title: Biological basis of personalized anticoagulation in cancer: oncogene and oncomir networks as putative regulators of coagulopathy.
abstract: Activation of stromal response pathways in cancer is increasingly viewed as both a local and systemic extension of molecular alterations driving malignant transformation. Rather than reflecting passive and unspecific responses to anatomical abnormalities, the coagulation system is a target of oncogenic deregulation, impacting the role of clotting and fibrinolytic proteins, and integrating hemostasis, inflammation, angiogenesis and cellular growth effects in cancer. These processes signify, but do not depend on, the clinically manifest coagulopathy and thrombosis. In this regard, the role of driver mutations affecting oncoprotein coding genes such as RAS, EGFR or MET and tumour suppressors (PTEN, TP53) are well described as regulators of tissue factor (TF), protease activated receptors (PAR-1/2) and ectopic coagulation factors (FVII). Indeed, in both adult and pediatric brain tumours the expression patterns of coagulation and angiogenesis regulators (coagulome and angiome, respectively) reflect the molecular subtypes of the underlying diseases (glioblastoma or medulloblastoma) as defined by their oncogenic classifiers and clinical course. This emerging understanding is still poorly established in relation to the transforming effects of non-coding genes, including those responsible for the expression of microRNA (miR). Indeed, several miRs have been recently found to regulate TF and other effectors. We recently documented that in the context of the aggressive embryonal tumour with multilayered rosettes (ETMR) the oncogenic driver miR (miR-520g) suppresses the expression of TF and correlates with hypocoagulant tumour characteristics. Unlike in adult cancers, the growth of pediatric embryonal brain tumour cells as spheres (to maintain stem cell properties) results in upregulation of miR-520g and downregulation of TF expression and activity. We postulate that oncogenic protein and miR coding genes form alternative pathways of coagulation system regulation in different tumour settings, a property necessitating more personalised and biologically-based approaches to anticoagulation.
authors.affiliation: McGill University, Montreal Children's Hospital, RI MUHC, McGill University, Montreal, Quebec, Canada.
authors.forename: Esterina
authors.initials: E
authors.lastname: D'Asti
authors.affiliation: McGill University, Montreal Children's Hospital, RI MUHC, McGill University, Montreal, Quebec, Canada. Electronic address: janusz.rak@mcgill.ca.
authors.forename: Janusz
authors.initials: J
authors.lastname: Rak
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D001778:Blood Coagulation Disorders / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D005909:Glioblastoma / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008527:Medulloblastoma / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes / Q000187:drug effects; D057285:Precision Medicine / Q000379:methods; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D035683:MicroRNAs; D013925:Thromboplastin
keywords: Angiome; Coagulome; Embryonal tumour with multiple rosettes; Glioblastoma; Medulloblastoma; Microrna; Oncomirs; Tissue factor