidogen, fibronectin, MBP, gelatin, IGFBPs, laminin, link protein, perlecan, tenascin, vitronectin aggrecan, collagens I, II, III aggrecan, collagens I, II, III, IV, IX, X, XIV, gelatin, fibronectin, laminin, large tenascin C, versican, fibrillin, osteonectin

Other substrates AAT, ACT, a2M, casein, C1q, fibrin,fibrinogen, IL-1b, MCP-1, -3, -4, proTNF-a, proMMP-1, proMMP-2 AAT, a2M, C1q, fibrinogen, substance P, proMMP-8, LIX a2M, casein, C1q, factor XII, fibrinogen, MCP-3, SDF-1, proMMP-2, proMMP-9, proMMP-13

Activated by MMP-3, MMP-7, MMP-10, plasmin, kallikrein, chymase

MMP-3, MMP-10, plasmin MMP-2, MMP-3, MMP-10, MMP14, MMP-15, plasmin

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2.2. Collagenase-2 (MMP-8)

3. Regulation of collagenase activity

Collagenase-2 (neutrophil collagenase, MMP-8) is synthesized by neutrophils during their maturation in bone marrow, stored in their intracellular granules and released in response to extracellular stimuli [25,26]. MMP-8 has six potential N-glycosylation sites and is secreted either as a 55 kDa unglycosylated form or as a 75 kDa glycosylated form [26,27]. The higher level of glycosylation of MMP-8 compared to other collagenases may aid in targeting this enzyme to intracellular secretory granules of neutrophils. In addition, MMP8 is expressed by chondrocytes in human articular cartilage, mononuclear fibroblast-like cells in rheumatoid synovium and also in bronchial epithelial cells and monocytes during bronchitis [28–30]. Human MMP-8 is expressed by various types of cells in culture, including human chondrocytes, rheumatoid synovial fibroblasts, gingival fibroblasts, oral mucosa keratinocytes, and melanoma cells [22,28,29,31]. The main substrates of MMP-8 are fibrillar collagens, and it cleaves type I collagen at significantly higher rate than type III collagen [27]. In addition, MMP-8 can regulate inflammation by cleaving and activating chemokines, e.g. LIX (Table 1).

In normal intact tissues, MMPs are usually expressed at low level, but their production and activation is rapidly induced when active tissue remodeling is needed. Neutrophils and epithelial cells in exocrine glands are exceptions, since they store MMP-8 and MMP-9 in secretory granules for rapid release if required. In other types of cells, the expression of MMPs is induced in response to exogenous signals, such as growth factors, cytokines, chemical agents like phorbol esters, physical stress, oncogenic transformation, cellcell and cell-matrix interactions. This results in activation of transcription factors that bind to specific DNA sequences on 5’-regulatory regions of genes. The transcriptional response to different stimuli then depends on the function of tissue specific regulatory elements on the MMP genes.

2.3. Collagenase-3 (MMP-13) Collagenase-3 (MMP-13) was originally cloned from human breast cancer tissue [24]. It is produced as a 60 kDa glycoprotein that is activated to a 48 kDa form via a 50 kDa intermediate by plasmin, stromelysins, MMP-2, and MT1MMP [7,32]. As compared to other MMPs, MMP-13 has a restricted expression pattern and a broad substrate specificity. In addition to fibrillar collagens of type I, II, and III, MMP13 cleaves type I collagen in N-terminal non-helical telopeptide [33], gelatin [7,34], type IV, IX, X, and XIV collagens, large tenascin C, fibronectin, aggrecan, versican, fibrillin-1, and osteonectin [7,14,35,36]. Furthermore, MMP-13 can inactivate chemokines, such as monocyte chemoattractant protein-3 (MCP-3) and stromal cell-derived factor-1 (SDF-1) [37,38]. MMP-13 also appears to be involved in the activation of proTGF-b3 [39]. Expression of MMP-13 is limited to few physiologic situations, which involve rapid and effective remodeling of collagenous ECM, e.g. fetal bone development [40], post-natal bone remodeling [41], and gingival and fetal skin wound repair [42,43]. Accordingly, mice with targeted disruption in MMP-13 gene show delayed formation of long bones providing further evidence for the role of MMP-13 in skeletal development [44,45]. MMP-13 expression is also detected in pathologic conditions that are characterized by the destruction of normal collagenous tissue architecture, e.g. in osteoarthritic cartilage, rheumatoid synovium, chronic cutaneous ulcers, intestinal ulcerations, chronic periodontitis, atherosclerosis, and aortic aneurysms (Table 2) [46–52]. Altogether, the wide proteolytic capacity of MMP-13 suggests that it is a powerful and potentially destructive proteinase, and therefore its expression is strictly controlled under normal physiologic conditions.

