Oncogenes and the coagulation system--forces that modulate dormant and aggressive states in cancer

Cancers arise and progress genetically amidst profound perturbations of the microenvironmental and systemic homeostasis. This includes the coagulation system, which is a part of the vascular milieu (niche) that remains under the control of molecular events occurring within the cancer cell genome. Thus, activation of several prototypic oncogenic pathways, such as RAS, EGFR, HER2, MET, SHH and loss of tumor suppressors (PTEN, TP53) alter the expression, activity and vesicular release of coagulation effectors, as exemplified by tissue factor (TF). The cancer-specific determinants of coagulopathy are also illustrated by the emerging link between the expression profiles of coagulation-related genes (coagulome) in glioblastoma multiforme (GBM), medulloblastoma (MB) and possibly other cancers and molecular subtypes of these respective tumors. The state of the coagulome is consequential for growth, metastasis and angiogenesis of established tumors, but could potentially also affect dormant cancer cells. For example, TF expression may trigger awakening of dormant glioma cells in mice in a manner involving recruitment of vascular and inflammatory cells, and resulting in lasting changes in the cancer cell genome and epigenome. Thus, coagulation system effectors could act as both targets and (indirect) inducers of genetic tumor progression, and a better understanding of this link may hold new diagnostic and therapeutic opportunities.