Matrix Metalloproteinases in Cancer Cell Invasion

Niina Reunanen; VeliMatti Kähäri

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Matrix Metalloproteinases in Cancer Cell Invasion

Niina Reunanen and VeliMatti Kähäri.

Controlled remodeling of extracellular matrix (ECM) is essential for growth, invasion, and metastasis of malignant tumors. Matrix metalloproteinases (MMPs) are a family of secreted, zinc-dependent endopeptidases collectively capable of degrading ECM components, and there is a considerable amount of evidence that they play an important role at different steps of malignant tumor growth. Recent observations also suggest that MMPs play a role in cancer cell survival. In this chapter, we discuss the role of MMPs and their inhibitors in tumor cell invasion as a basis for prognostication and targeted therapeutic intervention.

Matrix Metalloproteinases

MMPs are a family of structurally related, zinc-dependent endopeptidases collectively capable of degrading essentially all components of the extracellular matrix (ECM). There is strong evidence for the role of MMPs in physiological ECM remodeling, e.g., during tissue morphogenesis, growth, uterine cycling and postpartum involution, tissue repair, and angiogenesis. In addition, MMPs play a role in pathological conditions with excessive degradation of ECM, such as rheumatoid arthritis, osteoarthritis, atherosclerotic plaque rupture, aortic aneurysms, periodontitis, autoimmune blistering disorders of the skin, dermal photoaging, tumor invasion, and tumor metastasis.¹⁴

To date, 21 human MMPs are known, and they can be divided into subgroups based on their structure and substrate specificity (Fig. 1). These subgroups include collagenases, stromelysins and stromelysin-like MMPs, matrilysins, gelatinases, MMP19-like MMPs, membrane-type MMPs (MTMMPs), and other MMPs (Fig. 1).^14>

Figure 1

Domain structures of human MMPs. C, Cysteine; GPI, Glycosylphosphatidylinositol; CA, Cysteine Array.

MMPs have a multidomain structure (Fig. 1). N-terminal signal peptide directs the secretion of the proenzyme. Propeptide contains a highly conserved sequence PRCG(V/N)PD in which the cysteine forms a covalent bond with the catalytic zinc ion, the cysteine switch, which maintains the pro-MMP in latent form. The catalytic domain consists of two modules separated by a deep, active site cleft with zinc ion at the bottom.^5> Three histidine residues coordinate the binding of catalytic zinc at the active site. This zinc-binding motif HE××H××G××H, together with the zinc ion, is essential for the proteolytic activity of MMPs and is conserved among all MMPs. There is also a structural zinc and at least one calcium ion located approximately 12 Å from the catalytic zinc. Proline-rich hinge region links the catalytic domain to the C-terminal hemopexin domain, which is highly conserved and contains four repeats showing sequence similarity to hemopexin, a plasma protein. A disulfide bridge connects the ends of the domain, which plays a functional role in substrate binding and in interactions with the tissue inhibitors of metalloproteinases (TIMPs). In addition to these domains, some MMPs possess additional domains described here.

Collagenases

Collagenase-1 (MMP-1), collagenase-2 (MMP-8), and collagenase-3 (MMP-13), cleave the triple helix of fibrillar collagens of types I, II, III, and V. They all cleave native type I collagen between Gly⁷⁷⁵Ile⁷⁷⁶ of α1 chain, or Gly⁷⁷⁵Leu⁷⁷⁶ of α2 chain results in 3/4 N-terminal and 1/4 C-terminal triple-helical fragments, which then denature spontaneously in 37°C into gelatin and are further degraded by other MMPs, such as gelatinases.¹⁴ In addition, MMP-13 cleaves type I collagen at N-terminal nonhelical telopeptide.⁶ MMP-1 cleaves preferentially type III collagen over other fibrillar collagens, and MMP-8 cleaves type I collagen most efficiently.⁷⁹ MMP-13 preferentially cleaves type II collagen and also gelatin 40-fold more effectively than MMP-1 and MMP-8.⁷⁹

Human MMP-1 is secreted as major 52-kDa and minor glycosylated 57-kDa proenzymes, and cleavage of propeptide produces active forms of 42 kDa and 47 kDa, respectively.¹⁰ The nine residues RWTNNFREY(183-191) in catalytic domain together with the C-terminal hemopexin domain are essential for collagenolytic activity, but additional structural elements in the catalytic domain are also required.¹¹ MMP-1 substrates include type I, II, III, VII, VIII, and X collagens, aggrecan, serine proteinase inhibitors, and α2-macroglobulin. In contrast to many other MMPs, MMP-1 can not cleave BM components. MMP-1 expression is detected in vivo in many physiological situations, such as embryonal development and tissue repair, but also in pathological conditions, including chronic cutaneous ulcers and malignant tumors.¹²^,¹³ Production of MMP-1 is induced by growth factors and cytokines. In incision wounds and chronic ulcers, MMP-1 is expressed by basal keratinocytes bordering the sites of active reepithelialization¹⁴ and is needed for keratinocyte migration on type I collagen.¹⁵

