Cancer Therapy Vol 2, 29-38, 2004
Matrix metalloproteinases in multiple myeloma
Review Article
Els Van Valckenborgh, Kewal Asosingh, Ivan Van Riet, Ben Van Camp and Karin Vanderkerken*
Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
__________________________________________________________________________________
*Correspondence:
Dr. Karin Vanderkerken, Vrije Universiteit Brussel, Department HEIM, Laarbeeklaan 103, B-1090 Brussels, Belgium; Phone: 0032 2 477 44 18; Fax: 0032 2 477 44 05; E-mail: Karin.Vanderkerken@vub.ac.beKey Words: matrix metalloproteinases, multiple myeloma, angiogenesis, homing, osteolytic bone disease
Abbreviations: bone marrow (BM); bone marrow stromal cells (BMSCs); 1.25-dihydroxyvitamin D3, ([1.25(OH)2VitD3]); extracellular matrix (ECM); glycosylphosphatidylinositol (GPI); hepatocyte growth factor (HGF); human umbilical vein endothelial cells (HUVECs); insulin-like growth factor-1 (IGF-1); Interleukin-6 (IL-6); matrix metalloproteinases (MMPs); monoclonal gammopathy of unknown significance, (MGUS); Multiple myeloma (MM); Oncostatin M (OSM); tissue inhibitors of matrix metalloproteinases (TIMPs); transforming growth factor-b ‚ (TGF-b ); tumor necrosis factor-a (TNF-a )
Received: 30 March 2004; Accepted: 5 April 2004; electronically published: April 2004
Summary
Multiple myeloma is a B-cell malignancy characterized by the monoclonal proliferation of plasma cells in the bone marrow, the presence of monoclonal immunoglobulins in the serum, the development of osteolytic lesions and the induction of angiogenesis. Matrix metalloproteinases are described as endopeptidases and are known to be involved in cancer development. Formerly, it was believed that the enzymes were only important in the degradation of extracellular matrix components. However, new substrates have been discovered making the functions of matrix metalloproteinases extended and complex. Here, an overview has been given about the expression and regulation of matrix metalloproteinases in multiple myeloma. With the literature we demonstrate that the enzymes are involved in tumor growth, angiogenesis, homing and the development of osteolytic lesions, all important events in the progression of multiple myeloma.
I. Introduction
Multiple myeloma (MM) is a B-cell malignancy with several specific characteristics. Our group has demonstrated the postgerminal origin of MM cells (Bakkus et al, 1992). These cells migrate from the intravascular to the extravascular compartment of the bone marrow (BM), a process called "homing". In the BM, the myeloma cells receive signals from the microenvironment essential for survival and growth leading to the accumulation of the tumor cells in the BM. The malignant plasma cells produce a monoclonal immunoglobulin that can be detected in the serum of patients and can be used to follow the development of the disease. Osteoclast-activating factors and angiogenic factors, produced by MM cells and the BM environment, result in the induction of osteolytic lesions and the formation of new blood vessels (angiogenesis). In advanced stages of the disease, tumor cells can be observed in the peripheral blood and at extramedullary sites. Symptoms of MM are kidney problems, bone pain especially in the back or ribs, fatigue and recurrent infections. Despite a lot of research and progress in treatment, the disease remains incurable. More understanding of the biology of MM can lead to new approaches to therapy and better treatments of patients. An interesting target are the matrix metalloproteinases (MMPs). It has been suggested that matrix metalloproteinases are involved in a number of events underlying MM progression. This review focuses on the expression, regulation and the role of MMPs in MM disease.
