The interplay between hemostasis and malignancy: the oral cancer paradigm

Accumulating evidence has revealed the role of various components of the coagulatory system in different stages of carcinogenesis including precancerous and initial stages, tumor growth, angiogenesis, stroma generation, and metastasis of malignant cells. This comprehensive review discusses major points of evidence, in addition to recent findings on specific factors associated with the paradigm of oral squamous cell carcinoma. During carcinogenesis, angiogenesis is favored by local conditions of hypoxia, cell-to-cell interactions, and by expression of paracrine growth factors and inflammatory cytokines. In the oral region specifically, genetic association studies have revealed that constitutively high gene expression of certain inflammatory cytokines plays a major role in carcinogenesis. Tissue factor (TF) has a physiological role in hemostasis, but it also constitutes a notable procoagulant in many types of cancer, since it appears to be constitutively expressed by tumor cells. Furthermore, its pathway regulates mechanisms which involve plasmin and matrix metallo-proteinases, both of which seem to be critical in oral carcinogenesis. Thrombin has a central role in hemostasis but it may also promote angiogenesis through pathways independently of fibrin generation. Thrombomodulin may act through attenuation of the tumor-promoting properties of thrombin, but it also may function as a cell-to-cell adhesion molecule, independently of its anticoagulant action. The activation of fibrinogen by thrombin and its cleavage to fibrin monomers result in the rapid formation of fibrin matrix. Furthermore, it is well documented that fibrinogen and cross-linked fibrin reside inside the tumor stroma, facilitating its remodeling, angiogenesis, tumor growth and metastasis. In conclusion, the hemostatic system contributes to the development of the malignant phenotype acting on many different levels.