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Urokinase-type plasminogen activator (uPA) and its receptor (CD87): a new target in tumor invasion and metastasis
Abstract:
Extravasation and intravasation of tumor cells in solid malignant tumors is controlled by 3 steps: 1) attachment to and interaction of tumor cells with components of the basement membrane and the extracellular matrix, 2) local proteolysis, and 3) tumor cell migration. Evidence has accumulated that different types of tumor-associated proteases, their inhibitors and receptors are involved in tumor invasion and metastasis. Four different classes of proteases are known to be correlated with the malignant phenotype: 1) Matrix metalloproteases; including collagenases, gelatinases and stromelysins. 2) Cysteine proteases; including cathepsins B and L. 3) Aspartyl protease cathepsin D. 4) Serine proteases; including plasmin and tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). A strong independent prognostic value (relapse-free and/or overall survival) has especially been demonstrated for uPA and its inhibitor PAI-1 in patients with cancer of the breast, ovary, stomach, esophagus, colon, lung, and kidney thus predicting the course of the cancer disease. The strong correlation between elevated uPA and/or PAI-1 values in primary cancer tissues and the malignant phenotype of cancer cells has prompted to explore new tumor biology-oriented concepts in order to suppress uPA or uPA receptor (CD87) expression or to abrogate interaction of uPA with CD87. 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, inhibitors and recombinant or synthetic uPA and CD87 analogues.
Insights
Urokinase plasminogen activator (uPA) and its inhibitor PAI-1 are key indicators of cancer progression and patient survival. Targeting uPA or its receptor CD87 offers promising therapeutic strategies for various cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tumor cell invasion and metastasis involve complex steps including cell adhesion, proteolysis, and migration.
- Proteases, their inhibitors, and receptors play crucial roles in cancer progression.
- Four major protease classes (metalloproteinases, cysteine, aspartyl, and serine proteases) are linked to malignancy.
Purpose of the Study:
- To investigate the prognostic value of urokinase plasminogen activator (uPA) and its inhibitor PAI-1 in various solid tumors.
- To explore therapeutic strategies targeting the uPA/CD87 pathway for cancer treatment.
Main Methods:
- Analysis of uPA and PAI-1 expression and their correlation with patient outcomes.
- Evaluation of various therapeutic approaches including gene and protein level interventions.
- Testing of antisense oligonucleotides, antibodies, inhibitors, and analogues targeting uPA or CD87.
Main Results:
- Elevated uPA and PAI-1 levels demonstrate strong prognostic value for relapse-free and overall survival in multiple cancer types.
- These markers correlate with the malignant phenotype of cancer cells.
- Experimental approaches to inhibit uPA or CD87 showed success at gene and protein levels.
Conclusions:
- uPA and PAI-1 are significant biomarkers for predicting cancer prognosis.
- Targeting the uPA/CD87 pathway presents a viable strategy for developing novel anti-cancer therapies.
- Interference with uPA or CD87 expression or function can suppress tumor cell invasion and metastasis.