II. Matrix metalloproteinases
Matrix metalloproteinases are a family of zinc-dependent endopeptidases involved in physiological (embryogenesis and wound healing) (Matrisian, 1990) and pathological (multiple sclerosis, rheumatoid arthritis and cancer) tissue degradation (Jackson et al, 2001; Lindberg et al, 2001; Vihinen and Kähäri, 2002). More than 20 members of the human MMP family are known. They are able to degrade structural components of the extracellular matrix (ECM) (reviewed by Sternlicht and Werb, 2001 and Vihinen and Kähäri, 2002). New substrates, like growth factors (GF), GF binding proteins, GF receptors, adhesion molecules, chemokines and inhibitors, have been discovered, making the functions of MMPs diverse and complex. They cannot only regulate migration and invasion, but also cell growth, differentiation, angiogenesis and metastasis (Chang and Werb, 2001; Egeblad and Werb, 2002). Formerly, the members of the family were divided into subgroups depending on their substrate specificity (collagenases, gelatinases, stromelysines and membrane-type MMPs). Because of the growing list of substrates, all MMPs are given a number and can be classified according to their structure (Egeblad and Werb, 2002).
Table 1: The human MMP family and their new substrates
|
Structural class |
Enzyme names |
New substrates |
|
Minimal domain |
MMP-7 (matrilysin) |
a 1-PI, a 1-AT, b 4 integrin, FasL, TNF-a , plasminogen, TFPI, E-cadherin, OPN, IgG, CTGF, syndecan-1, fibrinogen |
|
MMP-26 (matrilysin-2) |
IGFBP-1, a 1-PI, fibrinogen |
|
|
Simple hemopexin domain |
MMP-1 (collagenase-1) |
a 1-AT, TFPI, CTGF, MCP-1, -2, -3 and -4, SAA, IGFBP-3, IL-1b , AFP, SDF-1, MBL, a 1-AC, a 2-M, a 1-PI, C1q, fibrinogen, TNF-a |
|
MMP-3 (stromelysin-1) |
a 1-AT, OPN, E-cadherin, IgG, CTGF, MCP-1, -2, -3 and -4, SAA3, IGFBP-3, IL-1b , SDF-1, HB-EGF, FasL, MBL, uPA, plasminogen, PAI-1, a (2)-antiplasmin, fibrinogen, a 1-AC, a 2-M, a 1-PI, C1q, TNF-a |
|
|
MMP-8 (collagenase-2) |
a 1-AT, TFPI, MBL, CXCL-6, CXCL-9, CXCL-10, fibrinogen, a 2-M, a 1-PI, C1q |
|
|
MMP-10 (stromelysin-2) |
Fibrinogen |
|
|
MMP-12 (metalloelastase) |
Fibrinogen, factor XII, plasminogen, apolipoprotein, uPAR, MBP, a 1-AT, pro-TNF, TFPI, a 2-M, a 1-PI |
|
|
MMP-13 (collagenase-3) |
CTGF, MCP-3, SDF-1, factor XII |
|
|
MMP-19 |
IGFBP-3 |
|
|
MMP-20 (enamelysin) |
Amelogenin |
|
|
Gelatin-binding |
MMP-2 (gelatinase A) |
MCP-3, IGFBP-3, IL-1b , SAA, AFP, FGFR1, plasminogen, big endothelin-1, SDF-1, LTBP1, MBL, KiSS-1, a 1-AC, a 1-PI, C1q, fibrinogen, proTGF-b , proTNF-a |
|
MMP-9 (gelatinase B) |
a 1-AT, plasminogen, TFPI, IL-1b , SDF-1, LTBP1, IL-8, CXCL-6, CXCL-5, MBP, substance P, IGFBP-3, MBL, KiSS-1, a B-crystallin, CXCL-9, CXCL-10, a 2-M, a 1-PI, C1q, fibrinogen, proTGF-b , proTNF-a |
|
|
Furin-activated secreted |
MMP-11 (stromelysin-3) |
a 1-PI, IGFBP, a 2-M |
|
MMP-28 (epilysin) |
||
|
Vitronectin-like insert |
MMP-21 |
a 1-AT |
|
Transmembrane |
MMP-14 (MT1-MMP) |
a 2-M, a 1-PI, SDF-1, MCP-3, KiSS, factor XII, MBL, pro-a v integrin, gC1qR, syndecan-1, CD44, tTG, fibrinogen, proTNF-a |
|
MMP-15 (MT2-MMP) |
tTG |
|
|
MMP-16 (MT3-MMP) |
KiSS-1, syndecan-1, tTG |
|
|
MMP-24 (MT5-MMP) |
KiSS-1 |
|
|
GPI-linked |
MMP-17 (MT4-MMP) |
pro-TNF-a |
