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-bβ (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 avb3 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-avb3 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-9 in 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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Els Van Valckenborgh

Structural class	Enzyme names	New substrates
Minimal domain	MMP-7 (matrilysin)	a1-PI, a1-AT, b4 integrin, FasL, TNF-a, plasminogen, TFPI, E-cadherin, OPN, IgG, CTGF, syndecan-1, fibrinogen
	MMP-26 (matrilysin-2)	IGFBP-1, a1-PI, fibrinogen
Simple hemopexin domain	MMP-1 (collagenase-1)	a1-AT, TFPI, CTGF, MCP-1, -2, -3 and -4, SAA, IGFBP-3, IL-1b, AFP, SDF-1, MBL, a1-AC, a2-M, a1-PI, C1q, fibrinogen, TNF-a
	MMP-3 (stromelysin-1)	a1-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, a1-AC, a2-M, a1-PI, C1q, TNF-a
	MMP-8 (collagenase-2)	a1-AT, TFPI, MBL, CXCL-6, CXCL-9, CXCL-10, fibrinogen, a2-M, a1-PI, C1q
	MMP-10 (stromelysin-2)	Fibrinogen
	MMP-12 (metalloelastase)	Fibrinogen, factor XII, plasminogen, apolipoprotein, uPAR, MBP, a1-AT, pro-TNF, TFPI, a2-M, a1-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, a1-AC, a1-PI, C1q, fibrinogen, proTGF-b, proTNF-a
	MMP-9 (gelatinase B)	a1-AT, plasminogen, TFPI, IL-1b, SDF-1, LTBP1, IL-8, CXCL-6, CXCL-5, MBP, substance P, IGFBP-3, MBL, KiSS-1, aB-crystallin, CXCL-9, CXCL-10, a2-M, a1-PI, C1q, fibrinogen, proTGF-b, proTNF-a
Furin-activated secreted	MMP-11 (stromelysin-3)	a1-PI, IGFBP, a2-M
	MMP-28 (epilysin)
Vitronectin-like insert	MMP-21	a1-AT
Transmembrane	MMP-14 (MT1-MMP)	a2-M, a1-PI, SDF-1, MCP-3, KiSS, factor XII, MBL, pro-av 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

Review Article

Received: 30 March 2004; Accepted: 5 April 2004; electronically published: April 2004

I. Introduction

II. Matrix metalloproteinases

III. Matrix metalloproteinases in multiple myeloma: expression, regulation and activation

IV. The role of matrix metalloproteinases in multiple myeloma

VI. Conclusion

Acknowledgements

References