Collagenase-2 (MMP-8) is synthesized by polymorphonuclear leukocytes maturing in bone marrow, stored in intracellular granules, and released in response to extracellular stimuli.¹⁶ It is also expressed by human articular cartilage chondrocytes in vivo and by mononuclear fibroblast-like cells in rheumatoid synovium.¹⁷^,¹⁸

Collagenase-3 (MMP-13) has a wide substrate specificity.⁷⁹^,¹⁹ ²² Physiological expression of MMP-13 is limited to fetal bone development, postnatal bone remodeling, gingival wound repair, and fetal cutaneous wound repair,²³ ²⁶ suggesting a role for MMP-13 in rapid and effective remodeling of collagenous ECM in these situations. MMP-13 expression in vivo is detected in inflammatory conditions, e.g., osteoarthritis,⁹ rheumatoid arthritis,²⁵ chronic cutaneous ulcers,²⁷ and chronic periodontitis,²⁸ and in invasive malignant tumors, such as breast carcinomas,⁷ squamous cell carcinomas (SCCs) of the head and neck²⁹ and vulva,³⁰ primary and metastatic melanomas,³¹^,³² and transitional cell carcinoma of the urinary bladder.³³ Accordingly, recent observations show that expression of MMP-13 enhances the invasion capacity of HT1080 fibrosarcoma cells.³⁴

Stromelysins and Stromelysin-like MMPs

Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10), have similar structure and substrate specificity. As stromelysin-3 (MMP-11) and macrophage metalloelastase (MMP-12) differ in their structure from stromelysins, they are included in this subfamily as a subgroup of stromelysin-like MMPs.¹⁴ MMP-3 and MMP-10 are expressed by keratinocytes and fibroblasts in culture and in vivo. MMP-3 is expressed by stromal cells during mammary gland development and is strongly up-regulated during postlactational mammary involution, when considerable ECM remodeling and alveolar apoptosis occur.³⁵^,³⁶ MMP-3 can induce apoptosis or promote proliferation, depending on the differentiation status of the target cell.³⁷ It also triggers angiogenesis and can act as a natural tumor promoter.³⁶^,³⁷ MMP-3 is a potent activator of latent MMP-1.³⁸ Deletion of MMP-3 impairs early dermal wound contraction, suggesting a role for MMP-3 in the organization of a multicellular actin network.³⁹

Stromelysin-3 (MMP-11) is expressed in many invasive human tumors,⁴⁰ and high expression levels correlate with poor clinical outcome in breast cancers patients.⁴⁰ MMP-11 is expressed by stromal fibroblasts adjacent to tumor cells,⁴⁰ but also by breast carcinoma cells that have undergone a degree of epithelial-to-mesenchymal transition.⁴¹ MMP-11 is important in the early stages of tumorigenesis by favoring cancer cell survival in a tissue environment initially not permissive for tumor growth.⁴² MMP-11-deficient mice have reduced chemical-induced tumorigenesis.⁴³ MMP-11 is expressed by fibroblasts in basal cell carcinomas, squamous cell carcinomas, and benign dermatofibromas,⁴⁴^,⁴⁵ MMP-11 prodomain contains a furin cleavage site, and the proenzyme is processed intracellularly and released as a mature enzyme.⁴⁶ MMP-11 degrades α1-proteinase inhibitor (α1PI),⁴⁷ but the ECM substrates have not been identified, although the existence of such substrates has been suggested.⁴⁸

Macrophage metalloelastase (MMP-12) is constantly expressed by macrophages⁴⁹ and in spindle-shaped stromal cells of placenta.⁴⁹ MMP-12 is expressed by macrophages in atherosclerotic lesions,⁵⁰ abdominal aortic aneurysms,⁵¹ and intestinal ulcerations.⁵² In skin, MMP-12 is expressed by tumor cells in cutaneous SCCs,⁵³ and by macrophages in areas devoid of normal elastic fibers or with disrupted basement membrane.⁵⁴ Deletion of MMP-12 in mice leads to impaired macrophage recruitment and protects from cigarette smoke-induced emphysema.⁵⁵

