Abstract
In 1878, Billroth discovered that tumor cells invest themselves in a fibrin thrombus,
and he hypothesized that fibrin promotes tumor growth and invasion. Since then, many
observations have supported this concept, showing that many hemostatic factors including
fibrinogen, fibrin, and components of the fibrinolytic system have indeed a complex
interaction with cancer growth and metastasis. Fibrin promotes cell migration by providing
a matrix for tumor cell migration and by interactions with adhesive molecules and
integrins. Fibrin-containing vascular endothelial growth factor promotes angiogenesis.
Fibrin interacts with platelets and leukocytes, and promotes their respective carcinogenic
properties. Fibrinolytic components exert different effects on tumors. Plasmin activates
latent growth factors, and breaks down extracellular matrix (ECM), while urokinase
plasminogen activator (uPA) and the uPA receptor (uPAR) form complexes with vitronectin
and integrins to promote tumor cells to adhere to the ECM. This complex also binds
the epidermal growth factor receptor on the tumor cell membrane, and signals the RAF-MEK-ERK
pathway. The complex also binds to the G protein-coupled receptors leading to cell
proliferation. Plasminogen activator inhibitor 1 (PAI-1) inhibits apoptosis, and increases
tumor cell survival. PAI-1 also enhances cell senescence, leading to production of
tumorigenic cytokines by the senescence secretome. The presence of uPA/uPAR and PAI-1
represents a strong biomarker for tumor aggressiveness and poor prognosis. Multiple
attempts by blocking various carcinogenic steps have shown tumor-suppressing effects
in experimental animals, but human responses are uncertain without clinical trials.
Keywords
fibrin - fibrinolysis - cancer - thrombosis - carcinogenesis - NETs
