Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carcinogenesis in the human colon is associated with a marked increase in the tissue content of the urokinase-type plasminogen activator (u-PA). This study was performed to determine the type of cells responsible for the u-PA increase in carcinomas of the colon and in their precursor lesions, the adenomas, by immunohistological evaluation applying monoclonal antibody 3689 directed to the beta-chain of u-PA. Normal intestinal mucosa (n = 17) showed hardly any staining of u-PA, but some lamina propria cells were faintly positive. Carcinomas (n = 17) and adenomas (n = 16) showed a considerable and comparable staining intensity of u-PA in neoplastic columnar epithelial cells, and this staining was found to be diffuse and cytoplasmic. In a majority of the neoplastic tissues the u-PA staining was found to be patchy and not related to known risk markers of malignancy such as dysplasia in the adenomas, or to prognostic determinants such as Dukes' classification or differentiation in the carcinomas. The observation of strong u-PA positive lamina propria cells in adenomas but infrequently observed in normal mucosa and carcinomas was noteworthy. u-PA staining intensity of the tissue sections was found to correlate well with the u-PA antigen level in the tissue extracts determined by ELISA (r = 0.52, P = 0.0001) but poorly with the u-PA activity determined enzymatically (r = 0.28, P = 0.05). In conclusion, the u-PA increase in neoplasia of the human colon can be attributed to an increased diffuse cytoplasmic content of u-PA in neoplastic columnar epithelial cells.
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PMID:Immunolocalization of urokinase-type plasminogen activator in adenomas and carcinomas of the colorectum. 191 97

Three hundred and forty-four patients with operable colorectal adenocarcinoma, Dukes' stage B or C, were entered into a randomized controlled trial of intraoperative and postoperative intravenous urokinase and/or long-term sodium warfarin therapy. The factorial design of the trial allowed evaluation of each therapy separately. Age, sex, Dukes' stage and cancer site were similar in the treatment groups. Using life-table methods, survival and recurrence/metastases free survival were estimated up to 6 years postoperatively. No significant effects of either therapy on these endpoints were found.
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PMID:The first international urokinase/warfarin trial in colorectal cancer. 201 15

The biofunctional activity of the plasminogen activators urokinase and tissue plasminogen activator has been measured in extracts from 50 colorectal carcinomas and 21 adenomas using a bioimmunoassay. Compared with control mucosa urokinase activity was significantly elevated in adenomas (P less than 0.001) and carcinomas, levels being significantly higher in carcinomas (P less than 0.05). In contrast tissue plasminogen activator activity was reduced in adenomas (P less than 0.01) and carcinomas, levels being significantly lower in carcinomas (P less than 0.01). Although enzyme activity did not relate to Dukes' stage or histological grade urokinase activity was higher in carcinomas with venous invasion (n = 17, P less than 0.05), in those with moderate or extensive local spread (n = 27, P less than 0.05) and in cases where a palliative resection only was feasible because of advanced disease (n = 8, P less than 0.05). Urokinase has been implicated in tissue degradation as well as fibrinolysis and may play a role in tumour invasion and metastasis in human colorectal neoplasia.
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PMID:Role of urokinase in colorectal neoplasia. 311 78

The distributions of urokinase and tissue plasminogen activators (uPA, tPA), uPA receptor (uPAR), and plasminogen activator inhibitors (PAI-1, PAI-2) were studied immunohistochemically in two subsets of colorectal adenocarcinomas with low and high aggressiveness, respectively: nine Dukes' stage A tumors with additional other good prognostic markers and 13 Duke's stage C tumors with also other poor prognostic markers (referred to as Dukes' stage A and Dukes' stage C tumors). The results showed that these components of the tissue destructive plasminogen activation system were accumulated at the invading front of the tumors. Both tumor groups showed accumulations of uPA, uPAR, and PAI-1 at the tumor-host interface compared with the location within the tumor epithelium and the adjacent normal mucosa and muscularis propria (all P < .05). However, the uPA level at the tumor-host interface in the Dukes' stage C tumors was twice the level in the Dukes' stage A tumors (P < .05). The uPAR level was also significantly higher in the Dukes' stage C tumors (P < .05), whereas the PAI-1 level was not significantly higher. This may indicate that uPA in more aggressive tumors exceeds the inhibitory capacity represented by PAIs, resulting in enhanced tissue destructive potential that promotes tumor invasion. uPA and uPAR antigen levels and the uPA/PAI-1 ratio at the tumor-host interface appeared to be related to tumor aggressiveness in colorectal cancer.
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PMID:Antigen levels of urokinase plasminogen activator and its receptor at the tumor-host interface of colorectal adenocarcinomas are related to tumor aggressiveness. 755 47