|
MMP-25 (MT6-MMP) |
||
|
Type II transmembrane |
MMP-23 |
Based on Sternlicht and Werb, 2001; Egeblad and Werb, 2002 and additional references: Winyard et al, 1991; Michaelis et al, 1992; Mitchell et al, 1993; Proost et al, 1993; Fowlkes et al, 1994; Sires et al, 1994; Chandler et al, 1996; Levi et al, 1996; Llano et al, 1997; Suzuki et al, 1997; von Bredow et al, 1997; Ugwu et al, 1998; Edelstein et al, 1999; Mañes et al, 1999; Fernandez-Patron et al, 1999; Powell et al, 1999; Belaaouaj et al, 2000; English et al, 2000; Lijnen et al, 2000, 2001; McQuibban et al, 2000, 2001, 2002; Van Den Steen et al, 2000, 2003a, 2003b; Agnihotri et al, 2001; Belkin et al, 2001; Matsuno et al, 2001; Stix et al, 2001; Andolfo et al, 2002; Butler et al, 2002; Cunningham et al, 2002; Dallas et al, 2002; Deryugina et al, 2002; Gearing et al, 2002; Hashimoto et al, 2002; Li et al, 2002; Park et al, 2002; Rozanov et al, 2002; Endo et al, 2003; Marchenko et al, 2003; Sadowski et al, 2003; Starckx et al, 2003; Takino et al, 2003; Nakamura et al, 2004.
Abbreviations:
a 1-PI: a 1-protease inhibitor; a 1-AT: a 1-antitrypsin; TNF: tumor necrosis factor; TFPI: tissue factor pathway inhibitor; OPN: osteopontin; CTGF: connective tissue growth factor; IGFBP: insulin-like growth factor-binding protein; MCP: monocyte chemoattractant protein; SAA: serum amyloid A; IL: interleukin; AFP: amyloid fibril protein; SDF: stromal cell-derived factor; MBL: mannose-binding lectin; a 1-AC: a 1-antichymotrypsin; a 2-M: a 2-macroglobulin; HB-EGF: heparin-binding epidermal growth factor-like growth factor; uPA: urokinase-type plasminogen activator; PAI: plasminogen activator inhibitor; uPAR: urokinase plasminogen activator receptor; MBP: myelin basic protein; FGFR: fibroblast growth factor receptor; LTBP: latent TGF-beta-binding protein; TGF: transforming growth factor; tTG: tissue transglutaminase.
The MMPs can be divided into 8 structural groups: minimal-domain MMPs, simple hemopexin-domain-containing MMPs, gelatin-binding MMPs, furin-activated secreted MMPs, vitronectin-like insert MMPs, transmembrane MMPs, glycosylphosphatidylinositol (GPI)-anchored MMPs and type II transmembrane MMPs. Enzymes belonging to the first 5 groups are secreted, the others are membrane-type MMPs. Table 1 gives an overview of the human MMP family and their new substrates.
The production of MMPs can be regulated at different levels. The transcription is under control of several cytokines, growth factors and tumor promoters. The enzymes are synthesized as inactive proenzymes and are activated by proteolytic cleavage of the propeptide domain, where the cysteine residue in the conserved sequence interacts with the zinc ion in the catalytic domain. Activation of MMPs can be achieved by interaction with other active MMPs or proteinases from the plasminogen/plasmin system. The activity of MMPs can be inhibited by endogenous inhibitors with the most important tissue inhibitors of matrix metalloproteinases (TIMPs). At this moment, four TIMPs have been described. The balance between active MMPs and TIMPs determines the net proteolytic activity of MMPs. This equilibrium is highly regulated in normal tissue remodeling, but is disturbed in pathological conditions.
