The Fibrinolytic System in Neoplasia

Abstract

During activation of the fibrinolytic system plasminogen is converted to plasmin by tissue plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). t-PA is predominantly released from endothelial cells, u-PA primarily by renal parenchymal cells. The activation of plasminogen is regulated by plasminogen activator inhibitor-1 (PAI-1), plasmin is controlled by alpha 2-plasmin inhibitor. The fibrinolytic system is not only involved in the intravascular dissolution of fibrin (thrombi), it also plays a vital role in normal physiologic reproduction, wound repair, angiogenesis, and tissue remodeling. Fibrinolysis is also a vital component in the pathogenesis of neoplastic disease. It is essential in releasing cells from their primary site of origin, providing nutrition for neoplastic cell growth and promoting cell mobility and motility. In neoplastic cells the degradation of the extracellular matrix proteins is facilitated by excessive expression of u-PA, t-PA, and u-PAR. In many forms of carcinoma increased expression of u-PAR and u-PA is associated with significantly shorter survival. Greater expression of u-PA in breast cancer cells, for example, is associated with shorter survival and increased relapse rate. Progressively aggressive neoplastic cells evidence high expression of u-PA and u-PAR activities, variable expression of t-PA, and enhanced PAI-1 and PAI-2 activities. In acute nonlymphocytic leukemias, poor outcome correlates with high t-PA levels. In acute progranulocytic leukemia there is a high incidence of DIC. Neoplastic prostatic tissue also expresses high u-PA activity and the more aggressive the cell line, the greater the number of u-PAR and the higher the u-PA activity. In gynecologic malignancies, a greater expression of u-PA in combination with cathepsin D is associated with widespread disease and poor prognosis. High u-PA values were also seen in patients with brain, gastric, and hepatic malignancies. It is evident that the plasminogen-plasmin system is a vital component in the biology of neoplastic disease and that it is, in theses conditions, in no way beneficial to the host.

Diagnostic Laparoscopy of Patient with Deep Vein Thrombosis before Diagnosis of Ovarian Cancer : A Case Report

“…Either invasion or compression of vessels is a common event. The clotting cascade can be activated by malignant cells (4). The plasma levels of factors I, V, VII, IX and XI may be increased in patients with cancer and such inhibitors as antithrombin III, protein C and protein S may be low due to poor synthesis.…”

“…Ovarian cancer cells are capable of thrombin formation and thrombin degradation. This, along with the increased fibrinolytic activity seen in many gynecologic malignancies, may be associated with the spread of disease and a poor prognosis (4), as well as the prothrombotic process. The general prothrombotic mechanisms are related to the host's response to cancer.…”

DAG–1 Carcinoma Cell in Studying the Mechanisms of Progression and Therapeutic Resistance in Bladder Cancer

“…This serine protease system plays a central role both in the progression and recurrence of carcinomas [5]. This major characteristic of the DAG–1 cell line is not shared with the six other bladder cell lines tested (RT4, RT112, T24, J82S, TCC sup and CHA 89) [21, 22], but it is also found in the epidermoid carcinoma cell line [23].…”

“…The balance of PAs and PAIs determines the individual cellular PA activity that correlates with the degree of differentiation and the metastatic potential of the tumor cells. PA activity is a prognosis factor for the overall survival of patients [5]. …”

Clinical Spectrum of Patients with Renal Cell Carcinoma

“…In fact, the variable expression of fibrinolysis system components in a given cancer may affect the prognosis. For instance, patients with greater expression of u-PA on breast cancer cells have shorter survival and increased chance of relapse (Bell, 1996).In renal cell carcinoma, it has been demonstrated that expression of plasminogen inhibitor-1 is an independent poor prognostic factor as it promotes tumor angiogenesis and metastasis (Choi et al,2011;Zubcaet al,2010). Therefore, changes in hematologic parameters are not only paraneoplstic features of RCC but also of prognostic value.…”