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 α2-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 diseases. 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 these conditions,
in no way beneficial to the host.
Keywords:
Fibrinolysis - u-PA - u-PAR - neoplasia - cancer prognosis
