title: Coagulation and angiogenic gene expression profiles are defined by molecular subgroups of medulloblastoma: evidence for growth factor-thrombin cross-talk.
abstract: 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 1β (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.
authors.affiliation: Cancer and Angiogenesis Laboratory, Montreal Children's Hospital, McGill University, Montreal, QC, Canada.
authors.forename: E
authors.initials: E
authors.lastname: D'Asti
authors.forename: M
authors.initials: M
authors.lastname: Kool
authors.forename: S M
authors.initials: SM
authors.lastname: Pfister
authors.forename: J
authors.initials: J
authors.lastname: Rak
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics* / Q000378:metabolism; D001777:Blood Coagulation / Q000235:genetics*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000097:blood / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D057225:Data Mining; D030541:Databases, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008527:Medulloblastoma / Q000097:blood / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D017228:Hepatocyte Growth Factor; D013925:Thromboplastin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D013917:Thrombin
keywords: angiogenesis modulating agents; blood coagulation factors; medulloblastoma; molecular pathology; oncogenes