III. Matrix metalloproteinases in multiple myeloma: expression, regulation and activation
A. Expression of MMPs in MM
Several groups reported the expression of MMPs in MM cells. The production of MMP-9 has been demonstrated in purified myeloma cells isolated from MM patients (Barillé et al, 1997) and 5T33MM cells isolated from the 5T33MM mouse model (Van Valckenborgh et al, 2002a). MMP-2 was not secreted by these cells. On the contrary, Vacca et al. were also able to detect MMP-2 in the human MM cell line U266 (1998) and bone marrow plasma cells from MM patients (1999). MMP-2 and -9 are gelatinases and belong to the gelatin-binding MMPs. MMP-7, a minimal domain MMP, has a large number of substrates and is produced by human MM cell lines and MM cells from patients (Barillé et al, 1999). Interestingly, MMP-2, -7 and -9 are involved in several processes in cancer, like tumor growth, angiogenesis, invasion and metastasis (Powell et al, 1993; Watanabe et al, 1993; Hua and Muschel, 1996; Deryugina et al, 1997; Wilson et al, 1997; Hasegawa et al, 1998; Itoh et al, 1998; Itoh et al, 1999; Nishizuka et al, 2001; Huang et al, 2002). The expression of MMP-8 and -13 has also been investigated and detected in the human MM cell line RPMI 8226 and malignant plasma cells from plasmacytomas (Wahlgren et al, 2001). Our group was able to detect MMP-8 and -13 by RT-PCR in 5T2MM-diseased bone marrow cells (Van Valckenborgh et al, 2003). MMP-8 and -13 are collagenases belonging to the structural group of the simple hemopexin-domain containing MMPs. The enzymes are expressed in several cancers and it is suggested that they are involved in invasion (Pendás et al, 2000; Kim et al, 2001; Ala-Aho et al, 2002; Moilanen et al, 2002). However, their possible role in the different processes in tumor progression is not yet defined. Since the bone marrow stromal microenvironment is involved in the development of MM, it appears important to investigate the production of MMPs in bone marrow stromal cells (BMSCs). BMSCs secrete MMP-2 and MMP-1 (Barillé et al, 1997). Endothelial cells (ECs) isolated from MM patientswere compared with human umbilical vein endothelial cells (HUVECs). MMECs secreted more (3-4 times higher) active MMP-2 and -9 than HUVECs (Vacca et al, 2003). Figure 1 gives an overview of the expression of MMPs in MM.
Figure 1. The secretion of MMPs by multiple myeloma (MM) cells, bone marrow stromal cells (BMSCs) and endothelial cells (ECs) in multiple myeloma-diseased bone marrow.
Expression of MMPs has also been investigated in other hematological malignancies. MMP-2 and -9 are the most studied and one or both enzymes seems to be produced by leukemia and lymphoma cells (Van Ranst et al, 1991; Ries et al, 1996, 1999; Devy et al, 1997; Kossakowska et al, 1998; Vacca et al, 1998).
B. Regulation of MMPs in MM
The expression of MMPs can be regulated by cytokines, hormones, growth factors, cell-matrix and cell-cell interactions.
1. Cytokines and hormones
Several cytokines are involved in the pathogenesis of MM. Therefore, it is interesting to investigate the role of these cytokines in the regulation of MMPs. Interleukin-6 (IL-6), Oncostatin M (OSM), IL-1, tumor necrosis factor-a (TNF-a ), transforming growth factor-b ‚ (TGF-b ) and IL-10 were not able to regulate MMP-2 and MMP-9 production in respectively BMSCs and MM cells (Barillé et al, 1997). Dexamethasone and 1.25(OH)2VitD3, which can inhibit myeloma cell growth, did not regulate MMP-2 and -9. MMP-1 on the other hand is upregulated by OSM, IL-1b and TNF-a and downregulated by dexamethasone (Barillé et al, 1997). The receptor for IL-6 consists of a signal-transducing molecule IL-6Rb and a specific ligand-binding protein IL-6Ra . This molecule can be found on the membrane, but also exists in a soluble form, sIL-6Ra . The latter molecule (sIL-6Ra ) is able to significantly increase MMP-1 and MMP-2 production by BMSCs (Barillé et al, 2000).
