Tumor cell invasion and
metastasis is a multifactorial process, which at each step may require the action of
proteolytic enzymes such as
collagenases,
cathepsins,
plasmin, or
plasminogen activators. An enzymatically inactive
proenzyme form of the
urokinase-type plasminogen activator (pro-uPA) is secreted by
tumor cells which may be converted to an enzymatically active two-chain uPA-molecule (HMW-uPA) by
plasmin-like
enzymes. Action of
proteases on pro-uPA may generate the enzymatically active or inactive high-molecular-weight form of uPA (HMW-uPA). Some
proteases (
plasmin,
cathepsin B and L,
kallikrein,
trypsin or
thermolysin) activate pro-uPA by cleaving the
peptide bond Lys158 and IIe159. Other
proteases (
elastase,
thrombin) cleave pro-uPA at different positions to yield enzymatically inactive HMW-uPA. HMW-uPA may be split into the enzymatically active LMW-uPA and the enzymatically inactive ATF (amino terminal fragment). ATF may be cleaved between
peptide sequence 20 and 40 within the receptor binding domain of uPA (GFD). Such impaired ATF does not bind to uPA-receptors. Action of the bacterial
endoproteinase Asp-N from Pseudomonas fragi mutant on pro-uPA or HMW-uPA, however, generates intact ATF which efficiently competes for binding of HMW-uPA or pro-uPA to receptors on
tumor cells. High uPA-
antigen content (pro-uPA, HMW-uPA, or LMW-uPA) in
breast cancer tissue (not in plasma) indicates an elevated risk for the patient of recurrences and shorter overall survival. Thus pro-uPA/uPA-
antigen content in
breast cancer tissue serves as an independent prognostic parameter for the outcome of the disease.
Cathepsin D is also an independent prognostic factor for recurrences and overall survival. High content of
cathepsin D in
breast cancer tumors is, however, not correlated with elevated levels of pro-uPA/uPA indicating that synthesis and release of
cathepsin D and pro-uPA/uPA are independent events.