[en] Matrix metalloproteinases (MMPs) are known to play a role in cell growth, invasion, angiogenesis, metastasis, and bone degradation, all important events in the pathogenesis of cancer. Multiple myeloma is a B-cell cancer characterized by the proliferation of malignant plasma cells in the bone marrow, increased angiogenesis, and the development of osteolytic bone disease. The role of MMPs in the development of multiple myeloma is poorly understood. Using SC-964, a potent inhibitor of several MMPs (MMP-2, -3, -8, -9, and -13), we investigated the role of MMPs in the 5T2MM murine model. Reverse transcriptase-polymerase chain reaction demonstrated the presence of mRNA for MMP-2, -8, -9, and -13 in 5T2MM-diseased bone marrow. Mice bearing 5T2MM cells were given access to food containing SC-964. The concentration of SC-964 measured in the plasma of mice after 11 days of treatment was able to inhibit MMP-9 activity in gelatin zymography. Treatment of 5T2MM-bearing mice resulted in a significant reduction in tumor burden, a significant decrease in angiogenesis, and partially protective effect against the development of osteolytic bone disease. The direct role of MMPs in these different processes was confirmed by in vitro experiments. All these results support the multifunctional role of MMPs in the development of multiple myeloma.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Van Valckenborgh, Els
Croucher, Peter I.
De Raeve, Hendrik
Carron, Chris
De Leenheer, Evy
Blacher, Silvia ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Devy, Laetitia
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S: Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 1998, 58:1048-1051
Noël A, Hajitou A, L'Hoir C, Maquoi E, Baramova E, Lewalle J, Remacle A, Kebers F, Brown P, Calberg-Bacq C, Foidart J: Inhibition of stromal matrix metalloproteases: effects on breast-tumor promotion by fibroblasts. Int J Cancer 1998, 76:267-273
Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002, 2:161-174
Watanabe H, Nakanishi I, Yamashita K, Hayakawa T, Okada Y: Matrix metalloproteinase-9 (92 kDa gelatinase/type IV collagenase) from U937 monoblastoid cells: correlation with cellular invasion. J Cell Sci 1993, 104:991-999
Hua J, Muschel RJ: Inhibition of matrix metalloproteinase 9 expression by a ribozyme blocks metastasis in a rat sarcoma model system. Cancer Res 1996, 56:5279-5284
Moses MA: The regulation of neovascularization by matrix metalloproteinases and their inhibitors. Stem Cells 1997, 15:180-189
O-Charoenrat P, Rhys-Evans P, Eccles S: A synthetic matrix metalloproteinase inhibitor prevents squamous carcinoma cell proliferation by interfering with epidermal growth factor receptor autocrine loops. Int J Cancer 2002, 100:527-533
Manes S, Llorente M, Lacalle RA, Gomez-Mouton C, Kremer L, Mira E, Martinez-AC: The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J Biol Chem 1999, 274:6935-6945
Barillé S, Akhoundi C, Collette M, Mellerin M, Rapp M, Harousseau J, Bataille R, Amiot M: Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells. Blood 1997, 90:1649-1655
Van Valckenborgh E, Bakkus M, Munaut C, Noël A, St Pierre Y, Asosingh K, Van Riet I, Van Camp B, Vanderkerken K: Upregulation of matrix metalloproteinase-9 in murine 5T33 multiple myeloma cells by interaction with bone marrow endothelial cells. Int J Cancer 2002, 101:512-518
Vande Broek I, Asosingh K, Allegaert V, Leleu X, Facon T, Vanderkerken K, Van Camp B, Van Riet I: Bone marrow endothelial cells increase the invasiveness of human multiple myeloma cells through upregulation of MMP-9: evidence for a role of hepatocyte growth factor. Leukemia 2004, Mar 4 [Epub ahead of print]