2. Bone marrow microenvironment
MM cells are in contact with the bone marrow microenvironment. Cocultures of MM cells with BMSCs is a way to investigate the role of the BM microenvironment in the regulation of MMPs. MMP-1 production by BMSCs is upregulated in response to MM cells and also MMP-9 production is slightly increased in cocultures (Barillé et al, 1997). The BM microenvironment is a complex structure of various extracellular components and many cell types. BM endothelial cells are the first cells encountered by the MM cells upon entry into the BM environment from the blood circulation. Interaction of BMECs with MM cells induces MMP-9 expression in MM cells. This was demonstrated in the 5T33MM mouse model (Van Valckenborgh et al, 2002a) and in human MM cells (Vande Broek et al, 2004). This is similar in T lymphoma where MMP-9 secretion was enhanced following coculture of lymphoma cells and ECs and where the role of ICAM-1/LFA-1 was evidenced in this upregulation (Aoudjit et al, 1998). However, in MM, it was demonstrated that hepatocyte growth factor (HGF) was involved in the induction of MMP-9 (Vande Broek et al, 2004).
MM cells express the integrin a vb 3 which can bind to ECM proteins present in the BM, like vitronectin and fibronectin. MM cells incubated with VN and FN resulted in an increased release of MMP-2 and MMP-9. This upregulation can be inhibited by a neutralizing anti-a vb 3 antibody (Ria et al, 2002).
3. Syndecan-1
It has been described that syndecan-1 is involved in the regulation of MMP-9. Syndecan-1 is a transmembrane heparan sulfate proteoglycan able to inhibit cell invasion, mediate cell-cell adhesion and regulate cell growth. Expression of syndecan-1 on the surface of MM cells downregulates MMP-9 production (Kaushal et al, 1999). Interestingly, syndecan-1 is shed from the surface of myeloma cells and it has been suggested that a non-matrix-type metalloproteinase, like ADAM (a disintegrin and metalloproteinase) is responsible for this process (Holen et al, 2001). A recent report demonstrated that soluble syndecan-1 promotes MM growth in vivo and enhances invasion (Yang et al, 2002). Inhibition of the shedding of syndecan-1 might decrease MMP-9 production by MM cells and might decrease MM progression.
C. Activation of MMPs in MM
Most of the MMPs are secreted as inactive proenzymes and are activated extracellularly by proteolytic cleavage. Interaction of MMPs with each other can lead to their activation. MMP-7, secreted by MM cells, is responsible for the activation of MMP-2 produced by BMSCs (Barillé et al, 1999). The uPA/plasmin system is also involved in MMP activation (Werb et al, 1977). This was demonstrated with leukemia cells which produce significant amounts of proMMP-9. Activation was achieved by adding plasminogen to the leukemia cells (Devy et al, 1997). uPA converts plasminogen to plasmin which in turn can activate MMPs. Recent results indicate that uPA is expressed by myeloma cells (Hjertner et al, 2000; Asosingh et al, 2002). Addition of plasminogen to proMMP-9 secreting 5T33MMvivo cells resulted in the activation of proMMP-9 (unpublished observations).
IV. The role of matrix metalloproteinases in multiple myeloma
A. MMPs and tumor growth
Several reports demonstrated that treatment with MMP inhibitors resulted in a significant decrease of tumor growth (Koivunen et al, 1999; Matsushita et al, 2001; Winding et al, 2002). This suggests that MMPs can generate growth-promoting signals. Two important growth factors in MM are IL-6 and insulin-like growth factor-1 (IGF-1). It has been described that the specific ligand-binding protein of the receptor for IL-6, IL-6Ra , is released from MM cells by proteolytic cleavage (Thabard et al, 1999). Soluble IL-6Ra binds to IL-6 leading subsequently to an increased proliferation of MM cells. IGFBPs regulate the bioavailability of IGF by binding the growth factor and are described, especially IGFBP-3, as one of the new substrates of MMPs (see Table 1). Serum levels of IGFBP-3 are decreased in MM patients, suggesting that the protein is cleaved (Standal et al, 2002). Shedding of IGFBPs might increase the amount of bioavailable IGF-1 resulting in increased tumor growth. It is not yet known which enzyme is responsible for the shedding of IL-6R and IGFBP-3 in MM. It has been suggested that members of the ADAM family might be responsible for the cleavage of growth factors (Hargreaves et al, 1998; Standal et al, 2002). Interesting to investigate is whether inhibiting the process of shedding might result in the inhibition of MM progression. Treatment of 5T2MM-diseased mice with the broadspectrum MMP inhibitor SC-964 resulted in a decreased number of tumor cells in the BM compared to vehicle treated animals (Van Valckenborgh et al, 2003). A minor effect of SC-964 on the proliferation of tumor cells has been demonstrated by 3H-thymidine incorporation (unpublished observations).
