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

Abstract

Glioblastomas (GBM) are aggressive tumors, characterized by heterogeneity, high proliferation and infiltration, resistance to treatments, and abundant vasculature. Angiogenesis, the formation of new vessels from pre-existing ones, involves endothelial cells (EC) migrating and proliferating to form new tubes. Various extracellular matrix (ECM) molecules can modulate EC survival, migration, and proliferation. In this study, we cultured human brain EC (HBMEC) on GBM-derived ECM and found that GBM ECM inhibited EC proliferation and modulated the branching process (average vessel length, number of junctions, and vessel endpoints) compared to the HBMEC ECM control. Through in silico analysis, we investigated whether GBM influences the expression of ECM molecules in EC and which of these molecules directly impact the overall survival (OS) of GBM patients. We observed increased expression of collagen alpha chains (COL5A3, 6A1, 22A1, and 27A1), laminin alpha and beta chains (LAMA1 and B1), fibulins (FBLN1 and 2), metalloproteinase (MMP)-9, hyaluronan synthase (HAS)1, integrin alpha chain (ITGA)3, transforming growth factor beta-1 (TGFB1), and wingless-related integration site (Wnt)-9B in EC influenced by GBM compared to normal brain EC. Furthermore, our study demonstrated that the expression of these ECM molecules, along with neurocan (NCAN), directly influenced the OS of GBM patients. In conclusion, this study identifies both established and novel ECM molecules that can regulate GBM angiogenesis and highlights NCAN, COL22A1, and COL27A1 as potential new biomarkers for GBM prognosis.