Human colorectal carcinogenesis has been shown previously to be associated with impressive changes in the tissue levels of plasminogen activators and their inhibitors, exemplified by an increase in the urokinase-type plasminogen activator (u-PA) and the inhibitors PAI-1 and PAI-2, and a decrease in tissue-type plasminogen activator (t-PA). In the present study we evaluated the prognostic significance of these parameters to the overall survival of patients with colorectal cancer, in conjunction with several major clinicopathological parameters like age, gender, differentiation grade, and Dukes' stage. Univariate analyses revealed that a low t-PA antigen level, low t-PA activity, and high u-PA/t-PA antigen ratio in normal mucosa and a high u-PA and PAI-2 antigen level in carcinomas are prognostic for a poor overall survival of patients with colorectal cancer. The prognostic value of t-PA antigen and activity in normal mucosa, the antigen ratio of u-PA in carcinoma (C) and t-PA in corresponding normal (N) mucosa [u-PA(C)/t-PA(N) antigen ratio], and PAI-2 antigen in carcinomas was found to be independent from clinicopathological parameters by multivariate analyses. These observations illustrate the clinical importance of the plasminogen activation cascade at the tissue level in colorectal cancer invasion, metastasis, and survival.
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PMID:Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. 803 38

In patients with colorectal cancer, profound alterations of the plasminogen activator system have been described at the tumor level, but conflicting results have been obtained for fibrinolytic parameters in plasma. Components of the fibrinolytic system, including tissue-type and urokinase-type plasminogen activators and their inhibitors type 1 and 2, were measured in tissue and/or plasma from 41 patients with colorectal cancer and in 40 controls. Procoagulant activity of freshly isolated mononuclear cells (basal activity) and the procoagulant activity and fibrinolytic proteins produced by the cells after incubation for 18 h without exogenous stimulation were also evaluated. Malignant tissue extracts had significantly higher levels of urokinase-type plasminogen activator and plasminogen activator inhibitor-1, but lower levels of tissue-type plasminogen activator than normal mucosa. Plasminogen activator inhibitor-1 alone was higher in advanced (Dukes' stages C + D) than limited (B) tumors. Plasminogen activator inhibitor-2 was not different in malignant tissue and normal mucosa. Plasma levels of plasminogen activator inhibitor-1 antigen were significantly increased in cancer patients compared with controls, but there were no differences in tissue-type and urokinase-type plasminogen activator, in plasminogen activator inhibitor-2, and D-dimer levels. Intra-patient analysis revealed no significant correlation between tumor and plasma levels of plasminogen activators or type 1 inhibitor. Tissue-type plasminogen activator, but not the urokinase type or inhibitor type 1, was higher in venous than in arterial blood collected at the tumor site during surgery. Basal procoagulant activity of mononuclear cells and the procoagulant activity and inhibitor type-2 produced by the cells after short-term culture were comparable in patients and controls. These findings indicate that, at least in our patients with colorectal cancer, the profound changes occurring at tumor level are barely detectable in the blood. Thus, the clinical relevance of plasma fibrinolytic parameters, especially urokinase-type plasminogen activator antigen, as tumor markers in colorectal cancer remains to be established.
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PMID:Blood and tissue fibrinolytic profiles in patients with colorectal carcinoma. 878 47

Despite the advances in pre-, peri- and post-operative medical care of colorectal carcinoma patients, the prognosis has improved only marginally over recent decades. Thus, additional prognostic indicators would be of great clinical value to select patients for adjuvant therapy. In previous studies we found that colorectal carcinomas have a marked increase of the urokinase-type of plasminogen activator (u-PA), and the inhibitors PAI-1 and PAI-2, whereas the tissue-type plasminogen activator (t-PA) is found to be decreased in comparison with adjacent normal mucosa. In the present study we evaluated the prognostic value of several plasminogen activation parameters, determined in both normal and carcinomatous tissue from colorectal resection specimens, for overall survival of 136 Dukes' stage B and C colorectal cancer patients, in relation to major clinicopathological parameters. Uni- and multivariate analyses indicated that a high PAI-2 antigen level in carcinoma, a low t-PA activity and antigen level and a high u-PA/t-PA antigen ratio in adjacent normal mucosa are significantly associated with a poor overall survival. A high ratio of u-PA antigen in the carcinomas and t-PA antigen in normal mucosa, i.e. u-PA(C)/t-PA(N), was found to be predictive of a poor overall survival as well. All these parameters were found to be prognostically independent of the clinicopathological parameters. Multivariate analysis of combinations of these prognostically significant plasminogen activation parameters revealed that they are important independent prognostic indicators and have in fact a better prognostic value than their separate components. Based on these combined parameters, subgroups of patients with Dukes' stage B and C colorectal cancer could be identified as having either a high or a low risk regarding overall survival. In conclusion, these findings emphasize the relevance of the intestinal plasminogen activation system for survival prognosis of patients with colorectal cancer and, in the future, might constitute a patient selection criterion for adjuvant therapy.
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PMID:Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes' stage B and C colorectal cancer. 919 84

