Profibrinolytic Factors and Cancer Progression, Metastasis, and Survival
Yohei Hisada, Nigel Mackman
Abstract
The primary role of the fibrinolytic system is to degrade fibrin clots. However, the fibrinolytic system is often activated in patients with cancer and may affect cancer progression, metastasis, and patient survival. Clinical studies have shown that elevated plasma levels of uPA (urokinase plasminogen activator) are associated with cancer progression in patients with prostate, bladder, and cervical cancers, whereas high plasma levels of soluble uPAR (uPA receptor) are associated with progression and metastasis in prostate, breast, bladder, and colorectal cancers. Elevated levels of plasmin-α 2 -antiplasmin complexes, a marker of activation of the fibrinolytic system, have been linked to reduced survival in patients with soft tissue sarcoma, lung, and metastatic breast cancers. Studies with mouse models have shown that uPA, uPAR, tPA (tissue-type plasminogen activator), and plasmin contribute to tumor growth, metastasis, and survival. For instance, uPA and uPAR can activate kinase signaling pathways in cancer cells, whereas tPA can activate LRP1 (lipoprotein receptor–related protein 1), which enhances tumor growth and metastasis. Plasmin can degrade the extracellular matrix, which would increase cancer cell migration. In addition, it can release extracellular matrix–bound growth factors, which could increase tumor growth and angiogenesis. Taken together, these studies suggest that the fibrinolytic system promotes cancer progression and metastasis through multiple mechanisms.