Identification of established and novel extracellular matrix components in glioblastoma as targets for angiogenesis and prognosis

Abstract

AbstractGlioblastomas (GBM) are aggressive tumors known for their heterogeneity, rapid proliferation, treatment resistance, and extensive vasculature. Angiogenesis, the formation of new vessels, involves endothelial cell (EC) migration and proliferation. Various extracellular matrix (ECM) molecules regulate EC survival, migration, and proliferation. Culturing human brain EC (HBMEC) on GBM-derived ECM revealed a decrease in EC numbers compared to controls. Throughin silicoanalysis, we explored ECM gene expression differences between GBM and brain normal glia cells and the impact of GBM microenvironment on EC ECM transcripts. ECM molecules such as collagen alpha chains (COL4A1,COL4A2, p < 0.0001); laminin alpha (LAMA4), beta (LAMB2), and gamma (LAMC1) chains (p < 0.0005); neurocan (NCAN), brevican (BCAN) and versican (VCAN) (p < 0.0005); hyaluronan synthase (HAS) 2 and metalloprotease (MMP) 2 (p < 0.005); MMP inhibitors (TIMP1-4, p < 0.0005), transforming growth factor beta-1 (TGFB1) and integrin alpha (ITGA3/5) (p < 0.05) and beta (ITGB1, p < 0.0005) chains showed increased expression in GBM. Additionally, GBM-influenced EC exhibited elevated expression ofCOL5A3,COL6A1,COL22A1andCOL27A1(p < 0.01);LAMA1,LAMB1(p < 0.001); fibulins (FBLN1/2, p < 0.01);MMP9,HAS1,ITGA3,TGFB1, and wingless-related integration site 9B (WNT9B) (p < 0.01) compared to normal EC. Some of these molecules:COL5A1/3,COL6A1,COL22/27A1,FBLN1/2,ITGA3/5,ITGB1andLAMA1/B1(p < 0.01);NCAN,HAS1,MMP2/9,TIMP1/2andTGFB1(p < 0.05) correlated with GBM patient survival. In conclusion, this study identified both established and novel ECM molecules regulating GBM angiogenesis, suggestingNCANandCOL27A1are new potential prognostic biomarkers for GBM.