Localization of Protein Z (PZ) In Situ in Human Neoplastic Tissues.

Abstract

Tumor cells synthesize and release procoagulants that lead to multi-factorial activation of factor X and subsequent thrombin generation and fibrin formation that in turn contribute to tumor growth and metastatic spread. The activity of factor Xa is inhibited by TFPI (tissue factor pathway inhibitor). Another mechanism of direct inhibition of factor Xa involves protein Z (PZ). Protein Z is a 62-kD, vitamin K-dependent plasma nonpeptidase glycoprotein, which, in complex with PZ-dependent protease inhibitor (ZPI), inhibits factor Xa in the presence of Ca2+ and phospholipids. However, data on the presence of the PZ in tumor malignant tissue are lacking. Results obtained from randomized clinical trials indicate that inhibition of blood coagulation may improve the results of anticancer therapy in selected tumor types. The purpose of the study was to evaluate the localization of PZ in situ in colon, breast, gastric, laryngeal, pancreatic, renal, endometrial cancer, non-small cell lung cancer (NSCLC), malignant melanoma and glial neoplasms. Studies were performed on tumor fragments obtained at surgical treatment of proviously untreated patients. Immunohistochemical procedures using the ABC method employed a specific polyclonal antibody directed against human PZ antigen. Protein Z was localized in cancer cell bodies in all types of malignant tumors examined. Staining intensity was more pronounced in less differentiated cancer cells of anaplastic gliomas. In contrast, more differentiated cancer cells of gastric cancer revealed stronger staining than more malignant ones. Cancer cell bodies of NSCLC and renal cancer were characterized by weak intensity of staining for PZ. In the case of pancreatic and renal cancer, as well as malignant melanoma, the intensity of staining for PZ in cancer cell bodies was irregular: both high and low expression of PZ was observed independent of the degree of malignancy. The expression of PZ was also revealed in association with tumor infiltrating macrophages in colon cancer, NSCLC and malignant melanoma. Furthermore, PZ was localized in small blood vessels of colon, renal, endometrial, gastric cancer, NSCLC, malignant melanoma and glial neoplasms. The observed localization of PZ, particularly in association with cancer cells of all malignant tumors examined, suggests that this protein may exert regulatory effects on tumor growth and metastatic dissemination.