Matrilysins

Matrilysin (MMP-7) and matrilysin-2 (endometase, MMP26) are the smallest MMPs, both lacking the hinge region and the hemopexin domain.⁵⁶^,⁵⁷ MMP-7 has a wide substrate specificity.⁵⁰^,⁵⁸ Unlike most MMPs, it is constitutively expressed by many epithelial cell types, often ductal epithelium of adult exocrine glands in skin, salivary glands, pancreas, liver, and breast, and by glandular epithelium of the intestine and reproductive organs.⁵⁹^,⁶⁰ MMP-7 is also expressed in the lumenal surface of dysplastic glands in the early-stage human colorectal tumors.⁶¹ As MMP-7 activates antibacterial peptides, defensins, in intestinal mucosa, it may function similarly also in the other epithelial sites of expression.⁶² Mice deficient of MMP-7 have reduced intestinal mucosal defence, but also reduced intestinal tumorigenesis.⁶¹^,⁶² MMP-7 is required for repair of airway epithelial injuries.⁶³

The prodomain of MMP-26 has a unique cysteine switch sequence, PHCGVPDGSD.⁵⁶ MMP-26 is most homologous to MMP-12. MMP-26 is expressed in human uterus and placenta, and in endometrial, lung, and prostate adenocarcinomas.⁵⁶^,⁵⁷^,⁶⁴ MMP-26 may be involved in tissue-remodeling events associated with tumor progression or reproductive processes including implantation and menstruation.⁵⁷

Gelatinases

GelatinaseA (72-kDa gelatinase, MMP-2) and gelatinase B (92-kDa gelatinase, MMP-9) have three tandem repeats of 58 amino acid residue long fibronectin type II-like modules in the catalytic domain. As gelatinases degrade components of basement membranes, they are believed to play a crucial role in processes requiring basement membrane disruption, such as tumor invasion and tissue infiltration of T lymphocytes.⁶⁵ ⁶⁷ MMP-2 is also thought to be important in malignancies, as its activation correlates with tumor spread and poor prognosis.⁶⁸ MMP-2-deficient mice show reduced angiogenesis and tumor progression,⁶⁹ and MMP-9-deficient mice show impaired metastasis formation and tumor growth.⁷⁰

Membrane-type MMPs

To date, six MT-MMPs have been described: MT1-MMP (MMP-14), MT2-MMP (MMP-15), MT3-MMP (MMP-16), MT4-MMP (MMP-17), MT5-MMP (MMP-24), and MT6-MMP (MMP-25). They have a R×KR motif between the propeptide and the catalytic domain, which can be cleaved intracellularly in the trans-Golgi network by members of the proprotein convertase family, such as furin resulting in activation of MT-MMPs.⁷¹^,⁷² They are bound to cell membrane with a stem/transmembrane/cytosolic domain of approximately 25 amino acids at the C-terminal end, except for MT4-MMP and MT6-MMP, which are glycosylphosphatidylinositol (GPI)-anchored. Localization of MT-MMPs at the cell surface implies that they play a role in cell-matrix interactions, and in cell invasion.⁷³^,⁷⁴ MT1-, MT3-, MT5-, and MT6-MMP activate pro-MMP-2, and MT1- and MT2-MMP also activate pro-MMP-13.⁷⁵^,⁷⁶ The activation of pro-MMP-13 is enhanced in the presence of a latent form of MMP-2.⁷⁷ Thus, in the degradation of ECM, a proprotein convertase/MT-MMP/MMP cascade may play an important role at the level of zymogen activation.⁷⁸

MT1-MMP (MMP-14) is widely expressed in normal tissues.⁷⁹^,⁸⁰ In addition, MT1-MMP expression has been detected in tumor cells and adjacent stromal cells in a large variety of tumors.⁸⁰^,⁸¹ MT1-MMP expression in stromal cells is thought to represent a tumor-induced host response similar to that in wound healing.⁸² MT1-MMP can cleave several ECM components (Table 1).²²^,⁷³^,⁸³ Expression of MT1-MMP in human fetal membranes and in early human placenta suggests a role for MT1-MMP in trophoblast invasion.⁸⁴^,⁸⁵ MT1-MMP-deficient mice have severe defects in skeletal development and angiogenesis,⁸⁶^,⁸⁷ and activation of pro-MMP-2 is also deficient in these mice,⁸⁷ emphasizing the importance of MMP-2 activation by MT1-MMP in tumor growth and metastasis,⁸⁸ and in the cartilage destruction of rheumatoid arthritis.⁸⁹

Table 1

Human MMPs, their expression profile, and substrates.

