The study of the expression of MMPs and TIMPs in malignant bone and soft tissue tumors, its regulation and therapeutic application

在恶性骨和软组织肿瘤的治疗中，远处转移仍然是一个问题。我们建立了体外侵袭实验系统来研究肿瘤细胞向远处器官转移的分子机制。肿瘤细胞对基底膜的侵袭是肿瘤转移的关键步骤之一，包括对基底膜的附着、基质的降解和肿瘤细胞的运动。基质的降解是由基质金属蛋白酶(MMPs)及其抑制物TIMP(TIMP)之间的平衡调节的。在本研究中，我们研究发现：(1)肿瘤坏死因子-α可增强骨肉瘤细胞对基底膜的侵袭能力，这种作用是通过激活细胞内的核因子-KB来实现的；(2)抗氧化剂可以阻断肿瘤坏死因子-α对核因子-kB的激活，从而抑制骨肉瘤细胞的侵袭。(3)新合成的口服型MMPI…更多的抑制剂OPB-3206在体内抑制血管生成、肿瘤生长和实验性转移，表明抑制基质金属蛋白酶活性是控制肿瘤生长和转移的关键。(4)RhoA是一种小的GTP结合蛋白，在控制细胞形态和运动方面起着重要作用。由于1-Oieoyl溶血磷脂酸(LPA)对RhoA具有特异性活性，我们用LPA处理骨肉瘤细胞。LPA处理可诱导应激纤维形成、细胞形态改变、膜型1基质金属蛋白酶(MT1-MMP)、TIMP-2和活化的基质金属蛋白酶-2(TIMP-2)的表达，以及细胞的侵袭。(5)RhoA的抑制剂肉毒毒素C3和Rho相关蛋白p160ROCK的抑制剂Y27632均能抑制LPA的作用，提示RhoA控制着骨肉瘤细胞的侵袭和基质金属蛋白酶的活性。(6)MT1-MMPs和TIMP-2参与了MMP一2的活化，对肿瘤细胞的侵袭表型起重要作用。MT1-MMP3、TIMP-2和MMP2的表达与软骨肉瘤的组织学分期及肉瘤细胞对基质的破坏密切相关。较少

In the treatment of malignant bone and soft tissue tumors, distant metastasis still remains a problem. We have established in vitro invasion assay system to investigate the molecular mechanisms by which the tumor cell can metastasize to distant organs.Tumor cell invasion to the basement membrane is one of the crucial steps for cancer metastasis, consisting of attachment to the basement membrane, matrix degradation and tumor cell motility. The degradation of matrix is mediated by the balance between degradation enzymes, matrix metalloproteinase (MMP), and their inhibitors, tissue inhibitor of metalloproteinase (TIMP). In this study, we investigated and found that (1) the ability of invasion to basement membrane of osteosarcoma cell can be enhanced by TNF-a, which is mediated by activation of NF-KB in the cells, (2) the antioxidants can block the activation of NF-KB by TNF-a and subsequently inhibit the invasion of the osteosarcoma cells. (3) A newly synthesized, oral-administrable MMP i … More nhibitor, OPB-3206, and inhibit angiogenesis, tumor growth and experimental metastasis in vivo, indicating that inhibition of MMP activity is essential to control tumor growth and metastasis. (4) RhoA, a small GTP-binding protein, is play important roles to control cell shape and motility. Since 1-oieoyl lysophosphatidic acid (LPA) specifically active RhoA, we treated of osteosarcoma cells with LPA. The treatment of LPA induces stressfiber formation, cell shape alteration, expression of membrane type-1 MMP (MT1-MMP), TIMP-2 and active from MMP-2, and invasion of the cells. (5) The botulinum toxin C3, inhibitor of RhoA, and Y27632, an inhibitor of Rho-associated kinase p160ROCK are both able to inhibit the effects of LPA, indicating that RhoA controls the activity of MMP and invasion of the osteosarcoma cells. (6) MT1-MMP and TIMP-2 are essential for the activation of MMP-2 and important for invasive phenotype of tumor cells. The expression of MT1-MMP, TIMP-2 and MMP-2 has significant correlation with the histologic stages of human chondrosarcoma and matrix destruction by the sarcoma cells. Less