Rosenthal E L, Johnson T M, Allen E D, Apel I J, Punturieri A, Weiss S J
Department of Otolaryngology-Head and Neck Surgery, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109, USA.
Cancer Res. 1998 Nov 15;58(22):5221-30.
Normal as well as neoplastic cells traverse extracellular matrix barriers by mobilizing proteolytic enzymes in response to epidermal growth factor (EGF)-EGF receptor (EGFR) or hepatocyte growth factor/scatter factor (SF)-c-Met interactions. The plasminogen activator-plasminogen axis has been proposed to play a key role during cell invasion, but the normal development of plasminogen activator- as well as that of plasminogen-deficient mice supports the existence of alternate proteolytic systems that permit cells to traverse extracellular matrix barriers. To characterize the role that matrix-degrading proteinases play in EGF- or SF-stimulated invasion, a human squamous carcinoma cell line (UM-SCC-1) was triggered atop the matrices of type I collagen or human dermal explants in a three-dimensional culture system. During EGF- or SF-induced invasion, UM-SCC-1 cells expressed urokinase-type plasminogen activator (uPA) and uPA receptor as well as the matrix metalloproteinases (MMPs), membrane-type MMP-1, collagenase 1, stromelysin 1, and gelatinase B. Despite the presence of a positive correlation between uPA receptor-uPA expression and growth factor-stimulated invasion, UM-SCC-1 invasion was not affected by inhibitors directed against the plasminogen activator-plasminogen axis. In contrast, both recombinant and synthetic MMP inhibitors completely suppressed invasion by either EGF- or SF-stimulated cells without affecting either proteinase expression or cell motility across collagen-coated surfaces. These data demonstrate that MMPs, but not the plasminogen activator-plasmin system, can directly regulate the ability of either EGF- or SF-stimulated tumor cells to invade interstitial matrix barriers.
正常细胞和肿瘤细胞通过激活蛋白水解酶来穿越细胞外基质屏障，这一过程是对表皮生长因子（EGF）-EGF受体（EGFR）或肝细胞生长因子/扩散因子（SF）-c-Met相互作用的响应。纤溶酶原激活物-纤溶酶原轴被认为在细胞侵袭过程中起关键作用，但纤溶酶原激活物缺陷小鼠和纤溶酶原缺陷小鼠的正常发育表明存在其他蛋白水解系统，这些系统允许细胞穿越细胞外基质屏障。为了表征基质降解蛋白酶在EGF或SF刺激的侵袭中所起的作用，在三维培养系统中，将人鳞状癌细胞系（UM-SCC-1）置于I型胶原或人真皮外植体基质上进行触发。在EGF或SF诱导的侵袭过程中，UM-SCC-1细胞表达尿激酶型纤溶酶原激活物（uPA）和uPA受体以及基质金属蛋白酶（MMP）、膜型MMP-1、胶原酶1、基质溶解素1和明胶酶B。尽管uPA受体-uPA表达与生长因子刺激的侵袭之间存在正相关，但针对纤溶酶原激活物-纤溶酶原轴的抑制剂对UM-SCC-1的侵袭没有影响。相反，重组和合成的MMP抑制剂都能完全抑制EGF或SF刺激的细胞的侵袭，而不影响蛋白酶的表达或细胞在胶原包被表面的运动。这些数据表明，MMPs而非纤溶酶原激活物-纤溶酶系统可直接调节EGF或SF刺激的肿瘤细胞侵袭间质基质屏障的能力。
