An association between cancer and thrombosis has long been described. Abnormal elevated expression of tissue factor (TF) , the physiological initiator of blood coagulation, has been well documented in several tumor types, including glioblastoma (GBM) , and seems to be directly correlated with thromboembolic complications in cancer patients. In the last few years, it has become clear that the processes responsible for the progression of cancer are highly dependent on components of the blood coagulation cascade and TF has been pointed as a key determinant of the coagulation/cancer interaction. Actually, TF expression, that has been shown to correlate with the histological grade of malignancy of glioma, is involved in modulation of several intracellular pathways relevant for malignant angiogenesis and tumor growth. GBM is one of the most vascularized malignant tumors and intense angiogenesis is a distinguishing pathological hallmark relative to lower-grade glioma. Moreover, there is a high incidence of thrombotic events throughout the course of malignant glioma. In fact, the prothrombotic properties of GBM cells seem to contribute to the appearance of hypoxic regions within the tumor and, ultimately, to the formation of the GBM-typical necrotic foci that are well-recognized predictors of poor prognosis. Most remarkable, TF is overexpressed in cells around these necrotic foci found in GBM, known as pseudopalisading cells. These regions are highly hypoxic and seem to play a key role in GBM aggressiveness, presenting an increased production of vascular endothelial growth factor (VEGF) , interleukin-8 (IL-8) and metalloproteases. In addition to prothrombotic role, TF enables the activation of the G protein-coupled protease-activated receptors (PARs) . These receptors might be activated through proteolytic cleavage by blood coagulation enzymes thus eliciting the production of several pro-tumoral factors including cytokines, angiogenic factors and metalloproteases among others. Given the importance of coagulation activation in human gliomas, it has been proposed that TF, as well as other clotting proteins, could serve as a therapeutic target. It has already been shown that argatroban, a specific thrombin inhibitor, reduced tumor mass and tumor induced behavioral deficits and prolongs survival time in animal models. We showed that Ixolaris, a potent anticoagulant that does not produce major bleeding when injected subcutaneously in different animal models, potently decreases tumor growth in a human GBM model. Notably, inhibition of tumor growth was accompanied by downregulation of VEGF and vessel density in tumor mass. Our results provide strong evidence that TF may be regarded as an important therapeutic target for GBM.
|Title of host publication||Glioblastoma|
|Subtitle of host publication||Risk Factors, Diagnosis and Treatment Options|
|Publisher||Nova Science Publishers, Inc.|
|Number of pages||26|
|Publication status||Published - 1 Jan 2012|
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)