Cysteine proteases [Cathepsin B and L (CATB, CATL)] and the serine protease urokinase type plasminogen activator (UPA) with its inhibitor type-1 (PAI-1) are thought to play an important part in colorectal cancer invasion and metastasis. To our knowledge, however, cathepsins and plasminogen activator/inhibitor system have not been evaluated in the same study. The authors using the ELISA method, determined the protease antigen concentrations in colorectal cancer tissue and in normal tissue distant from tumour, in 35 patients with colorectal cancer. They also evaluated the relationship that these proteases may have with the major histomorphological parameters and tumour staging. Significantly higher antigen levels were found: 1. in cancerous tissue vs. tumour free tissue (CATB, CATL, UPA, PAI-1); in colorectal cancer with vs. without metastasis (CATB, CATL, UPA, PAI-1); 3. in poorly vs. well differentiated tumours (CATB, UPA, PAI-1); 4. in advanced Dukes' stages (CATB, UPA, PAI-1). The simultaneous activation of cathepsins and plasminogen activator/inhibitor system in colorectal cancer confirms their role in colorectal tumor biology and particularly in the process of invasion and metastasis. Our results suggest the possible prognostic impact of these proteases in colorectal cancer.
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PMID:[The role of cathepsins and the plasminogen activator/inhibitor system in colorectal cancer]. 1048 82

Colorectal cancer is one of the most common tumour types with approximately one third of the tumours located within the rectum. Rectal cancer differs somewhat from colon cancer, e.g. regarding the method of operation and the use of preoperative radiotherapy due to a tendency for local tumour recurrence. Proteolytic enzymes have been identified as key molecules in tumour invasion and metastasis, and factors within the urokinase-plasminogen activation (uPA) system have been associated with prognosis in several tumour types, including colorectal cancer. Recently, methods have been developed to analyse the soluble fraction of the plasminogen activator receptor (suPAR) in blood samples. An association between elevated suPAR levels and poor prognosis has recently been demonstrated in colorectal cancer. We have measured suPAR levels in pretreatment plasma samples from 173 rectal cancer patients in order to confirm its prognostic strength in this clinical entity. suPAR levels were determined in ethylenediamine tetraacetic acid (EDTA) plasma by a kinetic enzyme-linked immunosorbent assay (ELISA) and analysed with respect to sex, age, Dukes' stage, tumour differentiation grade and survival. In a univariate analysis, continuous suPAR plasma levels were associated with survival (P<0.001) with shorter survival among patients with high suPAR values. Patients with suPAR values within the upper quartile had significantly shorter survival (hazard ratio (HR) 2.2, 95% confidence interval (CI) 1.3-43.7, P=0.002). In a multivariate Cox analysis, increasing suPAR values predicted shorter survival independent from Dukes' stage and tumour differentiation grade with an adjusted HR of 2.2 per ng/ml suPAR (95% CI 1.2-4.0, P=0.01). This study thus confirms that measurement of suPAR in preoperative plasma samples gives independent prognostic information in rectal cancer patients, higher values being associated with shorter survival.
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PMID:Prognostic importance of the soluble plasminogen activator receptor, suPAR, in plasma from rectal cancer patients. 1126 58

We report the case of a 62-year-old man who developed isolated splenic metastasis of sigmoid colon cancer. The patient underwent left hemicolectomy for Dukes C sigmoid colon cancer in February 1997. In March 1999, an abdominal CT scan revealed a tumor 3 cm in size at the inferior pole of the spleen. The tumor was hyperechoic on ultrasonography. The serum carcinoembryonic antigen level was normal. Since no other site of recurrence was identified, a splenectomy was performed with a curative intent. At laparotomy, neither hepatic metastasis, peritoneal dissemination, lymph node metastasis nor local recurrence was detected. Histological findings of the splenic tumor were compatible with metastasis of the previously resected sigmoid colon adenocarcinoma. The patient has been disease-free for 19 postoperative months. Immunohistochemical staining for urokinase-type plasminogen activator was positive in primary sigmoid colon cancer and splenic metastasis, but negative in lymph node metastasis; results that possibly reflect the difference in progenitor cells between splenic metastasis and lymph node metastasis or the difference in the microenvironment of cancer cells between the spleen and lymph nodes. Based on the present case, we recommend that clinicians pay close attention to the spleen for the early diagnosis of isolated splenic metastasis when routinely evaluating abdominal CT scans and abdominal ultrasonography following curative resection of primary colorectal cancer.
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PMID:Isolated splenic metastasis of sigmoid colon cancer: a case report. 1151 49


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