3.1. Transcriptional regulation of MMP gene expression A variety of growth factors stimulate the expression of MMP genes via signal transduction pathways that converge to activate AP-1 (activation protein-1) complex of transcription factors. Mitogen activated protein kinase (MAPK) pathways ERK1,2, JNK, and p38 induce the expression of AP-1 transcription factors. AP-1 transcription factors regulate the expression of a variety of genes involved in proliferation, development, differentiation, inflammation, stress response and tumor progression [53]. The promoters of MMP1 and MMP-13 genes contain an AP-1 binding site at the proximal promoter approximately at position –70 with respect to the transcription initiation site (Fig. 3). Another AP-1 site is found in the distal promoter of MMP-1. The Jun/Fos dimer binds to the AP-1 site that is often accompanied by another cis-acting sequence called PEA-3 (polyoma virus enhancer A binding protein 3) which binds members of the ETS transcription factor family [54,55]. AP-1 and ETS transcription factors can synergistically activate MMP-1 gene transcription [56]. Overexpression of ETS transcription factors enhances the activity of MMP-1 promoter, this way promoting invasive phenotype of cancer cells [57–59]. The expression of ETS-1 colocalizes with the expression of many MMPs at the invading edge of several types of tumors [60–62]. One STAT transcription factor binding element is found in the promoter of MMP-1 gene and it seems to cooperate with the AP-1 site mediating enhancement of MMP-1 expression by oncostatin M [63]. MMP-1 expression is induced at transcriptional level by activation of ERK1,2 pathway [64]. The promoter of MMP-8 gene contains target sequences for the Sp-1 transcription factor (Fig. 3). Sp-1 is commonly expressed in a variety of tissues and it regulates many genes including housekeeping genes [65]. The levels of Sp-1 can vary at different stages of development in certain cell types and Sp-1 can specifically regulate the expression of tissue specific genes [65]. Functional characterization of the regulatory elements in human MMP-13 promoter has revealed that the AP-1 site is

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Fig. 3. Regulatory elements in the promoter regions of human collagenase genes. Transcription factor binding sites include AG-rich element (AGRE), activator protein-1 site (AP-1), core-binding factor 1 site (CBFA1), CCAAT-binding protein site (CCAAT), CCAAT/enhacer-binding protein-b site (C/EBP), CAS-interacting zinc-finger protein site (CIZ), GATA1 site (GATA), hormone response element (HRE), immortalization-susceptible elements 1 and 2 (ISE1, ISE2), nuclear factor E1 site (NF-E1), nuclear factor jB site (NF-jB), polyomavirus enhancer activator-3 site (PEA3), a putative p53-binding element (p53), STAT binding element (SBE), Sp-1 transcription factor site (SP-1), TATA box (TATA), T-cell factor-4 site (TCF-4), TGF-b inhibitory element (TIE), TTCA element (TTCA). Single nucleotide polymorphism at site -1607 that generates an ETS site at MMP-1 promoter is also shown.

