S. Ganesh

Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma

Proteinases are involved in tumour invasion and metastasis. Several matrix metalloproteinases (MMPs) have been shown to be increased in various human carcinomas. We assessed the levels of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in 50 gastric carcinomas and corresponding mucosa using quantitative gelatin zymography. Both MMP levels were significantly enhanced in gastric carcinomas compared with adjacent mucosal tissue, showed a relatively poor intercorrelation and no relation was found with histopathological carcinoma classifications according to Laurén, WHO and tumour-node-metastasis (TNM). Coxs multivariate proportional hazards analyses revealed that high carcinomatous MMP values are of prognostic significance for a poor overall survival of the patients, independent of the major clinicopathological parameters.

Inactive Urokinase and Increased Levels of Its Inhibitor Type 1 in Colorectal Cancer Liver Metastasis

BACKGROUND/AIMS Human colorectal carcinogenesis was previously found to be associated with an increased urokinase-type plasminogen activator expression, both in antigen and activity, accompanied by simultaneously enhanced levels of plasminogen activator inhibitors type 1 and type 2. This increased proteolytic activity may contribute to invasive growth and metastasis of the tumors. METHODS In the present study, homogenates of liver metastases, primary colorectal carcinomas, and adjacent normal tissues were evaluated regarding the level and composition of urokinase, tissue-type plasminogen activator, and plasminogen activator inhibitors. RESULTS Concentrations of urokinase were significantly increased in primary carcinomas and liver metastases compared with normal tissues, whereas tissue-type plasminogen activator levels were significantly decreased. Liver metastases showed, in contrast to the carcinomas, hardly any activity of plasminogen activators, which could be attributed to the enhanced presence of the inactive proenzyme form of urokinase in combination with more complexes of plasminogen activators with inhibitors. Furthermore, liver metastases had an eightfold higher content of inhibitor type 1 compared with the primary carcinomas. The excess of inhibitors was confirmed by addition of plasminogen activators to metastasis homogenates, which resulted in increased complex formation. CONCLUSIONS Colorectal cancer metastasis in the liver is associated with an inactivation of the enhanced urokinase cascade, which might allow tumor cells to settle in the liver.

Plasminogen activators in normal tissue and carcinomas of the human oesophagus and stomach.

Carcinogenesis in the human colon is associated with a marked increase of urokinase type plasminogen activator and a decrease of tissue type plasminogen activator. This study was performed to determine the concentrations of urokinase type plasminogen activator and tissue type plasminogen activator in normal tissue and carcinomas along the upper part of the gastrointestinal tract. Activity and antigen levels of both activators were determined in homogenates of endoscopically obtained biopsies from normal and carcinomatous tissues. Although the concentrations of tissue type plasminogen activator and urokinase type plasminogen activator in normal squamous epithelium of the oesophagus were low compared with those in columnar epithelium from the stomach, the urokinase type plasminogen activator/tissue type plasminogen activator antigen ratio of the different locations showed hardly any difference. Significant but heterogeneous increases were found in urokinase type plasminogen activator concentrations of biopsy specimens originating from carcinomas of both epithelial cell types. A decrease in tissue type plasminogen activator concentrations, as found in human colon carcinomas, could only be shown in carcinomas of columnar epithelium origin but not in squamous cell carcinomas of the oesophagus. The increase of urokinase type plasminogen activator and urokinase type plasminogen activator/tissue type plasminogen activator antigen ratio and the decrease of tissue type plasminogen activator in the carcinomas did not show a significant correlation with known prognostic determinants as differentiation grade, TNM classification, intestinal metaplasia, inflammation, and ulceration. The heterogeneous increase of urokinase type plasminogen activator in oesophageal and stomach carcinomas, together with the recently described association of urokinase type plasminogen activator in tissue extracts of breast carcinomas with aggressiveness and prognosis, may be relevance to prognostic studies, may be of relevance to prognostic studies in oesophageal and gastric cancer.

Prognostic value of plasminogen activators and their inhibitors in colorectal cancer

Colorectal tumorigenesis is associated with remarkable changes in the plasminogen activation system at the tissue level. The sequence of normal mucosa-adenomatous polyp-adenocarcinoma-metastasis is accompanied by an increase in the urokinase-type of plasminogen activator, the urokinase receptor and the inhibitors type-1 and type-2, with a concurrent decrease in the tissue-type plasminogen activator. Overall survival analysis of colorectal cancer patients, with a follow-up of more than 5 years, revealed that several of these components, in both the carcinomas and their corresponding normal mucosa, are of prognostic value independent of major clinicopathological parameters. Therefore, the plasminogen activation cascade not only contributes to the invasive and metastatic growth of colorectal tumours, but might also have a clinical impact with respect to adjuvant and intervention therapy.

Clinical Applications of the Urokinase Receptor (uPAR) for Cancer Patients

Since decades the urokinase plasminogen activator (uPA) system has been associated with the invasion of malignant cells. The receptor of urokinase (uPAR) is one of the key players in this proteolytic cascade, because it focuses uPAs proteolytic activity to the cell surface and in addition functions as a signaling receptor. uPAR is highly expressed in virtually all human cancers, suggesting possible clinical applications as diagnostic marker, predictive tool of survival or clinical response, and as a target for therapy and imaging. This review summarizes the possibilities of uPAR in clinical applications for cancer patients.

Plasminogen activators and inhibitor type 1 in neoplastic colonic tissue from patients with familial adenomatous polyposis.

The plasminogen activation cascade is involved in carcinogenesis, invasion and metastasis. In this study plasminogen activators and their type 1 inhibitor were evaluated in colonic tissue from 19 patients with familial adenomatous polyposis coli, an inherited disorder characterised by the presence of thousands of adenomatous polyps in the colorectum which predispose to colorectal cancer. The conversion of normal-appearing colonic mucosa to neoplastic tissue in these patients was associated with an increase in urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, accompanied by a decreased level of tissue-type plasminogen activator. These observations are essentially similar to those found in solitary adenomas and carcinomas of the colon, and illustrate the uniform involvement of the plasminogen activation system in colorectal carcinogenesis.

Tetranectin expression in human colonic neoplasia

The expression of tetranectin in colonic neoplasia was evaluated by determining the tissue distribution by immunohistological analysis of tissue sections and the antigen levels in tissue homogenates and plasma. In normal colonic mucosa tetranectin staining was predominantly found in the goblet cells whereas in adenocarcinomas this staining was confined to the tumour stroma. Colonic adenomas, benign precursors of adenocarcinomas, showed fewer tetranectin positive goblet cells and in some cases showed tetranectin expression in the stroma. Within the tissue homogenates no differences were found in the tetranectin levels between normal mucosa, adenomas and carcinomas. Patients with colonic cancer were found to have significantly decreased plasma tetranectin levels compared to healthy controls. Thus, colonic neoplasia is associated with a change in the tissue distribution of tetranectin, without an obvious change in the tissue level, and a low plasma tetranectin level.