MT2-MMP is expressed in vivo in liver, placenta, testis, colon, intestine, pancreas, kidney, lung, heart, and skeletal muscle.⁹⁰ Human cell-associated, but not soluble, MT2-MMP is defective in pro-MMP-2 activation due to substitution of seven amino acids within the catalytic domain, as compared to mouse MT2-MMP capable of activating pro-MMP-2.⁹¹

MT3-MMP (MMP-16) is expressed in brain, heart, and placenta, in oral malignant melanoma,⁸⁰ and brain microglial cells.⁹² MT3-MMP is also expressed as an alternatively spliced soluble variant that activates pro-MMP-2 and cleaves type III collagen and fibronectin (Table 1).⁹³

MT4-MMP (MMP-17) has the least degree of sequence identity to other MT-MMPs.⁹⁴ Its lacks the cytoplasmic tail, and instead of a transmembrane domain, it is attached to the cell membrane with a GPI anchor.⁹⁵ MT4-MMP can be shed from the cell membrane by TIMP-insensitive metalloproteinases, possibly by certain ADAM family members.⁹⁵ MT4-MMP does not activate pro-MMP-2, but sheds proform of tumor necrosis factor-a.(TNFa).⁹⁶ MT4-MMP mRNA is expressed in vivo in brain, leukocytes, colon, ovary, testis, and in breast carcinomas.⁹⁴

MT5-MMP (MMP-24) is predominantly expressed in kidney, pancreas, lung, and brain tissues, especially in brain tumors.⁷⁸^,⁹⁷ MT5-MMP can activate MMP-2 in a TIMP-2-sensitive fashion. MT5-MMP may have a role in synaptic plasticity during nervous system development,⁹⁸ whereas activation of pro-MMP-2 in tumor tissues may facilitate tumor progression.⁹⁷

MT6-MMP (MMP-25, leucolysin), is specifically expressed by peripheral blood leucocytes,⁹⁹ and in lung and spleen tissue.¹⁰⁰ It has also been found in anaplastic astrocytomas and glioblastomas.¹⁰⁰ It shares sequence similarity to MT4-MMP and is also GPI anchored.¹⁰⁰ MT6-MMP may serve as a potent proteolytic tool for leukocytes during inflammatory responses,⁹⁹^,¹⁰¹ and may also facilitate tumor progression through its ability to activate pro-MMP-2 at the colon carcinoma and brain tumor cell membrane.¹⁰⁰

Matrix Metalloproteinase 19-like MMPs

Human MMP-19 is expressed in injured and acutely inflamed synovium, especially in capillary endothelial cells.¹⁰² ¹⁰⁴ The substrate specificity of MMP-19 (Table 1) also suggests a role for MMP-19 in angiogenesis.¹⁰⁴^,¹⁰⁵

Epilysin (MMP-28) is most closely related to MMP-19, with which it shares 46% amino acid identity in the catalytic domain.¹⁰⁶^,¹⁰⁷ MMP-28 gene contains 8 exons in contrast to other MMPs, which usually have 10 exons. Exon 4 is alternatively spliced to a transcript that does not encode the N-terminal half of the catalytic domain. MMP-28 has a furin activation sequence (RRKKR) but has no transmembrane sequence. MMP-28 is expressed in testis and lung and at lower levels in heart, colon, intestine, and brain.¹⁰⁶^,¹⁰⁷ MMP-28 can be detected in the basal and suprabasal epidermis of intact skin, and in wounded skin, MMP-28 is seen in basal keratinocytes both at and some distance from the wound edge.¹⁰⁷

Other MMPs

Enamelysin (MMP-20) has an expression pattern restricted to ameloblasts and odontoblasts of developing teeth. It is able to degrade amelogenin, the major protein component of the enamel matrix, aggrecan, and cartilage oligomeric matrix protein (COMP).¹⁰⁸ Enamelysin has been suggested to play a central role in matrix remodeling during tooth development and enamel maturation.

MMP23 lacks the signal sequence, the cysteine switch, and the C-terminal domain lacks any similarity with hemopexin. N-terminal signal anchor localizes MMP-23 to the cell membrane. A single proteolytic cleavage on the RRRR motif activates MMP-23 prior to secretion.¹⁰⁹ Although MMP-23 mRNA is found in heart, intestine, colon, placenta, lung, and pancreas, the predominant expression in ovary, testis, and prostate suggests a specialized role in reproductive processes, e.g., during ovarian follicle development.¹¹⁰

Regulation of MMP Activity

In general, MMP production and activity is strictly regulated in vivo. Cells within intact tissues usually do not store MMPs, and constitutive expression is minimal. Neutrophils are an exception, as they store MMP-8 and MMP-9 in secretory granules for rapid release. In addition, expression of MMP-7 is constitutive in ductal epithelium of adult exocrine glands. Activity of MMPs is regulated at multiple levels including transcription, modulation of mRNA half-life, secretion, localization, activation, and inhibition. The natural inhibitors include tissue inhibitors of metalloproteinases (TIMPs 14) and nonspecific proteinase inhibitors.