functional and responsible for at least part of the inducibility by phorbol ester, TGF-b and IL-1b in human fibroblasts [66,67]. The adjacent PEA-3 site does not seem to play a significant role in the transcriptional regulation of the human MMP-13 gene [68]. In addition, the promoter region of human MMP-13 contains an osteoblast-specific element 2 (OSE2) that mediates the expression of osteoblastic specific genes, like osteocalcin [69]. OSE2 is recognized by Cbfa1 (Runx2), a transcription factor of the runt domain gene family involved in bone formation [70]. Since this element is present in the promoters of human, as well murine and rabbit MMP13 genes, it is not surprising that the MMP-13 is expressed in osteoblasts during fetal bone development and postnatal bone remodeling [40,41]. Furthermore, the OSE2 element is functional and mediates the induction of the MMP-13 gene by Cbfa1 in osteoblastic cells. Therefore, it may be involved in stimulating bone tumors or osteosarcomas [71]. Cbfa1 is activated by ERK1/2 in response to TGF-b1 stimulation in osteoblastic cells and mediates stimulation of MMP-13 expression [72]. The OSE2 element also participates in IL1 induction of MMP-13 in chondrocytes [73]. The p53 protein is a transcription factor that binds to a specific consensus sequence in the promoter consisting of two copies of a 10-bp DNA motif, separated by 0 to 13 bp [74]. In addition, p53 can repress the expression of a variety of cellular and viral genes [75–78]. It has been shown that wild-type and mutant p53 differentially regulate human MMP-1 and MMP-13 promoter activity in synovial cells [79,80]. In addition, over-expression of wild-type p53 in squamous carcinoma cells with p53 inactivation has been shown to reduce MMP-13 expression and suppress invasive phenotype of these cells [81].

ingly, the p38 MAPK pathway has been implicated in the regulation of the mRNA stability of several AU-rich genes [84]. However, the mechanism for p38 mediated regulation of mRNA stabilization is not well known, but it is suggested that a zinc finger protein tristetraprolin is activated by p38 and regulates the stability of some AU-rich mRNAs [85–87]. MMP-13 mRNA contains AU-rich elements which function in stabilization of the transcript in rat osteoblasts [88]. It was found that 3’-UTR of MMP-13 mRNA interacts with FUSEbinding protein-2 and vinculin, which may mediate both stabilization and cytoskeletal targeting of transcripts in osteoblasts [88]. 3.3. Activation of latent precursors Most MMPs are secreted as latent, inactive proenzymes or zymogens, and their activity is controlled in extracellular space by zymogen activation and inhibition of the catalytic activity of the enzyme. A cysteine switch formed by the interaction between the conserved cysteine residue near the C-terminal end of the propeptide and the zinc ion in the catalytic site maintains the latency of proMMPs [89]. Activation of proMMPs requires disruption of the cysteine-zinc bond by cleavage of the propeptide by proteinases such as plasmin, trypsin, kallikrein, chymase, and mast cell tryptase. Many MMPs can also activate other latent MMPs (Fig. 4). In addition, disruption of the cysteine switch by various organic and inorganic components, like organomercurials, SH-reactive

3.2. Regulation by mRNA stabilization Regulation of mRNA stability is also an important step in regulating collagenase gene expression. The 3’-untranslated region (3’-UTR) of human MMP-1 mRNA contains an AU-rich element, which plays a role in stabilization of the message [82]. Activation of p38a has been shown to result in stabilization of MMP-1 mRNA in fibroblasts [83]. Accord-

Fig. 4. Summary of MMP ability to activate each other. Arrows indicate the activation of one MMP by another.

