AI-08SUBGROUP-SPECIFIC DEREGULATION OF COAGULATION AND ANGIOGENIC GENE EXPRESSION PROFILES IN MEDULLOBLASTOMA- EVIDENCE FOR CROSS-TALK BETWEEN GROWTH FACTOR AND COAGULATION PATHWAYS

摘要

INTRODUCTION: Pediatric medulloblastoma (MB) is comprised of 4 distinct disease subtypes including WNT, SHH, group 3, and group 4, which co-segregate with specific clinical features and activation of distinct oncogenic pathways. Oncogenes deregulate tumour cell interactions with the vascular system including the expression, activity, and signaling properties of specific coagulation factors and their cellular receptors. The latter are often activated in aggressive cancers and involved in shaping the tumour microenvironment via coupling of coagulant, inflammatory, and angiogenic responses. Key elements of this circuitry include the tissue factor (TF), PAR-1, and PAR-2 receptors. We studied whether coagulation system effectors are expressed and activated in a manner corresponding to MB subtypes. METHODS: Using R2: microarray analysis and visualization platform, we mined MB datasets for differential expression of coagulation and angiogenesis-related factors between tumour subtypes. Focusing on TF and PAR-1 receptors, we determined whether their expression is correlated with known drivers of growth factor and pro-angiogenic pathways. We evaluated the relevance of these relationships in DAOY MB cells in vitro following SHH and HGF treatment. RESULTS: TF and PAR-1 mRNA expression is upregulated in SHH tumours and correlated with levels of MET receptor. Using DAOY as a model of SHH MB, we documented selective upregulation of PAR-1 mRNA following combined treatment with SHH + HGF. This induced hypersensitivity to a PAR-1 agonist upregulating the expression of the pro-inflammatory and pro-angiogenic factor interleukin-1β. CONCLUSION: Coagulation factors are differentially expressed between MB subtypes, and change the cellular phenotype in a manner dependent on the activation state of key oncogenic pathways. These data suggest a reciprocal interaction between classical oncogenic pathways and coagulation signaling in SHH MB and implicate the coagulation system in tumour progression.