Regulation at the Transcriptional Level

The expression of MMPs in general is regulated by growth factors, cytokines, chemical agents like phorbol esters, physical stress, oncogenic transformation, cell-cell and cell-ECM interactions.¹⁴ MMP genes responsive to extracellular stimuli (MMP-1, MMP-13, MMP-3, MMP-10, MMP-7, MMP-12, MMP-9, and MMP-19) contain an AP-1 (activator protein-1) binding site in the proximal promoter approximately at position −70 with respect to the transcription initiation site. Another distal AP-1 or related element is found in the promoters of MMP-1, MMP-3, and MMP-9. Jun and Fos bind to the AP-1 cis-element and activate the transcription of the MMP gene. The proximal or distal AP-1 site is often accompanied by another cis-element, PEA-3 (polyomavirus enhancer A binding protein-3) site, that binds ETS transcription factors. AP-1 and PEA-3 together confer responsiveness to a variety of growth factors, oncogene products, and tumor promoters.¹¹¹ Transforming growth factor-β (TGF-β) inhibitory element is found in MMP-1, MMP-7, and MMP-13 promoters.

Promoter regions of MMP-2, MMP-11, and MT1-MMP genes do not contain a conserved AP-1 element.⁴^,¹¹²^,¹¹³ The promoter region of human MT1-MMP has an Sp1 site crucial for maintaining MT1-MMP transcription, four CCAAT boxes, and additional unidentified positive and negative regulatory sequences.¹¹³ It lacks the typical MMP promoter regulatory sites TATA box and AP-1 and TGF-β-responsive elements, as does its murine counterpart.¹¹⁴

Zymogen Activation

Most MMPs are secreted as inactive proenzymes, and their proteolytic activity is regulated by zymogen activation and enzyme inhibition. MT-MMPs, MMP-11, and MMP-28 are activated intracellularly by Golgia-ssociated, furin-like proteases. For MMP-23, a single cleavage both activates it and releases it from the cell surface, where it is anchored.¹⁰⁹ The latency of pro-MMPs is maintained by the so-called cysteine switch,¹¹⁵ i.e., a covalent bond between the cysteine residue in the prodomain and the Zn²⁺ in the catalytic domain. This interaction is disrupted by activation of the pro-MMP by proteinases such as plasmin, trypsin, kallikrein, chymase, and mast cell tryptase.¹⁴ Pro-MMPs can also be activated by mercurial compounds (aminophenyl mercuric acetate), SH-reactive agents, reactive oxygen, and detergents.³^,¹¹⁵ Many MMPs can activate other MMPs, forming a complex network regulating the tissue proteolysis. TIMP-2 N-terminal domain and the active site of MT1-MMP can associate to form a pro-MMP-2 receptor at the cell surface, leaving the C-terminus of TIMP-2 free to bind pro-MMP-2. This allows efficient activation of pro-MMP-2 by adjacent TIMP-2-free, active MT1-MMP and may be a common mechanism for pro-MMP-2 activation by MT-MMPs.⁷⁶^,¹¹⁶^,¹¹⁷ Thus, at low concentrations TIMP-2 enhances the activation process by concentrating MMP-2 to the site where the activator is available and in high concentrations, TIMP-2 inhibits MMP-2 activation.¹¹⁶^,¹¹⁷ In tissues, physiological MMP activators are likely to include tissue or plasma proteinases or opportunistic bacterial proteinases. The plasminogen activator/plasmin system is an important activator of pro-MMPs in pathological situations.¹¹⁸

Localization and Trafficking

An important aspect of the regulation of MMP activity is localizing the proteolytic activity to the pericellular space.¹¹⁹ Anchoring MMPs to the cell surface prevents them from rapidly diffusing away and also keeps them under close regulatory control. Binding to cell surface also allows positioning of MMPs for activation, their interaction with cell surface adhesion molecules or receptors, regulation of their turnover, and focused pericellular proteolysis, as with MMP-14 localized in invadopodia.¹²⁰ Accordingly, heparan sulfate proteoglycan has been shown to anchor MMP-7 on cell surface and possibly in the basement membrane in vivo.¹²¹ Similarly, MMP-2 interacts with integrin a_vb₃,¹²² MMP-9 binds to cell surface hyaluronan receptor CD44¹²³, and integrin a_vb₆¹²⁴, and pro-MMP-1 interacts with collagen receptor α2b1.¹²⁵

Inhibition of MMP Activity

MMP activity can be inhibited by tissue inhibitors of metalloproteinases (TIMPs), by serine proteinase inhibitors (serpins), and by nonspecific serum proteinase inhibitors, such as α2-macroglobulin, which is important in blocking MMP activity in the synovial fluid, serum, and other body fluids.¹⁴ Serpins are glycoproteins of 50–100 kDa, abundant in all human tissues, and involved in controlling the general proteolytic activity in several tissues. Serpins include α1-antitrypsin (α1-proteinase inhibitor) and plasminogen activator inhibitor (PAI)1 and PAI2.