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agents, reactive oxygen and detergents results in autocatalytic cleavage of the propeptide and in a conformational change into catalytically active form [10,89]. Activation of proMMP-1 is well characterized. MMP-1 is secreted in a 55 and 57 kDa latent form and converted into a 42 and 47 kDa activated form. Serine proteinases attack a cleavage site in the middle of the propeptide and produce a short-lived intermediate of 46 kDa that is rapidly cleaved to a relatively stable 43 kDa form by a cleavage between the Val67 and Met-68 residues. To obtain full activity, MMP1 needs to be cleaved between the Gln-80 and Phe-81 residues by MMP-3, MMP-10, or MMP-7 [90–92]. Human mast cell chymase can activate proMMP-1 by direct cleavage of the propeptide between Leu83 and Thr84 residues [93]. The activation of latent MMPs by other MMPs and other proteinases forms a complex network (Fig. 4), in which potent proteolytic activity is rapidly achieved locally when required. For example, MMP-13 can be activated by MT1-MMP either directly or indirectly by MMP-2 after it has been activated by MT1-MMP. In addition, proMMP-13 can be activated by MMP-3, MMP-10, and MT2-MMP [7,32,94], and MMP13 can in turn activate progelatinases (proMMP-2 and proMMP-9) [95]. 3.4. Inhibition of collagenase activity by TIMPs The proteolytic activity of MMPs in the extracellular space is controlled by specific tissue inhibitors of metalloproteinases (TIMPs). The TIMP gene family consists of four members, TIMP-1, -2, -3, and -4. They are major regulators of MMP activity in the extracellular space and they can inhibit the activity of all members of the MMP family [96]. They bind to the highly conserved zinc binding site of the active MMPs at molar equivalence. In addition, TIMPs can inhibit the activation of several proMMPs. Their molecular sizes vary from 21 to 28 kDa and although their primary structure homology is low, the tertiary structures of TIMPs are remarkably similar. They have a two-domain structure in which the N-terminal part is necessary for MMP inhibition, while the C-terminal end is responsible for their specificity. The inhibitory activities of TIMPs against MMPs are similar, but they differ with respect to tissue distribution, interactions with progelatinases, and the regulation of their expression [97,98]. TIMP-1 inhibits the catalytic activity of MMP-1 more efficiently than TIMP-2 and the acitivity of MMP-13 can be inhibited by all TIMPs [7]. TIMP-4 shows a slight preference for MMP-8 over other collagenases [98].

blasts and inflammatory cells produce MMPs in response to stimulation by different exogenous factors, like cytokines and tumor promoters. In addition, this may contribute to proteolytic remodeling of the peritumoral ECM. Numerous studies have demonstrated overexpression of collagenases in malignant tumors in comparison to normal tissue, suggesting a role for them in cancer cell invasion [1,2,99]. 4.1. Tumor cell invasion and metastasis Malignant tumor progression is a complex, multistage process in which normal cells undergo genetic alteration, lose their normal proliferative control and invade and colonize surrounding tissue and distant target organs. Benign and malignant intraepithelial tumors have an intact basement membrane that separates the neoplastic epithelium from the stromal connective tissue, whereas malignant epithelial tumors have dissolved the basement membrane allowing neoplastic cells to invade the underlying stroma [100]. The initial stage of tumor invasion is the loss of an intact basement membrane. In general, tumor cell invasion through the basement membrane is thought to be a three-step process. First, neoplastic cells attach themselves to the underlying basement membrane. Then the malignant cells produce proteolytic enzymes to dissolve the basement membrane. Finally, the tumor cells pass through the basement membrane and spread into the adjacent stromal connective tissue (Fig. 5). The steps of attachment, degradation, and invasion are repeated within the ECM during tumor growth and spread. A malignant tumor spreads to other parts of the body by first invading through the wall of a blood vessel or a lymphatic vessel. The tumor cells are then carried within the blood or lymph circulation, and attach to a distant location and degrade the basement membranes and ECM at the site of the metastasis. In general, anamomic location of the primary tumor dictates the site of initial metastases [101]. Furthermore, angiogenesis is required for the continuous growth of a tumor and tumor-induced lymphangiogenesis also plays an important role in tumor metastasis [102].

