Matrix metalloproteinases participate in osteosarcoma invasion

被引:141
作者
Bjornland, K [1 ]
Flatmark, K
Pettersen, S
Aaasen, AO
Fodstad, O
Maelandsmo, GM
机构
[1] Univ Oslo, Rikshosp, Inst Surg Res, N-0027 Oslo, Norway
[2] Univ Oslo, Rikshosp, Dept Surg, N-0027 Oslo, Norway
[3] Univ Oslo, Norwegian Radium Hosp, Canc Res Inst, Dept Tumor Biol, Oslo, Norway
关键词
marimastat; tissue inhibitor of metalloproteinases; TIMP-1; TIMP-2; gelatinase; MMP-2; MMP-9; p53; docycycline; osteosarcoma;
D O I
10.1016/j.jss.2004.12.016
中图分类号
R61 [外科手术学];
学科分类号
摘要
Background. Osteosarcoma (OS) is a highly malignant bone tumor and is the most frequent malignant bone tumor in children and adolescents. Metastases are the major cause of death, and patients with relapse have poor prognosis. Several solid tumors display enhanced expression of matrix metalloproteinases (MMPs), and recently AMP-inhibitors have entered clinical trials. A disturbance of the AMP system in favor of enhanced proteolytic activity may be suspected in OS because OS growth is accompanied by both enhanced local bone destruction and bone formation, two processes that are dependant on proteolytic enzymes. Thus, the aim of the present study was to evaluate the involvement of MMPs in a panel of human OS cell lines, xenografts and biopsies. Material and methods. Expression of MMPs and their endogenous inhibitors were studied by zymography and Northern blot analyses. In vitro invasion of OS cell lines and effects of MMP-inhibitors (Marimastat and doxycycline) were assessed in the transwell. chamber assay. Results. In vitro invasiveness was compared with gelatinase activity, and the most invasive cell line secreted the highest amounts of MMP-2 and MMP-9. Two different MMP-inhibitors significantly reduced OS cell invasion. The majority of the OS xenografts expressed both the inactive and active form of MMP-2 and in some cases also MMP-9. The biopsies from primary and metastatic OS also expressed MMP-2 mRNA. However, MMP-9 levels were higher in the biopsies than in the xenografts. C onclusion. The obtained results support the hypothesis that MMPs and their endogenous inhibitors participate in the invasive process of human OS. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:151 / 156
页数:6
相关论文
共 43 条
[1]   Medical Progress - Common musculoskeletal tumors of childhood and adolescence [J].
Arndt, CAS ;
Crist, WM .
NEW ENGLAND JOURNAL OF MEDICINE, 1999, 341 (05) :342-352
[2]   Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter [J].
Bian, JH ;
Sun, Y .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (11) :6330-6338
[3]   Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial [J].
Bramhall, SR ;
Hallissey, MT ;
Whiting, J ;
Scholefield, J ;
Tierney, G ;
Stuart, RC ;
Hawkins, RE ;
McCulloch, P ;
Maughan, T ;
Brown, PD ;
Baillet, M .
BRITISH JOURNAL OF CANCER, 2002, 86 (12) :1864-1870
[4]   THE USE OF MULTICELLULAR SPHEROIDS IN ESTABLISHING HUMAN SARCOMA CELL-LINES INVITRO [J].
BRULAND, O ;
FODSTAD, O ;
PIHL, A .
INTERNATIONAL JOURNAL OF CANCER, 1985, 35 (06) :793-798
[5]   Changing views of the role of matrix metalloproteinases in metastasis [J].
Chambers, AF ;
Matrisian, LM .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1997, 89 (17) :1260-1270
[6]   Alendronate regulates cell invasion and MMP-2 secretion in human osteosarcoma cell lines [J].
Cheng, YY ;
Huang, L ;
Lee, KM ;
Li, K ;
Kumta, SM .
PEDIATRIC BLOOD & CANCER, 2004, 42 (05) :410-415
[7]   Effect of combined cyclooxygenase-2 and matrix metalloproteinase inhibition on human sarcoma xenografts [J].
Dickens, DS ;
Cripe, TP .
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, 2003, 25 (09) :709-714
[8]   DEGRADATION OF COLLAGEN IN THE BONE-RESORBING COMPARTMENT UNDERLYING THE OSTEOCLAST INVOLVES BOTH CYSTEINE-PROTEINASES AND MATRIX METALLOPROTEINASES [J].
EVERTS, V ;
DELAISSE, JM ;
KORPER, W ;
NIEHOF, A ;
VAES, G ;
BEERTSEN, W .
JOURNAL OF CELLULAR PHYSIOLOGY, 1992, 150 (02) :221-231
[9]  
FEINBERG AP, 1984, P NATL ACAD SCI USA, V81, P1991
[10]   Role of MMP-9 and its tissue inhibitor TIMP-1 in human osteosarcoma - Findings in 42 patients followed for 1-16 years [J].
Ferrari, C ;
Benassi, MS ;
Ponticelli, F ;
Gamberi, G ;
Ragazzini, P ;
Pazzaglia, L ;
Balladelli, A ;
Bertoni, F ;
Picci, P .
ACTA ORTHOPAEDICA SCANDINAVICA, 2004, 75 (04) :487-491