Melanoma-mediated dissolution of extracellular matrix: contribution of urokinase-dependent and metalloproteinase-dependent proteolytic pathways.
Melanoma-mediated dissolution of extracellular matrix: contribution of urokinase-dependent and metalloproteinase-dependent proteolytic pathways.
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发表时间：
1993-02
期刊：
影响因子：
11.2
通讯作者：
Anthony;M. P. Montgomery;Y. Clerck;Keith E. Langley;Ralph A. Reisfeld;Barbara;M. Mueller
中科院分区：
文献类型：
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作者：
Anthony;M. P. Montgomery;Y. Clerck;Keith E. Langley;Ralph A. Reisfeld;Barbara;M. Mueller
尿激酶和基质金属蛋白酶（MMP）活性的组成性过度表达经常在个体恶性肿瘤中观察到。在这项研究中，我们描述了这些不同的酶系统的高转移性人黑色素瘤细胞系（M24 met）的侵袭性表型的综合贡献。发现M24 met细胞分泌一系列MMP，包括间质胶原酶、IV型胶原酶（M（r）92，000和72，000明胶酶）和基质溶解素。尿激酶，但不是组织型纤溶酶原激活剂，检测到M24 MET条件培养基和细胞表面。这些酶对细胞外基质溶解的贡献通过利用特异性抑制剂，即金属蛋白酶-2和纤溶酶原激活物抑制剂-2的组织抑制剂来确定。由于尿激酶和MMP依赖性活性的共表达，观察到M24 met细胞降解细胞外基质的多种组分，并显著降解间质和基底膜基质。尿激酶依赖性的基质糖蛋白的去除被观察到之前MMP依赖性的胶原溶解作为一个先决条件的限速步骤。我们目前的证据表明，这种时间关系是由基质的结构架构，使基质糖蛋白用于保护相关的胶原蛋白MMP依赖性降解。除了介导显著的胶原溶解外，MMP活性还与基质弹性蛋白原的溶解有关。尿激酶/纤溶酶活性没有发现所需的MMP-酶原激活。
Constitutive overexpression of both urokinase and matrix metalloproteinase (MMP) activity is frequently observed in individual malignant tumors. In this study we describe the combined contribution of these distinct enzyme systems to the invasive phenotype of a highly metastatic human melanoma cell line (M24met). M24met cells were found to secrete a spectrum of MMPs, including interstitial collagenase, type IV collagenases (M(r) 92,000 and 72,000 progelatinases), and stromelysin. Urokinase, but not tissue-type plasminogen activator, was detected in M24met-conditioned media and on cell surfaces. The contribution of these enzymes to extracellular matrix dissolution was determined by exploiting specific inhibitors, namely tissue inhibitor of the metalloproteinases-2 and plasminogen activator inhibitor-2. Due to the coexpression of urokinase and MMP-dependent activity, M24met cells were observed to degrade multiple components of the extracellular matrix and to significantly degrade both interstitial and basement membrane matrices. Urokinase-dependent removal of matrix glycoprotein was observed to precede MMP-dependent collagenolysis as a prerequisite rate-limiting step. We present evidence which suggests that this temporal relationship is imposed by the structural architecture of the matrix such that matrix glycoprotein serves to protect associated collagen from MMP-dependent degradation. In addition to mediating significant collagenolysis, MMP activity was further implicated in the dissolution of matrix tropoelastin. Urokinase/plasmin activity was not found to be required for MMP-zymogen activation.