4. Collagenases in cell invasion Secreted collagenases play an important role in the cleavage of interstitial fibrillar collagens of types I, II, and III. It is conceivable, that degradation of collagenous ECM by these MMPs is essential for invasion of malignant cells. It is evident, that not only malignant cells but also stromal fibro-

Fig. 5. The process of cancer metastasis. BM, basement membrane.

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4.2. MMP-1 in tumor progression MMP-1 is expressed by tumor cells or adjacent stromal fibroblasts in response to stimulating factors produced by tumor cells [103]. In both cases, MMP-1 is expressed at the site of invasive tumor, and overexpression of MMP-1 has been demonstrated in a variety of advanced cancers and its expression is associated with poor prognosis in colorectal, gastric, and oesophageal carcinomas, metastatic melanoma and pancreatic adenocarcinoma [104–109]. MMP-1 expression is often localized to stromal cells surrounding SCC tumor islands, while the expression levels are low in normal, hyperplastic and dysplastic oral mucosa [110–112]. High levels of MMP-1 expression have been noted in human breast cancer cells with elevated metastasis capacity to bone providing further evidence for the role of MMP-1 in cancer cell invasion and metastasis [113]. Insertion of a guanine nucleotide at location –1607 bp in the MMP-1 promoter generates a new binding site (5’-GGAT3’) for Ets transcription factors and augments its transcriptional activity [114]. The presence of this 2G allele in the MMP-1 promoter may favor the growth and metastatic process of some tumors since homozygosity for this allele is associated with the progression of ovarian, endometrial and colorectal carcinomas [115–117]. However, the degree of tumor progression can be determined by the response of promoter to the cytokines and growth factors indicating that the polymorphism may not affect the expression level of MMP-1 in all cells. 4.3. MMP-8 in tumor progression MMP-8 is mainly expressed by neutrophils in inflammatory reactions to help neutrophils to migrate through basement membranes and connective tissue, but the expression of MMP-8 is also detected in certain type of malignant tumors including head and neck squamous cell carcinoma and ovarian cancer [118,119]. Since MMP-8 is the most effective collagenase to initiate type I collagen degradation, MMP-8 may have a potential role in the proteolysis of connective tissue associated with the spread of invasive squamous cell carcinoma [118]. It has also been suggested that MMP-8 plays an important role in the progression of ovarian cancer since its expression correlates with tumor grade and stage in ovarian cancer and is enhanced by inflammatory cytokines [119]. However, MMP-8 may play a dual role in tumor progression since the incidence of chemically induced skin carcinomas is increased in MMP-8 deficient male mice [120]. This may be due to the role of MMP-8 in proteolytic processing of inflammatory mediators, which contribute to the host antitumor defence system [120]. For example, MMP-8 processes and activates lipopolysaccharide-induced CXC chemokine LIX, a potent chemoattractant for monocytes and activator of neutrophil functions. 4.4. MMP-13 in tumor cell growth and survival MMP-13 plays an important role in tumor cell invasion by degrading various components of ECM and thus facilitating

