Multifaceted transforming growth factor-beta (TGFβ) signalling in glioblastoma

Birch, Joanna L.; Coull, Barry J.; Spender, Lindsay C.; Watt, Courtney; Willison, Alice; Syed, Nelofer; Chalmers, Anthony J.; Hossain-Ibrahim, Mohammed K.; Inman, Gareth J.

doi:10.1016/j.cellsig.2020.109638

Cited by 27 publications

(21 citation statements)

References 183 publications

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“…TGF-β is a cytokine with multiple functions which are dependent on the cell type and its associated microenvironment [4]. In GBM, TGF-β is well characterized as a cytokine that promotes invasion, angiogenesis as well as suppression of the immune system [5]. Thus, our results add an additional function of TGF-β to its divergent roles in GBM development.…”

Section: Discussionmentioning

confidence: 68%

TGF-β promotes microtube formation in glioblastoma through Thrombospondin 1

Joseph

Magaut

Storevik

et al. 2021

Preprint

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Microtubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. To identify potential signaling pathways involved in microtube formation we performed a bioinformatics analysis of TCGA data showing that the TGF-beta pathway is highly activated in GBMs compared to oligodendroglial tumors. In particular we observed that signaling pathways involved in extracellular matrix organization are differentially expressed between these tumor entities. Using patient-derived GBM stem cell lines, we demonstrated that TGF-beta 1 stimulation promotes enhanced MT formation and communication via Calcium signaling. Inhibition of the TGF-beta pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-beta, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-beta stimulation and enhanced microtube formation, which was inhibited by TSP1 shRNAs in vitro and in vivo. In conclusion, TGF-beta and its downstream mediator TSP1 are important mediators of the microtube network in GBM and blocking this pathway could potentially help to break the complex MT driven invasion/ resistance network.

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Section: Discussionmentioning

confidence: 68%

TGF-β promotes microtube formation in glioblastoma through Thrombospondin 1

Joseph

Magaut

Storevik

et al. 2021

Preprint

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“…Here, we focused on TGF-β and E2 found in high concentrations within the tumor [ 44 , 55 ]; both play an essential role in the progression of GBM [ 42 , 43 , 44 , 45 , 46 , 61 , 62 , 63 ], and signaling intersects to be inhibited in other cell types [ 41 , 42 , 43 , 64 , 65 , 66 , 67 ]. Furthermore, increasing evidence suggests that TGF-β signaling inhibition would provide new therapeutic options for GBM tumors in which TGF-β acts to promote proliferation, survival, and EMT [ 68 , 69 , 70 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between 17β-Estradiol and TGF-β Signaling Modulates Glioblastoma Progression

Hernández-Vega

2021

Brain Sciences

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Epithelial–mesenchymal transition (EMT) is an essential mechanism contributing to glioblastoma multiforme (GBM) progression, the most common and malignant brain tumor. EMT is induced by signaling pathways that crosstalk and regulate an intricate regulatory network of transcription factors. It has been shown that downstream components of 17β-estradiol (E2) and transforming growth factor β (TGF-β) signaling pathways crosstalk in estrogen-sensitive tumors. However, little is known about the interaction between the E2 and TGF-β signaling components in brain tumors. We have investigated the relationship between E2 and TGF-β signaling pathways and their effects on EMT induction in human GBM-derived cells. Here, we showed that E2 and TGF-β negatively regulated the expression of estrogen receptor α (ER-α) and Smad2/3. TGF-β induced Smad2 phosphorylation and its subsequent nuclear translocation, which E2 inhibited. Both TGF-β and E2 induced cellular processes related to EMT, such as morphological changes, actin filament reorganization, and mesenchymal markers (N-cadherin and vimentin) expression. Interestingly, we found that the co-treatment of E2 and TGF-β blocked EMT activation. Our results suggest that E2 and TGF-β signaling pathways interact through ER-α and Smad2/3 mediators in cells derived from human GBM and inhibit EMT activation induced by both factors alone.

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“…Dysregulation of TGFβ signaling or its downstream pathways have been associated with the pathogenesis of multiple CNS tumors, including adult gliomas such as GBM ( Kaminska et al, 2013 ), pediatric high-grade gliomas like diffuse intrinsic pontine glioma (DIPG; Caja et al, 2015 ), and medulloblastomas ( Kool et al, 2008 ). Recent reviews have detailed the role of TGFβ signaling in proliferation, invasion, angiogenesis, immune responses, and therapeutic treatments for malignant gliomas ( Han et al, 2015 ; Birch et al, 2020 ; Kaminska and Cyranowski, 2020 ). Most notably, TGFβ has been implicated in glioma progression as a regulator of cellular proliferation, infiltrative growth, angiogenesis, and immune suppression ( Fogarty et al, 2005 ).…”

Section: Early Embryogenic Pathways and Morphogensmentioning

confidence: 99%

The Role of Neurodevelopmental Pathways in Brain Tumors

Curry

Glasgow

2021

Front. Cell Dev. Biol.

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Disruptions to developmental cell signaling pathways and transcriptional cascades have been implicated in tumor initiation, maintenance and progression. Resurgence of aberrant neurodevelopmental programs in the context of brain tumors highlights the numerous parallels that exist between developmental and oncologic mechanisms. A deeper understanding of how dysregulated developmental factors contribute to brain tumor oncogenesis and disease progression will help to identify potential therapeutic targets for these malignancies. In this review, we summarize the current literature concerning developmental signaling cascades and neurodevelopmentally-regulated transcriptional programs. We also examine their respective contributions towards tumor initiation, maintenance, and progression in both pediatric and adult brain tumors and highlight relevant differentiation therapies and putative candidates for prospective treatments.

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Multifaceted transforming growth factor-beta (TGFβ) signalling in glioblastoma

Cited by 27 publications

References 183 publications

TGF-β promotes microtube formation in glioblastoma through Thrombospondin 1

TGF-β promotes microtube formation in glioblastoma through Thrombospondin 1

Crosstalk between 17β-Estradiol and TGF-β Signaling Modulates Glioblastoma Progression

The Role of Neurodevelopmental Pathways in Brain Tumors

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