Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression

Abstract

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human braintumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cellproliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficientcurative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiplegenetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. Thetransforming growth factor β (TGFβ) superfamily is a large group of structurally related proteins including TGFβsubfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiationfactor (GDF). It is involved in important biological functions including morphogenesis, embryonic development,adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is alsoconsidered to impact on cancer biology including that of GBM, with various effects depending on the member. TheTGFβ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. Thissubfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and majorhistocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenicfactors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulinlikegrowth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases(MMPs), “pro-neoplastic” integrins (αvβ3, α5β1) and GBM initiating cells (GICs) as well as inducing a GBMmesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBMcell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDFyields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivityto chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategiesin anti-cancer therapy. While suppressing the TGFβ subfamily yields advantageous results, enhancing BMPsproduction is also beneficial.