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tumor growth and invasion. The expression of MMP-13 has been detected in several invasive neoplastic tumors, including breast carcinomas [24,66,121], squamous cell carcinomas (SCCs) of the head and neck [110,122,123], vulva [124], and esophagus [125], in chondrosarcomas [126], primary and metastatic melanomas [127,128], and urothelial carcinomas [129]. In SCCs of the head and neck, vulva, and esophagus, MMP-13 is expressed by cancer cells at the invading edge of the tumor [110,122–125]. However, no expression of MMP13 is noted in premalignant tumors in human skin [122], or by normal epidermal keratinocytes in culture or in vivo in intact skin or during wound repair [52,110,122,130]. Therefore, MMP-13 expression appears to serve as a marker for squamous epithelial cell transformation. MMP-13 expression is detected mainly in tumor cells at the invading front of the SCCs, but it is also expressed to some extent by stromal fibroblasts surrounding tumor cells [110,123]. Interestingly, the expression of MMP-13 colocalizes with the expression of MT1-MMP and MMP-2 in laryngeal and vulvar carcinomas [123,124]. This suggests that in these tumors these three MMPs form a proteolytic cascade that leads to potent extracellular collagenolytic activity [32]. Expression of MMP-13 in the head and neck SCCs correlates with the invasion and metastasis capacity of the tumor, indicating that MMP-13 expression could be an indicator for the invasive capacity of SCCs [110,123]. Since MMP-13 is not expressed in most adult human tissues under normal conditions, inhibition of MMP-13 expression may serve as an important and safe strategy for targeted cancer therapy for MMP-13 expressing malignant tumors. Accordingly, specific inhibition of MMP-13 expression by antisense ribozyme resulted in suppression of tumor growth associated with decreased cell invasion and viability and induction of apoptosis [131]. Inhibition of cell proliferation and induction of apoptosis was also seen in transformed keratinocytes after IFN-c mediated suppression of invasionassociated MMPs, MMP-1 and MMP-13 [132]. In addition, p53 possessed two temporally distinct anti-tumor effects on malignantly transformed squamous epithelial cells by displaying an initial anti-invasive effect which was followed by induction of programmed cell death [81]. Several studies have shown that MMPs can proteolytically process both cell surface anchored and secreted proteins, thus altering their biological activity [133,134]. MMP13 has been shown to degrade several non-matrix proteins including chemokines MCP-3 and SDF-1 [37,38]. MMP13 also appears to be involved in TGF-b3 activation [39]. MMP-13 may also have more yet undefined substrates and may function in releasing growth factors or other proteins. The proteolytic activity of MMPs is associated in both stimulatory and repressive processes during cellular proliferation. In summary, inhibition of cellular growth by inhibiting MMP13 expression suggests that MMP-13 can regulate cell survival by as yet unknown mechanism.

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4.5. MT1- MMP in tumor cell invasion

5.1. Blocking the MMP activity

It has been shown, that MT1-MMP (MMP-14) can cleave various components of ECM, including fibrillar collagens [4], and that the membrane-bound collagenolytic activity of MMP-14 also plays an important role in tumor cell invasion [135]. It it therefore likely, that MMP-14 can promote cancer progression both by degrading collagenous ECM and by activating latent MMP-2 and MMP-13 in the pericellular space.

The first synthetic MMP inhibitors (MMPIs) were small peptide derivates mimicking the structure of the collagen molecule at the collagenase cleavage site. These inhibitors bind reversibly and competitively to the active site of MMPs and interact with the active zinc ion inhibiting the MMP activity. Several zinc-binding groups have been tested, but the hydroxyamates have been found to be the most potent inhibitors and are thus the major MMPIs currently being tested in clinical trials. Hydroxyamate batimastat (BB-94) and its successor marimastat (BB-2516) are small molecule inhibitors that have a broad inhibitory specificity for members of the MMP family. They were the first MMPIs to enter clinical trials for the treatment of malignant tumors. Marimastat has been studied in several phase III clinical trials in cancer patients [see,99,137,138]. Maristat improved the survival of stable gastric cancer patients, who had received prior chemotherapy, as compared to patients receiving placebo [139], but in other phase III clinical cancer trials marimastat has shown no significant advantages. Design of nonpeptidic MMP inhibitors is based on the conformation of the active site of MMPs. They are more specific and have better oral bioavailability than peptidic inhibitors. Nonpeptidic MMP inhibitors include prinomastat (AG3340), BAY 12-9566, and rebimastat (BMS-275291), and they can inhibit activities of several MMPs including collagenases. They have been studied in several phase II and III studies with no beneficial results [138,140]. Chemically modified tetracyclines, like metastat (CMT3 or Col-3), have no antimicrobial activity, but they possess significant tumor cell toxicity and antimetastatic activity [141]. Metastat inhibits the activity of MMP-1, MMP-2, MMP-8, MMP-9, and MMP-13. It has also been shown to inhibit malignant cell invasion and tumor-induced angiogenesis in rodent models [142,143]. Metastat is currently being examined in phase II clinical trial in patients with Kaposi sarcoma Bisphosphonates were originally developed for treatment of patients with bone resorption and bone metastasis of malignant tumors [144]. Their molecular mechanisms responsible for the down-regulation of bone resorption have not been completely elucidated, but they have been shown to inhibit the expression and activity of MMPs. Additionally, bisphosphonates reduce the invasion capacity of malignant cells through an artificial basement membrane, Matrigel [145]. Beyond synthetic MMP inhibitors, naturally occurring MMP inhibitors have been tested in clinical trials. Neovastat (AE-941) is an orally bioavailable extract from shark cartilage that contains TIMP-like proteins. It inhibits the activity of MMP-1, MMP-2, MMP-7, MMP-9, MMP-12, and MMP-13 [138], and it is being evalutated in phase III clinical trials in patients with non-small cell lung carcinoma and in phase II clinical trial in patiets with multiple myeloma [138,146]. Since TIMPs can inhibit cell invasion, tumor growth, metastasis and angiogenesis, they could also have beneficial

