A cadherin switch underlies malignancy in high-grade gliomas

Appolloni, Irene; Barilari, Manuela; Caviglia, Sara; Gambini, Eleonora; Reisoli, Elisa; Malatesta, Paolo

doi:10.1038/onc.2014.122

Cited by 31 publications

(39 citation statements)

References 58 publications

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“…The roles of EMT in glioma cell migration remain controversial, mainly due to the physiological difference between glial and epithelial cells along with the lack of an E-cadherin to N-cadherin switch, which is characteristic of EMT, in glioma cells3839. In fact, most malignant glioma cells express very low levels of endogenous E-cadherin (Figs 3 and 4)394041.…”

Section: Discussionmentioning

confidence: 99%

Nicotinic acid inhibits glioma invasion by facilitating Snail1 degradation

Shi

et al. 2017

Sci Rep

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Malignant glioma is a formidable disease that commonly leads to death, mainly due to the invasion of tumor cells into neighboring tissues. Therefore, inhibition of tumor cell invasion may provide an effective therapy for malignant glioma. Here we report that nicotinic acid (NA), an essential vitamin, inhibits glioma cell invasion in vitro and in vivo. Treatment of the U251 glioma cells with NA in vitro results in reduced invasion, which is accompanied by a loss of mesenchymal phenotype and an increase in cell-cell adhesion. At the molecular level, transcription of the adherens junction protein E-cadherin is upregulated, leading to accumulation of E-cadherin protein at the cell-cell boundary. This can be attributed to NA’s ability to facilitate the ubiquitination and degradation of Snail1, a transcription factor that represses E-cadherin expression. Similarly, NA transiently inhibits neural crest migration in Xenopus embryos in a Snail1-dependent manner, indicating that the mechanism of action for NA in cell migration is evolutionarily conserved. We further show that NA injection blocks the infiltration of tumor cells into the adjacent brain tissues and improves animal survival in a rat model of glioma. These results suggest that NA treatment may be developed into a potential therapy for malignant glioma.

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Section: Discussionmentioning

confidence: 99%

Nicotinic acid inhibits glioma invasion by facilitating Snail1 degradation

Shi

et al. 2017

Sci Rep

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“…This choice was supported by the recent demonstration that pdgf-a/pdgfr-α inhibition causes a downregulation of N-cadherin (NCad) in Xenopus NCCs during epithelial-to-mesenchimal transition (EMT), 12 and further supported by the observation that overexpression of PDGF-B, causing high-grade glioma on murine neural progenitor cells, can regulate the expression level of cdh4 (also known as retinal cadherin). 27,28 We therefore evaluated the expression of the Ecad and Ncad, key players of the EMT both in NCC development and glioma cell migration in brain parenchyma. 23,28 In pdgf-b morphants at stages 18 to 20, we found no significant alteration of Ecad and Ncad by qRT-PCR ( Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

“…27,28 We therefore evaluated the expression of the Ecad and Ncad, key players of the EMT both in NCC development and glioma cell migration in brain parenchyma. 23,28 In pdgf-b morphants at stages 18 to 20, we found no significant alteration of Ecad and Ncad by qRT-PCR ( Figure 5A). On the other hand, we observed a significant decrease of cdh6 and cdh11 expression in pdgf-b morphants analyzed by qRT-PCR and WISH ( Figure 5A-E).…”

Section: Resultsmentioning

confidence: 99%

PDGF‐B: The missing piece in the mosaic of PDGF family role in craniofacial development

Corsinovi

Giannetti

Cericola

et al. 2019

Developmental Dynamics

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Background The platelet‐derived growth factor (PDGF) family consists of four ligands (PDGF‐A, PDGF‐B, PDGF‐C, PDGF‐D) and two tyrosine kinase receptors (PDGFR‐α and PDGFR‐β). In vertebrates, PDGF signaling influences cell proliferation, migration, and matrix deposition, and its up‐regulation is implicated in cancer progression. Despite this evidence, the role of each family member during embryogenesis is still incomplete and partially controversial. In particular, study of the role of pdgf signaling during craniofacial development has been focused on pdgf‐a, while the role of pdgf‐b is almost unknown due to the lethal phenotypes of pdgf‐b‐null mice. Results By using a pdgf‐b splice‐blocking morpholino approach, we highlighted impairment of neural crest cell (NCC) migration in Xenopus laevis morphants, leading to alteration of NCC derivatives formation, such as cranial nerves and cartilages. We also uncovered a possible link between pdgf‐b and the expression of cadherin superfamily members cdh6 and cdh11, which mediate cell‐cell adhesion promoting NCC migration. Conclusions Our results suggested that pdgf‐b signaling is involved in cranial NCC migration and it is required for proper formation of craniofacial NCC derivatives. Taken together, these data unveiled a new role for pdgf‐b during vertebrate development, contributing to complete the picture of pdgf signaling role in craniofacial development.

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“…Adjacent glioma cells physically interact via adhesion proteins, microtubes, membrane fusing, microvesicles, and by gap junctions [34][35][36][37]. Although the mechanisms by which adjacent tumor cells interact are numerous, substantial evidence indicates that gap junctions play key roles in intercellular communication, and can regulate both glioma proliferation and invasion [36,[38][39][40].…”

Section: Resultsmentioning

confidence: 99%

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

Katakowski

Charteris

Chopp

et al. 2016

Cancer Microenvironment

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The phenotypic axis of invasion and proliferation in malignant glioma cells is a well-documented phenomenon. Invasive glioma cells exhibit a decreased proliferation rate and a resistance to apoptosis, and invasive tumor cells dispersed in brain subsequently revert to proliferation and contribute to secondary tumor formation. One miRNA can affect dozens of mRNAs, and some miRNAs are potent oncogenes. Multiple miRNAs are implicated in glioma malignancy, and several of which have been identified to regulate tumor cell motility and division. Using rat 9 L gliosarcoma and human U87 glioblastoma cell lines, we investigated miRNAs associated with the switch between glioma cell invasion and proliferation. Using micro-dissection of 9 L glioma tumor xenografts in rat brain, we identified disparate expression of miR-9 between cells within the periphery of the primary tumor, and those comprising tumor islets within the invasive zone. Modifying miR-9 expression in in vitro assays, we report that miR-9 controls the axis of glioma cell invasion/proliferation, and that its contribution to invasion or proliferation is biphasic and dependent upon local tumor cell density. In addition, immunohistochemistry revealed elevated hypoxia inducible factor 1 alpha (HIF-1α) in the invasive zone as compared to the primary tumor periphery. We also found that hypoxia promotes miR-9 expression in glioma cells. Based upon these findings, we propose a hypothesis for the contribution of miR-9 to the dynamics glioma invasion and satellite tumor formation in brain adjacent to tumor.

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A cadherin switch underlies malignancy in high-grade gliomas

Cited by 31 publications

References 58 publications

Nicotinic acid inhibits glioma invasion by facilitating Snail1 degradation

Nicotinic acid inhibits glioma invasion by facilitating Snail1 degradation

PDGF‐B: The missing piece in the mosaic of PDGF family role in craniofacial development

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

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