Human tetranectin: methodological and clinical studies.

Abstract

From its discovery in 1986 tetranectin (TN) has been suggested to participate in proteolytic processes through its binding to plasminogen, which enhances the activation of plasminogen to plasmin. Because extracellular proteolysis is an important factor in the ability of malignant cells to infiltrate normal tissues and metastasize, TN was considered to be a potential marker for this proteolysis. We have studied the variations in blood and tissue levels of TN in clinical conditions such as cancer and infection, where increased proteolysis can be expected. Five monoclonal antibodies (MAbs) were produced against human TN, and our study is the first report of stable hybridomas producing MAbs against human TN. All the MAbs reacted with epitopes located within aa-residues 50-181 of the primary sequence. In relative epitope mapping with enzyme immuno assay and isotachophoresis the five MAbs defined two independent epitope groups. Different combinations of MAbs were suitable for enzyme immuno assays and two MAbs could be used for immunohistochemical detection of TN in both fresh frozen and paraffin embedded tissues. The MAbs will facilitate future studies on structure, function, clinical significance and immunolocalization of TN. In primary ovarian cancer neither s/p-TN nor CA 125 were found valuable for diagnosis of localized cancer versus benign tumors. However, s/p-TN combined with CA 125, increased both sensitivity and specificity. S/p-TN should therefore be considered one of the screening markers in conjunction with CA 125, or other comparable markers, in future ovarian cancer screening research studies. Preoperative s-TN was significantly correlated to residual tumor and survival in ovarian cancer patients undergoing second or third look surgery. In conjunction with CA 125 and CASA the predictive value of TN for residual tumor was greatly improved, as the markers were found to supplement each other. If the second look operation had been restricted to patients who had a marker negative test, up to 37% would have avoided surgery. We therefore recommend that these tests are included as potential selection parameters in other studies evaluating second-look surgery. Low p-TN concentration and heavy extracellular staining of TN in the tumors was significantly correlated with a poor prognosis for patients with localized stage I or II or advanced primary ovarian cancer. The prognostic information can be especially valuable for patients with a localized ovarian cancer stage I or II, because about 20% of these patients, believed to be radically operated later present with relapse. We found the p-TN level to be especially useful for patients with localized cancer, indicating that adjuvant chemotherapy may be considered if the p-TN level is low. For patients with advanced primary ovarian cancer and low p-TN the survival was significantly reduced compared to patients with a higher p-TN. The p-TN level was significantly negatively correlated to the extracellular (stromal) staining of TN in the tumors. A heavy stromal TN staining was correlated with a shortened survival and was an independent prognostic factor in the Cox analyses. Patients with advanced primary cancer and a low p-TN, possibly in combination with a heavy stromal staining of TN in the tumors, should tentatively be offered palliative treatment or experimental chemotherapy. Furthermore, patients receiving chemotherapy may be monitored by s/p-TN measurements, as a decrease in TN concentration indicated recurrence 3.6 months prior to clinical diagnosis. A decrease in TN concentration during chemotherapy may therefore indicate change of treatment. Serum TN was a very strong independent prognostic factor of poor treatment response and a shortened survival in patients with metastatic breast cancer. A low pre-chemotherapy s-TN value together with clinical signs of poor treatment response may be an ominous combination, which may suggest change of treatment. For patients with Dukes' stage