Tissue Inhibitors of Metalloproteinases (TIMPs)

Tissue inhibitors of metalloproteinases (TIMPs) -1, -2, -3, and -4 are important endogenous regulators of MMP activity in tissue (see George et al., in this book). TIMPs inhibit the MMP activity through noncovalent binding of the active zinc-binding sites of MMPs at molar equivalence.¹²⁶ Although the primary amino acid sequence identity between the TIMPs is low, about 30%, their tertiary structure is remarkably similar. They have 12 conserved cysteine residues required for the formation of six disulfide bonds, which hold the two domains in a rigid conformation¹²⁷. N-terminal domain, that contains the TIMP consensus sequence VIRAK, is necessary for MMP inhibition.¹²⁸ ¹³⁰ The C-terminal domains are more divergent and appear to be important in forming differences in specificity to each TIMP family member.¹³¹ ¹³³

In general, TIMPs can inhibit the activity of all MMPs in vitro, except for MT1-MMP and MT3-MMP, which are not inhibited by TIMP-1.⁷⁶^,¹³⁴ Due to structural similarities in the active site of MMPs and ADAMs, some ADAMs are also inhibited by TIMPs. TIMP-1 and TIMP-3 inhibit ADAM10, whereas TNF-α convertase (TACE, ADAM17) is only inhibited by TIMP-3.¹³⁵^,¹³⁶ TIMP-1 and TIMP-3 inhibit aggrecanase-1 (ADAMTS4) (aggrecanase-1), and TIMP-3 also inhibits aggrecanase-2 (ADAMTS5).¹³⁷^,¹³⁸ TIMP-1 has a role in tissue remodeling during embryonal growth and tumor progression, in gonadal steroidogenesis, ovulation, pregnancy, and parturition, and in inhibiting migration of vascular smooth muscle cells and endothelial cells, angiogenesis, tumor cell invasion and metastasis.¹²⁷^,¹²⁸^,¹³⁹^,¹⁴¹ It also possesses growth factor activity¹⁴² and inhibits shedding of heparin-binding epidermal growth factor and its receptor HER2.¹⁴³^,¹⁴⁴

TIMP-2 is expressed in a constitutive manner by cells in culture. TIMP-2 can inhibit the shedding of TNF-α receptors (TNF-αRI and II).¹⁴⁵ Mice with an inactivating mutation of TIMP-2 gene have normal phenotypes, in spite of severe impairment of pro-MMP-2 activation in vivo.¹⁴⁶ In human tumors, high levels of TIMP-2 at the interface between malignant cells and stromal cells correlate with poor prognosis, suggesting that overexpression of TIMP-2 reflects a host reaction against highly invasive cells.¹⁴⁷

Whereas other TIMPs are present in soluble form, TIMP-3 is insoluble, bound to the ECM.¹⁴⁸ TIMP-3 promotes the detachment of transformed cells from the ECM and accelerates morphological changes associated with cell transformation.¹⁴¹ In addition, up-regulation of TIMP-3 has been associated with a block in the G₁ phase of the cell cycle during differentiation of HL-60 leukemia cells.¹⁴⁹ TIMP-3 can block the cellular shedding of pro-TNF-α, L-selectin and IL-6 receptor.¹³⁵^,¹³⁶^,¹⁵⁰^,¹⁵¹ Adenovirus-mediated gene delivery of TIMP-3 inhibits invasion and induces apoptosis in various normal and malignant cells.¹⁴¹^,¹⁵²^,¹⁵³ TIMP-4 is mostly expressed in the adult human heart, though very low levels of mRNA and protein are found in many tissues.¹⁵⁴

MMPs in Tumor Growth and Invasion

MMPs have a dual role in tumor growth and metastasis processes. They promote tumor growth by degrading matrix barriers and by enhancing angiogenesis.^4> On the other hand, MMPs can limit tumor neovascularization. Angiostatin is a specific inhibitor of endothelial cell proliferation and one the most effective and specific natural inhibitors of angiogenesis. It is cleaved from plasminogen by the action of plasmin and plasmin reductase,^155> and by MMPs, the most efficient being MMP-12, followed by MMP-9, MMP-3, and MMP-7, with collagenases exhibiting practically no activity.^156>^,^157> In α1 integrin knockout mice, which lack the α1b1 collagen receptor, the synthesis of MMP-7 and MMP-9 is markedly increased. This increased the plasma levels of angiostatin, leading to markedly decreased vascularization of implanted tumors.^158> Endostatin, another natural angiogenesis inhibitor, is a fragment of type XVIII collagen.^159> Although MMPs are not required for generation of endostatin, they are involved in the processing of collagen XVIII.^160>

