Matrix-degrading Proteinases and their inhibitors in invasive and metastatic ovarian carcinomas.

点击翻译按钮获取中文摘要

<Objective> To elucidate themechanisms of invasion and metastasis of human ovarian carcinomas, we studied matrix-metalloproteinases, such as gelatinase A and B (type IV collagenase), andmultiple serine proteinases in vivo and in vitro. <Study design> Human ovarian carcinoma cell lines, transplanted tumor, and surgical samples obtained during operation, were employed for the study. Distribution of matrix-metalloproteinases and serine proteinases in ovarian carcinomas were analyzed by gelatin zymography. Their inhibitors were examined by reverse zymography. These proteinases and inhibitors were identified by immunoblotting methods. Trypsin (ogen) expression in ovarian carcinomas was determined by Northern blot analysis and immunohistochemical studies. <Results> By zymographic and Western blot analyzes, ovarian adenocarcinoma cell lines secreted multiple types of serine proteinases such as tissue-type and urokinase-type plasminogen activators, while undifferentiated adenocarcinomas mainly … More secreted gelatinase A or B.The high proteinase producers hardly secreted their corresponding inhibitors, such as tissue inhibitor of metalloproteinases (TIMP)-1, -2 or plasminogen activator inhibitor-1 (PAI-1). As for clinical samples, we showed high gelatinase activity in the cyst fluids derived from high grade human ovarian adenocarcinomas. When the ovarian carcinoma cell lines formed cystic xenoplant tumors in nude mice, high levels of these proteinase activities were demonstrated in the cystfluid. These high levels of gelatinase activities in transplanted cystic tumors were derived from the interaction of the tumor cells and surrounding interstitial fibroblasts. Trypsinogen mRNA and immunohistochemical stainings were detected in all of advanced ovarian adenocarcinomas, whereas it was undetectable in early stage carcinoma, low malignant potential and benign ovarian tumors as well as normal ovarian tissues. Especially, all of the serous cystadenocarcinmas tested showed high expression of trypsinogen mRNA compared to mucinous cystadenocarcinomas and clear cell adenocarcinomas at advanced stages. I<Conclusion> The present study suggests that the balance between the proteinases and their inhibitors might determine the malignant potential of the ovarian tumor cells to degrade matrix proteins and their capability of invasion and metastatic behavior. These data also strongly suggest that tumor-derived trypsin may implicate in the invasive and metastatic behavior of ovarian malignant tumors. Less