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.

Coagulation-related factors, thrombomodulin and protein Z, are not associated with risk for oral cancer.

BACKGROUND: The link between thrombosis and cancer has been well established. Levels of protein Z and thrombomodulin indirectly regulate thrombin productionl and therefore may affect cancer susceptibility. PATIENTS AND METHODS: The functional polymorphisms -13A/G and -33G/A in protein Z and thrombomodulin genes (respectively) influence transcription. The two polymorphisms were investigated in 160 oral cancer patients and 168 controls of equivalent age, gender and ethnicity using restriction fragment length polymorphism typing. RESULTS: The frequency of the -13G allele, which results in lower expression of protein Z gene, was not significantly elevated in patients compared to controls (8.1% and 6.3%, respectively; odds ratio 1.35, 95% confidence interval 0.72-2.56). No carriers of the thrombomodulin low expression -33A allele were identified, underscoring the rarity of this allele in Caucasians. CONCLUSION: Inherited predisposition affecting protein Z or thrombomodulin levels does not modulate susceptibility to oral cancer. Any possible contribution of thrombin to oral oncogenesis may involve other factors.

The 1040C/T polymorphism influencing thermal stability and activity of thrombin activatable fibrinolysis inhibitor is associated with risk for oral cancer.

No studies thus far have investigated the contribution of thrombin activatable fibrinolysis inhibitor (TAFI) to oral oncogenesis. We studied the activity-related 1040C/T polymorphism in 150 patients with oral cancer and 138 healthy controls matched by age, gender, and ethnicity. The increased-activity T allele frequency was significantly reduced in patients compared with controls (28.7% vs. 37.0%, P < 0.05). T/T homozygotes had about half the probability of developing oral cancer (O.R. 0.39, 95%C.I. 0.13-1.14), while no significant difference was observed in C/T heterozygotes. The observed prophylactic effect of increased TAFI activity might result from reduction of plasmin and inhibition of extracellular matrix dissolution.