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 brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor β (TGFβ) superfamily is a large group of structurally related proteins including TGFβ subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (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 also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The TGFβ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulinlike growth 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 GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the TGFβ subfamily yields advantageous results, enhancing BMPs production is also beneficial.

Epithelial membrane protein 3 regulates TGF-β signaling activation in CD44-high glioblastoma

“…TGF-β activation in mammalian cells leads to a transcriptional program that typically affects 5-10% of the genes in the genome [18, 19]. High expression of known TGF-β downstream targets, including SERPINE1, TIMP1, COL6A1, and TGIF represented strong TGF-β transcriptional response and contribute to GBM progression [18].…”

Blockade of transforming growth factor‐β signaling enhances oncolytic herpes simplex virus efficacy in patient‐derived recurrent glioblastoma models

“…The transforming growth factor beta (TGF-β) family of cytokines, TGF-1, 2, and 3, have diverse functions in the pathogenesis of cancer including GBM 16–18 . TGF-β1 and 2 are highly expressed in malignant gliomas and association with poor prognosis has been reported 19, 20 .…”

“…TGF-β interacts with its cognate cell surface receptor tyrosine kinase TGF-βR2, which forms heterodimers with TGF-βR1 (also termed ALK5) and activates both canonical signaling pathways through phosphorylating the signaling transducer Smads and non-canonical pathways such as MAP kinase pathways. TGF-β signaling drives a variety of malignant phenotypes of GBM, including invasion/migration, angiogenesis, drug/radiation resistance and immune-suppression 17, 18 . Importantly, accumulating evidence indicates that TGF-β signaling plays a vital role in the maintenance of GSC stemness and promotes GBM oncogenesis 21, 22 .…”

Some growth factors in neoplastic tissues of brain tumors of different histological structure

“…Агрессивность злокачественных новообразований головного мозга связана не только с биологической природой опухоли, поддерживающей множественные генетические и эпигенетические изменения, но и с по-следствиями аномальных сигналов, обусловленных факторами роста [13].…”

“…Известно, что EGF участвует в развитии нервной системы, и полиморфизмы гена EGF на хро-мосоме 4q25 группы связаны со злокачественными опухолями мозга [19]; вероятно, с этим связаны низкие показатели EGF в ткани менингиом. Известно также, что подсемейство TGF-ß, в частности, избыточно экс-прессируется в некоторых видах глиобластом, которые проявляют агрессивные фенотипы [13], что тоже объ-ясняет сниженный уровень эпидермального фактора роста в ткани менингиом. Вместе с тем имеются данные, что высокий уровень IGF-II обеспечивает рост опухоли при менингиомах [11].…”