MMPs have also other functions.^161> They can release active growth factors and angiogenic factors from the cell surface and ECM.^162> They can cleave growth factor-binding proteins^163> and cell surface growth factor receptors.^164> They can generate an α1-antitrypsin cleavage product that promotes tumor growth and invasion.^165> They may alter cell cycle checkpoint control and promote genomic instability by affecting cell adhesion.^166> MMPs can also induce programmed cell death in anchorage-dependent cells.^36> This can either inhibit tumor progression or promote it by enhancing selection of anchorage-independent and apoptosis-resistant subpopulations.^37>

Tumor growth involves alterations in the stromal ECM and malignant tumors often induce a fibroproliferative response in the adjacent stroma, characterized by increased expression of type I and III procollagens.^167> During metastasis formation, malignant cells detach from the primary tumor, invade through stromal tissue, enter the circulation, arrest at the peripheral vascular bed, and extravasate, invade the target organ, and form a metastatic colony.^4>^,^163> Tumor cells must escape the host immune surveillance, and only a fraction of circulating tumor cells establish metastatic colonies.^168> Tumor-induced angiogenesis is essential for growth of the primary tumor and metastases, and new blood vessels are sites for entry of tumor cell entry into the circulation. It is conceivable that proteolytic degradation of ECM plays a crucial role in all the above-mentioned aspects of tumor development.

A considerable body of evidence is available implicating MMPs in cancer spread. A number of studies have demonstrated a positive correlation between MMP expression and invasive and metastatic potential of malignant tumors including colon, lung, head and neck, basal cell, breast, thyroid, prostate, ovarian, and gastric carcinomas.^4> For example, expression of MMP-1 correlates with poor prognosis in colorectal cancer and oesophageal cancer^169>^,^170> and MMP-2 and MMP-3 expression is associated with lymph node metastasis and vascular invasion in SCC of esophagus.^171> Similarly, high expression of MMP-13 in SCCs of the head and neck and vulva is associated with their metastasis capacity.^29>^,^30> MMP-11 expression correlates with increased local invasiveness in head and neck SCCs^172> and the level of MMP2 expression with poor prognosis of cervical SCCs.^173> In general, all MMPs, the expression of which has been documented in malignant tumors, can also be expressed by nonneoplastic cells. However, MMP-13, MMP-7, MMP-12, and MMP-14 are expressed by malignantly transformed keratinocytes in SCCs but not in normal keratinocytes, indicating that their expression serves as a marker for transformation.^29>^,^30> In addition, MMP-2 expression serves as a marker for malignant transformation of cervical epithelial cells.^173>^,^174>

MMPs are mainly produced by nonmalignant stromal cells in malignant tumors. Tumor cells also secrete factors, such as extracellular MMP inducer (EMMPRIN), which enhance the expression of MMPs by stromal fibroblasts (see Toole, in this book). In addition, growth factors and cytokines secreted by tumor-infiltrating inflammatory cells as well as by tumor or stromal cells modulate MMP expression. Tumor invasion involves interaction between tumor cells, adjacent stromal cells, and infiltrating inflammatory cells, and it is likely that all these cells express distinct MMPs, which may complement each other's substrate specificity and form a network of MMP cascades in which one MMP cleaves a particular native or partially degraded ECM component and activates other MMPs.

TIMPs in Tumor Growth and Invasion

A number of studies have demonstrated the expression of TIMPs in tumor stroma and tumor tissue. In general, there is convincing evidence that overexpression of TIMPs by cancer cells or by the host reduces invasive and metastatic capacity of tumor cells. In cutaneous and oral SCCs, expression of TIMP-1, TIMP-2, and TIMP-3 is detected in stromal cells adjacent to the tumor,^175>^177> suggesting that their expression represents a host attempt to limit tumor invasion and tumor-induced angiogenesis. This notion is supported by observations indicating that the presence of TIMP-1 and TIMP-2 in SCCs correlates with less aggressive growth.^178> However, in breast cancer TIMP-2 expression correlates with tumor recurrence,^179> and in cervical carcinomas TIMP-2 expression correlates with poor prognosis.^180> Similarly, in malignant breast cancer TIMP-1 expression is enhanced, as compared to nonmalignant breast tumor.^181> However, the MMP:TIMP ratio is elevated in cervical carcinomas with poor prognosis, indicating that evaluation of either MMP or TIMP expression alone is not sufficient for prognostication of malignancies.^180>