Barillé S, Bataille R, Rapp M, Harousseau J, Amiot M: Production of metalloproteinase-7 (matrilysin) by human myeloma cells and its potential involvement in metalloproteinase-2 activation. J Immunol 1999, 163:5723-5728
Kelly T, Borset M, Abe E, Gaddy-Kurten D, Sanderson R: Matrix metalloproteinases in multiple myeloma. Leuk Lymphoma 2000, 37:273-281
Hajitou A, Sounni N, Devy L, Grignet-Debrus C, Lewalle J, Li H, Deroanne CF, Lu H, Colige A, Nusgens BV, Frankenne F, Maron A, Yeh P, Perricaudet M, Chang Y, Soria C, Calberg-Bacq C, Foidart J, Noël A: Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: effect on in vivo mammary tumor growth and angiogenesis. Cancer Res 2001, 61:3450-3457
Ahonen M, Baker AH, Kahari V: Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res 1998, 58:2310-2315
Bloomston M, Shafii A, Zervos EE, Rosemurgy AS: TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis. J Surg Res 2002, 102:39-44
McCarthy K, Maguire T, McGreal G, McDermott E, O'Higgins N, Duffy MJ: High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer. Int J Cancer 1999, 84:44-48
Vanderkerken K, Goes E, De Raeve H, Radl J, Van Camp B: Follow-up of bone lesions in an experimental multiple myeloma mouse model: description of an in vivo technique using radiography dedicated for mammography. Br J Cancer 1996, 73:1463-1465
Vanderkerken K, Asosingh K, Croucher P, Van Camp B: Multiple myeloma biology: lessons from the 5TMM models. Immunol Rev 2003, 194:196-206
Van Valckenborgh E, De Raeve H, Devy L, Blacher S, Munaut C, Noël A, Van Marck E, Van Riet I, Van Camp B, Vanderkerken K: Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo. Br J Cancer 2002, 86:796-802
Radl J, De Glopper ED, Schuit HR, Zurcher C: Idiopathic paraproteinemia. II. Transplantation of the paraprotein-producing clone from old to young C57BL/KaLwRij mice. J Immunol 1979, 122:609-613
Radl J, Croese JW, Zurcher C, Van den Enden-Vieveen MH, de Leeuw AM: Animal model of human disease. Multiple myeloma. Am J Pathol 1988, 132:593-597
Asosingh K, Radl J, Van Riet I, Van Camp B, Vanderkerken K: The 5TMM series: a useful in vivo mouse model of human multiple myeloma. Hematol J 2000, 1:351-356
Vanderkerken K, De Raeve H, Goes E, Van Meirvenne S, Radl J, Van Riet I, Thielemans K, Van Camp B: Organ involvement and phenotypic adhesion profile of 5T2 and 5T33 myeloma cells in the C57BL/KaLwRij mouse. Br J Cancer 1997, 76:451-460
Vanderkerken K, Asosingh K, Braet F, Van Riet I, Van Camp B: Insulin-like growth factor-1 acts as a chemoattractant factor for 5T2 multiple myeloma cells. Blood 1999, 93:235-241
Croucher PI, Shipman CM, Lippitt J, Perry M, Asosingh K, Hijzen A, Brabbs AC, van Beek EJR, Holen I, Skerry TM, Dunstan CR, Russell GR, Van Camp B, Vanderkerken K: Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood 2001, 98:3534-3540
Vanderkerken K, De Greef C, Asosingh K, Arteta B, De Veerman M, Vande Broek I, Van Riet I, Kobayashi M, Smedsrod B, Van Camp B: Selective initial in vivo homing pattern of 5T2 multiple myeloma cells in the C57BL/KaLwRij mouse. Br J Cancer 2000, 82:953-959
Blacher S, Devy L, Burbridge MF, Roland G, Tucker G, Noël A, Foidart J: Improved quantification of angiogenesis in the rat aortic ring assay. Angiogenesis 2001, 4:133-142
Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F, Dammacco F: Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 1994, 87:503-508
