Extravasation and intravasation of solid malignant
tumors is controlled by attachment of
tumor cells to components of the basement membrane and the extracellular matrix, by local proteolysis and
tumor cell migration. Strong clinical and experimental evidence has accumulated that the
tumor-associated
serine protease plasmin, its activator uPA (
urokinase-type plasminogen activator), the receptor uPA-R (CD87), and the inhibitors
PAI-1 and
PAI-2 are linked to
cancer invasion and
metastasis. In
cancer, increase of uPA, uPA-R, and/or
PAI-1 is associated with
tumor progression and with shortened disease-free and/or overall survival in patients afflicted with malignant solid
tumors. uPA and/or its inhibitor
PAI-1 appear to be one of the strongest prognostic markers so far described. Strong prognostic value to predict disease recurrence and overall survival has been documented for patients with
cancer of the breast, ovary, cervix, endometrium, stomach, colon, lung, bladder, kidney, brain, and soft-tissue. Due to the strong correlation between elevated uPA and/or
PAI-1 values in primary
cancer tissues and the
tumor invasion/
metastasis capacity of
cancer cells, proteolytic factors have been selected as targets for
therapy. Various very different approaches to interfere with the expression or reactivity of uPA or CD87 at the gene or
protein level were successfully tested including
antisense oligonucleotides,
antibodies,
enzyme inhibitors, and recombinant or synthetic uPA and uPA-R analogues.