Oncogenic regulation of tissue factor and thrombosis in cancer

Abstract

Tumor associated coagulopathy is a complex phenomenon that has been the subject of study for more than a century. Many mechanisms have been implicated in this process including tumor-host interactions, growth factor-, and cytokine-mediated signaling in the tumor microenvironment. Tissue factor (TF), a potent procoagulant, is considered to be critical for physiologic and pathological coagulation. The genetic and microenvironmental features of cancer appear to strongly influence the expression of TF and lead to a procoagulant state both locally within the neoplasm as well as systemically. In association with cytokines and other procoagulants, upregulated TF and its downstream effectors such as thrombin not only lead to abnormal blood clotting in cancer patients but also stimulate a wide number of oncogenic signaling mechanisms that may prove important in cancer progression. In glioblastoma multiforme (GBM), EGFR expression and PTEN loss both lead to increased TF expression and thrombosis in a manner that appears to cause hypoxia-induced tumor progression. This review consolidates aspects of aberrant coagulation in cancer, the relevance of TF and its regulation by oncogenic alterations, with specific reference to GBM.