5. Strategies for inhibition of collagenase activity Invasion of malignant cells is a multi-step process in which cellular motility is coupled to proteolysis and which involves interactions of cells with the ECM. Degradation of fibrillar collagens by collagenolytic MMPs is essential for invasion of malignant cells, as fibrillar collagens of type I and III constitute the majority of stromal ECM. Therefore, inhibition of MMP activity has been considered a potent way of inhibiting tumor growth and invasion. In general, the expression of MMPs can be inhibited at several levels during their synthesis and activation (Fig. 6). Instead of using broad-spectrum inhibitors, the selective inhibition of distinct MMPs has been suggested to serve as a preferable way of inhibiting tumor progression. This is particular important, because certain MMPs also display antitumor activity by releasing angiogenesis inhibitors, such as arrestin, angiostatin, canstatin, endostatin, and tumstatin from ECM [136].

Fig. 6. Levels of regulation of MMP expression and activity and possible inhibition mechanisms.

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therapeutic effects. Adenovirus-mediated delivery of TIMP3 has been shown to inhibit invasion of an MMP-13-positive cell line [147]. Adenoviral delivery of the TIMP-3 gene into tumor cells inhibits the invasion and tumor growth, and induces apoptosis both in vitro and in vivo [148,149]. In addition, adenoviral transfer of the TIMP-2 gene into colorectal liver metastasis reduced the tumor cell growth [150]. Overexpression of TIMP-1 in pancreatic cancer cells is seen to inhibit cancer cell implantation, growth, metastasis and angiogenesis [151]. TIMP-4 has an antitumoral function since TIMP-4 inhibits the growth and metastasis of breast cancer [152]. Intramuscular administration of naked TIMP-4 DNA has also seen shown to inhibit Wilms tumor growth in nude mice [153]. In general, the clinical use of TIMPs in cancer therapy is hampered by difficulties in effective delivery of the TIMP gene into the tumor tissue. 5.2. Inhibition of MMP transcription Modulation of the activity of distinct MAPKs may serve as a potent way of inhibiting collagenase expression and invasion. Inhibition of signal transduction pathways involved in the activation of AP-1 transcription factors can markedly inhibit the expression of collagenases and the invasive potential of cancer cell lines. Inhibition of the p38 signaling pathway by a specific pyridinyl imidazole compound, SB 203580 inhibits expression of MMP-1 and MMP-13 by transformed keratinocytes and inhibits their invasion [154]. Tumor suppressor p53 has been shown to inhibit the activity of human MMP-1 gene promoter [79]. In addition, the promoter of the human MMP-13 gene contains a putative p53 binding element suggesting that p53 may regulate MMP13 transcription. In fact, adenovirus-mediated delivery of wild-type p53 into cell lines derived from head and neck SCCs resulted in significant reduction in MMP-13 expression and inhibited invasion of SCC cells through Matrigel and induced apoptosis in these cells [81]. Adenovirus-mediated transfer of the normal p53 gene back into tumor cells has been evaluated in several preclinical and clinical studies, including head and neck SCCs [155–159]. Although efficacy without unspecific toxicity is seen in both cell culture and animal models, responses in early human clinical trial have not been convincing [160]. 5.3. Inhibition of MMP translation by antisense techniques The appropriate targets for therapeutic intervention varies in each type of tumor because different MMPs are overexpressed in various tumors. The expression of a specific MMP can be inhibited by antisense oligonucleotides or by targeting the MMP mRNA with catalytic RNA or siRNA molecules. The advantage of antisense strategies is their ability to selectively inhibit the expression of a specific MMP and thereby potentially diminish harmful side effects due to widespread inhibition of MMP activity. Antisense oligonucleotides for MMP-7 have been shown to inhibit the invasion of