Wahlgren J, Maisi P, Sorsa T, Sutinen M, Tervahartiala T, Pirilä E, Teronen O, Hietanen J, Tjäderhane L, Salo T: Expression and induction of collagenases (MMP-8 and -13) in plasma cells associated with bone-destructive lesions. J Pathol 2001, 194:217-224
Asosingh K, Menu E, Van Valckenborgh E, Vande Broek I, Van Riet I, Van Camp B, Vanderkerken K: Mechanisms involved in the differential bone marrow homing of CD45 subsets in 5T murine models of myeloma. Clin Exp Metastasis 2002, 19:583-591
Hargreaves PG, Wang F, Antcliff J, Murphy G, Lawry J, Russell RG, Croucher PI: Human myeloma cells shed the interleukin-6 receptor: inhibition by tissue inhibitor of metalloproteinase-3 and a hydroxamate-based metalloproteinase inhibitor. Br J Haematol 1998, 101:694-702
Thabard W, Barillé S, Collette M, Harousseau J, Rapp M, Bataille R, Amiot M: Myeloma cells release soluble interleukin-6Ralpha in relation to disease progression by two distinct mechanisms: alternative splicing and proteolytic cleavage. Clin Cancer Res 1999, 5:2693-2697
Mangi MH, Newland AC: Angiogenesis and angiogenic mediators in haematological malignancies. Br J Haematol 2000, 111:43-51
Sezer O, Niemoller K, Eucker J, Jakob C, Kaufmann O, Zavrski I, Dietel M, Possinger K: Bone marrow microvessel density is a prognostic factor for survival in patients with multiple myeloma. Ann Hematol 2002, 79:574-577
Huang S, Van Arsdall M, Tedjarati S, McCarty M, Wu W, Langley R, Fidler IJ: Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J Natl Cancer Inst 2002, 94:1134-1142
Naglich JG, Jure-Kunkel M, Gupta E, Fargnoli J, Henderson AJ, Lewin AC, Talbott R, Baxter A, Bird J, Savopoulos R, Wills R, Kramer RA, Trail PA: Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. Cancer Res 2001, 61:8480-8485
Sounni NE, Devy L, Hajitou A, Frankenne F, Munaut C, Gilles C, Deroanne C, Thompson EW, Foidart J, Noël A: MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. EMBO J 2002, 16:555-564
Nemeth JA, Yousif R, Herzog M, Che M, Upadhyay J, Shekarriz B, Bhagat S, Mullins C, Fridman R, Cher ML: Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis. J Natl Cancer Inst 2002, 94:17-25
Sato T, Foged NT, Delaisse JM: The migration of purified osteoclasts through collagen is inhibited by matrix metalloproteinase inhibitors. J Bone Miner Res 1998, 13:59-66
Everts V, Delaisse JM, Korper W, Beertsen W: Cysteine proteinases and matrix metalloproteinases play distinct roles in the subosteoclastic resorption zone. J Bone Miner Res 1998, 13:1420-1430
Holliday LS, Welgus HG, Fliszar CJ, Veith GM, Jeffrey JJ, Gluck SL: Initiation of osteoclast bone resorption by interstitial collagenase. J Biol Chem 1997, 272:22053-22058
Croucher PI, De Raeve H, Perry MJ, Hijzen A, Shipman CM, Lippitt J, Green J, Van Marck E, Van Camp B, Vanderkerten K: Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 2003, 18:482-492
Vanderkerken K, De Leenheer E, Shipman C, Asosingh K, Willems A, Van Camp B, Croucher P: Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma. Cancer Res 2003, 63:287-289
Xu JL, Lai R, Kinoshita T, Nakashima N, Nagaska T: Proliferation, apoptosis, and intratumoral vascularity in multiple myeloma: correlation with the clinical stage and cytological grade. J Clin Pathol 2002, 55:530-534
Arlt M, Kopitz C, Pennington C, Watson KL, Krell HW, Bode W, Gansbacher B, Khokha R, Edwards DR, Krüger A: Increase in gelatinase-specificity of matrix metalloproteinase inhibitors correlates with antimetastatic efficacy in a T-cell lymphoma model. Cancer Res 2002, 62:5543-5550