B. MMPs and angiogenesis
Angiogenesis is the formation of new blood vessels and in solid tumors it has been demonstrated that it is required for tumor growth. Like in solid tumors, it has been demonstrated that neovascularization is enhanced in MM (Vacca et al, 1994; Van Valckenborgh et al, 2002b). MMPs are involved in the different processes of angiogenesis, like proteolysis of the ECM, migration of ECs and the release of angiogenic factors from the ECM (Moses, 1997). Vacca et al (1999) demonstrated a larger microvessel area and a higher secretion of MMP-2 and -9 in patients with active MM than in those with nonactive MM, MGUS (monoclonal gammopathy of unknown significance) of or control subjects. ECs isolated from the bone marrow of MM patients produce a higher level of MMP-2 and -9 compared to HUVECs (Vacca et al, 2003). Treatment of MM-diseased mice with the broadspectrum MMP inhibitor SC-964 resulted in an almost complete inhibition of angiogenesis (Van Valckenborgh et al, 2003). This was confirmed in the rat aortic ring assay where the outgrowth of blood vessels was significantly decreased with the MMP inhibitor SC-964 (unpublished observations). It has to be elucidated whether selective targeting of the enhanced neovascularisation in MM results in a protective effect against MM disease.
C. MMPs and homing of MM cells
MM cells home from the intravascular to the extravascular compartment of the bone marrow. This is a multistep process consisting of adhesion of myeloma cells to the ECs followed by chemoattraction and migration through the endothelium and invasion through the basement membrane into the BM. In a recent report, the differential homing capacity of CD45- and CD45+ MM cells was investigated in the 5TMM mouse model (Asosingh et al, 2002). CD45- MM cells have a decreased homing capacity compared to CD45+ MM cells. This could be due to the higher MMP-9 secretion by CD45+ compared to CD45- cells which secrete little or no MMP-9. Further experiments revealed a significant lower invasive capacity of CD45- MM cells compared to CD45+ MM cells. Treatment of the 5TMM cells with the gelatinase inhibitor EGCG resulted in the inhibition of invasion and thus demonstrated the involvement of MMP-9 in invasion, the last step of homing. The upregulation of MMP-9 after interaction of MM cells with BMECs also indicates that MMP-9 might play a role in the homing process (Van Valckenborgh et al, 2002a; Vande
Broek et al, 2004).D. MMPs and osteolytic bone disease in MM
An important characteristic of MM is the development of osteolytic lesions. MMPs play a role in normal bone remodeling. MMPs are involved in osteoclast recruitment to sites of bone remodeling (Sato et al, 1998) and the enzymes can degrade mineralized bone matrix (Holliday et al, 1997; Everts et al, 1998). In several cancers, the use of MMP inhibitors have clearly evidenced a role of MMPs in osteolytic bone disease. In the SCID-human model of prostate cancer metastasis, treatment with a broadspectrum MMP inhibitor batimastat prevented mineralized trabeculae degradation in vivo and reduced the number of osteoclasts on trabecular surfaces (Nemeth et al, 2002). Also in breast cancer, MMP inhibitors inhibited the development of osteolytic lesions in mice (Lee et al, 2001; Winding et al, 2002). Collagen I is a major constituent of the bone and can be degraded by collagenases like MMP-1, -8 and -13. The denatured collagen I becomes a substrate for MMP-2 and -9. Our group performed a study to investigate the role of MMPs in the development of osteolytic bone disease in MM. Treatment of 5T2MM-diseased mice with the MMP inhibitor SC-964 resulted in a significant decrease in the number of osteolytic lesions and the prevention of cancellous bone loss induced by the presence of 5T2MM cells (Van Valckenborgh et al, 2003). Other evidence suggesting the role of MMPs in osteolytic bone disease is the inhibition of MMPs by biphosphonates. These are used as therapy in MM for preventing bone resorption. Zoledronate significantly inhibits MMP-1 secretion by BMSCs, but strongly upregulates MMP-2 production (Derenne et al, 1999). Clodronate can inhibit in vitro the activities of several MMPs, like MMP-2, -9, -13 and MT1-MMP (Teronen et al, 2000).
