hepatic metastasis in their resected liver have shown recurIt is well known that a urokinase-type plasminogen rence within 3 years, 9 prompting us to seek a new predictor activator receptor (uPAR) is a key protein in the plasfor this recurrence. minogen activation system, which plays a proteolyti-The metastatic process in malignant tumors involves local cally important role in the invasion and metastasis of invasion, intravasation, and extravasation. 10 These events various cancer cells. To assess the expression of uPAR depend on the tumor-associated proteolytic process including in hepatocellular carcinoma (HCC), we analyzed the exthe plasminogen activation system, and many reports have pression of uPAR messenger RNA (mRNA) and the proshown that the urokinase-type plasminogen activator (uPA) tein in 31 pair-samples of solitary HCC and nontumorous plays an important role in this process. 11-13 uPA is released liver tissues from the same patients. Fifteen samples exfrom tumor and stromal cells [14][15][16] in a single-chain zymogen hibited no histological potential of recurrence, such as form, pro-uPA. 17,18 pro-uPA is converted into a two-chain acportal involvement or intrahepatic metastasis (group A), tive form of uPA, which converts the ubiquitous zymogen and 16 samples exhibited such histological features plasminogen into the proteolytically active form, plasmin. (group B). Seventy-one percent of the cases showedPlasmin by itself degrades the extracellular matrix and actiuPAR signals, and these signals were mainly localized vates collagenases. 19 Some authors have described that poor at the cytoplasm of the tumor cells and tended to be at prognostic types of cancer cells show high levels of uPA. 20-22the front of invasive foci. 87.5% of the cases in group B The mechanism of the initial activation of pro-uPA under showed uPAR signals against 53.3% of the cases in group physiological conditions is unknown. uPA has a specific re-A (P õ .05). The rate of recurrence in the uPAR positive/ ceptor (uPAR) anchoring to the cell surface by glycosyl-phonegative cases in group A was 75.0% and 14.3%, respecphatidyl-inositol. [23][24][25][26][27] uPAR is a protein with an Mr55000-tively (P õ .05). In non-neoplastic cases, e.g., chronic ac-60000 (55-60 Kd molecular weight of uPAR antigen), tive hepatitis and cirrhosis, weak uPAR mRNA and protranslated from a 1.4-kb messenger RNA (mRNA) 28 and its tein signals were detected in hepatocytes neighboring amino-terminal domain has a high affinity with an epidermal the portal tracts, suggesting that this protein plays some growth factor-like domain in the pro-uPA and uPA molerole in such cases. The present study indicates that cules. 29,30 uPAR synthesis is regulated by growth factors such uPAR plays an important role at least in its initial stage as transforming growth factors b 1 and b 2 , epidermal growth in invasion and metastasis of HCC, and that uPAR exfactor, 31,32 and phorbol 12-myristate 13-acetate. 33 Binding of pression can be a candidate predictor of these factors.pro...

Background-The urokinase type plasminogen activator receptor (uPAR) may play a critical role in cancer invasion and metastasis. Aims-To study the involvement of uPAR in colorectal carcinogenesis. Methods-The cellular expression and localisation of uPAR were investigated in colorectal adenomas and invasive carcinomas by in situ hybridisation, immunohistochemistry, and northern and western blot analyses. Results-uPAR mRNA expression was found mainly in the cytoplasm of dysplastic epithelial cells of 30% of adenomas with mild (19%), moderate (21%), and severe (47%) dysplasia, and in that of carcinomatous cells of 85% of invasive carcinomas: Dukes' stages A (72%), B (93%), and C (91%). Some stromal cells in the adjacent neoplastic epithelium were faintly positive. Immunoreactivity for uPAR was detected in dysplastic epithelial cells of 14% of adenomas and in carcinomatous cells of 49% of invasive carcinomas. uPAR mRNA and protein concentrations were significantly higher in severe than in mild or moderate dysplasia (p<0.05); they were notably higher in Dukes' stage A than in severe dysplasia (p<0.05), and significantly higher in Dukes' stage B than in stage A (p<0.05), but those in stage B were not diVerent from those in stage C or in metastatic colorectal carcinomas of the liver. Conclusions-Colorectal adenoma uPAR, expressed essentially in dysplastic epithelial cells, was upregulated with increasing severity of atypia, and increased notably during the critical transition from severe dysplasic adenoma to invasive carcinoma. These findings implicate uPAR expression in the invasive and metastatic processes of colorectal cancer. (Gut 1998;43:798-805)