Fibrin and Fibrinolysis in Cancer

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.

Aggregation of platelets, proliferation of endothelial cells and motility of cancer cells are mediated by the B?1(15)-42 residue of fibrin(ogen)

“…Study of motility of cancer cells. Having sites of interactions with cancer cells on its surface, fibrinogen can stimulate cancerogenesis, as well as promote tumor growth and invasion [37]. Using our model, we estimated the role of the Bβ1-42 fragment of fibrinogen in the motility of the lung cancer cell line H1299.…”

Plasma Fibrinogen Acts as a Predictive Factor for Pathologic Complete Response to Neoadjuvant Chemotherapy in Breast Cancer: A Retrospective Study of 1035 Chinese Breast Cancer Patients

“…Several mechanisms can explain the contribution of Fib to tumour cell in ltration and expansion. First, due to the strong procoagulant effect of tumour cells, a large amount of Fib is aggregated around tumour cells and converted into brin, which is involved in metastasis and new vessel formation and promotes the formation of tumour stromal tissue [22,23]. Second, Shu et al demonstrated that high concentrations of Fib can induce epithelial-mesenchymal transition [24], which confers migration, invasion and metastasis capacities to tumour cells and renders tumour cells resistant to multiple drugs [25].…”

Circulating Fibrinogen to Pre-albumin Ratio for Chemotherapy Efficacy Prediction and Prognosis of Colorectal Cancer Patients

“…Particularly, Fib is a driver of chronic low-grade in ammation, owing to its effect on platelets, eukocyte migration and role in promoting carcinogenic properties. In addition, it has been shown to function as a scaffold for cancer growth, migration and metastasis [23][24][25]. On the other hand, Alb and pAlb represent the main sources of energy and nutrition for tumor growth.…”