Coagulation and angiogenic gene expression profiles are defined by molecular subgroups of medulloblastoma: evidence for growth factor-thrombin cross-talk.

BACKGROUND: The coagulation system becomes activated during progression and therapy of high-grade brain tumors. Triggering tissue factor (F3/TF) and thrombin receptors (F2R/PAR-1) may influence the vascular tumor microenvironment and angiogenesis irrespective of clinically apparent thrombosis. These processes are poorly understood in medulloblastoma (MB), in which diverse oncogenic pathways define at least four molecular disease subtypes (WNT, SHH, Group 3 and Group 4). We asked whether there is a link between molecular subtype and the network of vascular regulators expressed in MB. METHODS: Using R2 microarray analysis and visualization platform, we mined MB datasets for differential expression of vascular (coagulation and angiogenesis)-related genes, and explored their link to known oncogenic drivers. We evaluated the functional significance of this link in DAOY cells in vitro following growth factor and thrombin stimulation. RESULTS: The coagulome and angiome differ across MB subtypes. F3/TF and F2R/PAR-1 mRNA expression are upregulated in SHH tumors and correlate with higher levels of hepatocyte growth factor receptor (MET). Cultured DAOY (MB) cells exhibit an up-regulation of F3/TF and F2R/PAR-1 following combined SHH and MET ligand (HGF) treatment. These factors cooperate with thrombin, impacting the profile of vascular regulators, including interleukin 1ß (IL1B) and chondromodulin 1 (LECT1). CONCLUSIONS: Coagulation pathway sensors (F3/TF, F2R/PAR-1) are expressed in MB in a subtype-specific manner, and may be functionally linked to SHH and MET circuitry. Thus coagulation system perturbations may elicit subtype/context-specific changes in vascular and cellular responses in MB.