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colon carcinoma cells and suppress the development of liver metastasis in a nude mouse model [161]. The antisense techniques may benefit from the addition of a catalytic loop to the antisense RNA molecule allowing effective cleavage of specific mRNA molecules. The hammerhead ribozymes are well-characterized, naturally occurring, small catalytic RNA molecules that pair with the specific sequence of the target RNA, catalyze a cleavage of the phosphodiester bond generating two products, and release the products from the ribozyme [162]. The advantage of ribozymes over traditional antisense techniques is that one ribozyme molecule can cleave several targeted mRNA molecules. Specific inhibition of overexpression of a particular MMP in cancer or other MMP-related diseases by ribozyme or siRNA may serve as a useful tool for efficient gene therapy. The antisense ribozymes have been evaluated for their ability to inhibit the expression of many potentially harmful proteinases, including MMP-3, MMP-9, and MMP-13 [131,163,164]. Because MMP-13 is specifically expressed by tumor cells at the invading edge of SCCs of the head and neck and vulva [110,122–124], it could be an appropriate target for therapy aimed at inhibiting growth and invasion of these SCCs. Therapeutic efficacy of specific inhibition of MMP-13 expression by MMP-13 antisense ribozyme has been shown in SCID mouse xenograft model where cutaneous SCC growth was suppressed by adenoviral delivery of MMP13 antisense ribozyme [131].

6. Conclusions It has become clear after first finding of collagenolytic activity in tadpoles by Gross and Lapiére [13], that the function of collagenases in turnover of ECM is more complex. The ECM also has other functions besides serving as structural support for cells and tissues. ECM can regulate several aspects of cell behaviour such as growth and survival, or it can serve as a reservoir for a variety of biologically active molecules [136]. MMPs can proteolytically activate or release fragments from ECM but they can also process several nonmatrix substrates. There is a considerable amount of evidence that collagenases have an important role in tumor progression. Several synthetic MMP inhibitors have been tested in clinical trials evaluating their ability to inhibit growth and invasion of malignant tumors in vivo. However, limited performance of MMP inhibitors in phase III clinical trials has been disappointing [99,137,138]. Therefore, using broad spectrum MMP inhibitors selectively targeting certain MMPs may be preferable. Improved understanding of the roles and regulation of the collagenases in tumor progression, will help in developing therapeutic approaches targeted to specific proteolytic enzymes. Novel inhibition strategies for collagenases may serve as important approach for targeted therapy for invasive malignant tumors.

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Acknowledgements The work of authors has been supported by grants from the Academy of Finland (project 45996), Sigrid Jusélius Foundation, the Cancer Research Foundation of Finland, Turku University Central Hospital (project 13336), European Union Framework Programme 6 (LSHC-CT-2003-503297), and by a post-doctoral grant to R.A. from the Foundation of Finnish Cancer Institute.

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