Cancer cell invasion can be inhibited by recombinant TIMPs or by overexpression of either TIMPs using a variety of gene-delivery vehicles. TIMP-2 inhibited the invasion of HT1080 fibrosarcoma cells in vitro,^182>^,^183> but had no effect on tumor cell growth. Overexpression of TIMP-1 reduced metastasis of gastric carcinoma cells.^184> TIMP-1 also reduced the growth rate and invasion of astrocytoma and mammary carcinoma cells,^185>^,^186> and prevented metastasis of gastric carcinoma cells.^187> The ability of TIMP-1 to inhibit tumor development at different stages has been demonstrated by transgenic mouse models. Constitutive overexpression of TIMP-1 in the liver suppressed tumor initiation, growth, and angiogenesis in transgenic mice, which develop hepatocellular carcinomas as a result of SV40 T antigen expression.^188> These observations were also supported by a recent study in which TIMP-1 overexpression in the brain prevented tumor formation.^189>

Overexpression of TIMP-2 reduced the MMP activity and suppressed growth of melanomas in the skin of immunodeficient mice,^190> and melanoma cells overexpressing TIMP-2 showed a reduced metastatic capacity.^191>Melanoma cells overexpressing TIMP-1 were shown to have reduced metastasis capacity due to inhibition of tumor growth following extravasation.^192> TIMP-4 overexpression in breast carcinoma cells also inhibits invasion in vitro and tumor growth in vivo and results in reduction in lymph node and lung metastasis.^193> Together these studies highlight both similar and diverse effects of overexpression of individual TIMPs on tumor cell phenotype in vivo. Adenoviral delivery of TIMP-2 has been shown to inhibit growth of liver metastases.^194> In contrast, systemic delivery of TIMP-4 enhances mammary tumorigenesis but inhibits growth of Wilms' tumor in vivo.^195>^,^196>

Further studies have demonstrated distinct effects of individual TIMPs on cell survival. Overexpression of TIMP-2 reduced invasion and angiogenesis but also protected the melanoma cells from apoptosis, although it increased necrosis.^197> TIMP-1 has also been shown to promote survival of B cells through modulation of CD40 levels.^198> However, we and others have shown that adenoviral-mediated gene delivery of TIMP-3 promotes apoptosis of a number of malignant cell types associated with reduced capacity of TIMP-3-transduced cells to bind to ECM components.^141>^,^152>^,^153> TIMP-3 expressing stable colon carcinoma cell lines display reduced tumor growth,^199> and in these cells TIMP-3 overexpression resulted in apoptosis through stabilization of TNF-α receptors on the cell surface.^200> This suggests that individual TIMPs may modulate the levels of death proteins from the cell surface, as demonstrated by findings that shedding of FAS from the cell surface is mediated by MMP-induced cleavage and is inhibited by synthetic MMP inhibitors.^201> Furthermore, TIMP-3 inhibits activity of TNF-α convertase (ADAM17), providing further evidence for complex regulation of death ligands and receptors by MMPs and TIMPs,^202> which may play an important role in survival, growth, and invasion of malignant cells.

At present, several synthetic MMP inhibitors are in clinical trials evaluating their ability to inhibit growth and invasion of malignant tumors in vivo (see Turpeenniemi-Hujanen, in this book). Gene delivery of TIMP-1, -2, -3, and -4 into malignant cells may also be a potent way of inhibiting tumor growth and invasion.^145>^,^152>^,^153>^,^196> Furthermore, an effective way of inhibiting MMP expression may be blocking signaling pathways mediating activation of MMP gene expression.^4> The ongoing clinical trials are expected to show whether synthetic MMP inhibitors have a place in the therapeutic arsenal aimed at inhibiting growth, invasion, and metastasis of malignant tumors.

Acknowledgments

The original work of authors has been supported by grants from the Academy of Finland, Sigrid Jusélius Foundation, the Cancer Foundation of Finland, and Turku University Central Hospital, and by research contract with Finnish Life and Pension Insurance Companies.

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Reunanen N, Kähäri VM. Matrix Metalloproteinases in Cancer Cell Invasion. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Madame Curie Bioscience Database [Internet].

Matrix Metalloproteinases in Cancer Cell Invasion

Matrix Metalloproteinases

Figure 1

Collagenases

Stromelysins and Stromelysin-like MMPs

Matrilysins

Gelatinases

Membrane-type MMPs

Table 1

Matrix Metalloproteinase 19-like MMPs

Other MMPs

Regulation of MMP Activity

Regulation at the Transcriptional Level

Zymogen Activation

Localization and Trafficking

Inhibition of MMP Activity

Tissue Inhibitors of Metalloproteinases (TIMPs)

MMPs in Tumor Growth and Invasion

TIMPs in Tumor Growth and Invasion

Acknowledgments

References

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