V. Natural inhibitors in multiple myeloma
TIMPs are the natural inhibitors of MMPs, but it has been suggested that they are multifunctional. There have been 4 TIMPs described and they are called TIMP-1, -2, -3 and -4. There is some controversy on the functions of TIMPs in cancer development. Because they are able to inhibit MMPs, it was believed that they could inhibit tumor growth, invasion, angiogenesis and metastasis. Several studies confirm this hypothesis (Ahonen et al, 1998; Hajitou et al, 2001; Bloomston et al, 2002; Spurbeck et al, 2002; Ikenaka et al, 2003). However, it has also been demonstrated that high TIMP levels in certain types of malignant tumors in humans are associated with poor outcome (Curran and Murray, 1999; McCarthy et al, 1999). This could be due to the multifunctional role of TIMPs. TIMP-1 and -2 are able to stimulate the growth of several cells (Docherty et al, 1985; Hayakawa et al, 1992, 1994; Gomez et al, 1997) and TIMP-2 has been described to be involved in the activation of proMMP-2 (Hernandez-Barrantes et al, 2000). TIMP-3 possesses pro-apoptotic capacity (Ahonen et al, 1998; Baker et al, 1999), whereas TIMP-1 have anti-apoptotic effects on certain cell types (Guedez et al, 1998; Li et al, 1999). Recently, DNA array demonstrated a higher level of TIMP-1 and the same level of TIMP-2 in the MMECs compared to the HUVECs (Vacca et al, 2003). This is the only report where TIMPs were investigated in MM. More research is necessary to find out more about the expression and role of TIMPs in MM disease.
Neovastat is an orally bioavailable extract from shark cartilage able to inhibit the activity of MMP-2, -9, -12 and -13 and has also been described to be anti-angiogenic. A phase II clinical trial is going on to evaluate the efficacy of neovastat as monotherapy treatment for patients with MM not responding to standard therapies (Vihinen and Kähäri, 2002).
VI. Conclusion
Research on MMPs in MM demonstrated that certain enzymes are expressed in the tumor cells and the BM microenvironment and that they are involved in certain processes important for the development of MM. Formerly, it was believed that MMPs were only necessary for the degradation of several components of the ECM. Recently, it has been described that the enzymes are also able to cleave growth factors, cytokines and adhesion molecules resulting in a more complex role of MMPs. The multifunctional role of MMPs suggests further investigations for the recently discovered MMPs in their expression and role in MM. Although clinical trials with MMP inhibitors have not been promising, MMPs are still interesting targets for therapy. More knowledge about the function of the specific MMPs is needed for the beginning of new clinical trials. Recently, it has been demonstrated in a T-cell lymphoma model that an inhibitor with greater selectivity/specificity for MMP-9in vitro showed greater efficacy against liver metastasis in vivo (Arlt et al, 2002). The development of specific inhibitors for the different MMPs makes it possible to investigate the role of each MMP in MM disease. TIMPs, the natural inhibitors of MMPs and also described as multifunctional molecules, have not yet been described in MM. It is interesting to know whether they are expressed in MM cells and what impact the molecules will have on MM development when they are overexpressed.
Acknowledgements
This work was financially supported by the Onderzoeksraad-Vrije Universiteit Brussel (OZR-VUB), Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Belgische Federatie tegen Kanker, Fortis. Karin Vanderkerken and Kewal Asosingh are postdoctoral fellows of the "Fonds voor Wetenschappelijk Onderzoek-Vlaanderen" (FWO-Vl).
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