Expression of TGF-β isoforms, TGF-β receptors, and SMAD molecules at different stages of human glioma

Kjellman, Christian; Olofsson, Sabine P.; Hansson, Oskar; Schantz, Torbjörn von; Lindvall, Magnus; Nilsson, Ingar; Salford, Leif G.; Sjögren, Hans‐Olov; Widegren, Bengt

doi:10.1002/1097-0215(20000520)89:3<251::aid-ijc7>3.0.co;2-5

Cited by 195 publications

(127 citation statements)

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“…In comparison to TGF-b1 and TGF-b3, TGF-b2 is the predominant isoform of TGF-b secreted by human malignant glioma cells (Kjellman et al, 2000). TGF-b2-targeted therapies are currently evaluated in randomised clinical trials (Fakhrai et al, 2006;Schlingensiepen et al, 2006) in consistent with the reports on the relevance of TGF-b2 for the progression of high-grade gliomas.…”

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confidence: 87%

“…In early stages of tumour development, it inhibits tumour growth, but later on, it turns to a highly tumorigenic molecule, including increased tumour cell motility and invasion, induction of angiogenesis and immune suppression. The three different isoforms of TGF-b (TGFb1, TGF-b2, TGF-b3) are differentially expressed in high-grade glioma (Kjellman et al, 2000).…”

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confidence: 99%

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The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

et al. 2007

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Versican is a large chondroitin sulphate proteoglycan produced by several tumour cell types, including high-grade glioma. The increased expression of certain versican isoforms in the extracellular matrix (ECM) plays a role in tumour cell growth, adhesion and migration. Transforming growth factor-b2 (TGF-b2) is an important modulator of glioma invasion, partially by remodeling the ECM. However, it is unknown whether it interacts with versican during malignant progression of glioma cells. Here, we analysed the effect of TGF-b2 on the expression of versican isoforms. The expression of versican V0/V1 was upregulated by TGF-b2 detected by quantitative polymerase chain reaction and immunoprecipitation, whereas V2 was not induced. Using time-lapse scratch and spheroid migration assays, we observed that the glioma migration rate is significantly increased by exogenous TGF-b2 and inhibited by TGF-b2-specific antisense oligonucleotides. Interestingly, an antibody specific for the DPEAAE region of glycosaminoglycan-b domain of versican was able to reverse the effect of TGF-b2 on glioma migration in a dose-dependent manner. Taken together, we report here that TGF-b2 triggers the malignant phenotype of high-grade gliomas by induction of migration, and that this effect is, at least in part, mediated by versican V0/V1.

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confidence: 87%

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confidence: 99%

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

et al. 2007

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“…Furthermore, TGFβ is well known by its anti-inflammatory and immunosuppressive properties and might as well favor tumor growth by inhibiting the immune surveillance against cancer cells 22 . Indeed, both TGFβ1 and TGFβ2 have been reported to be involved in development and progression of high-grade gliomas 57 . Due to its pro tumorigenic properties, modulation of TGFβ signaling pathway is currently under investigation as a therapeutic strategy in gliomas 58 .…”

Section: Molecular Pathways and Tumorigenesismentioning

confidence: 99%

Aberrant signaling pathways in medulloblastomas: a stem cell connection

Rodini

Suzuki

Nakahata

et al. 2010

Arq. Neuro-Psiquiatr.

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Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio-and chemoresistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFb, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers. Key words: medulloblastoma, neurobiology, signal transduction, stem cells, transforming growth factor beta, biological therapy.Vias de sinalização aberrantes no meduloblastoma: uma conexão com célula-tronco RESUMO Meduloblastoma é um tumor maligno do sistema nervoso central (SNC). Na infância, representa o tumor sólido mais frequente e a principal causa de morte relacionada ao câncer. Tratamentos atuais incluem cirurgia, quimioterapia e radioterapia, que podem trazer prejuízos cognitivos e desenvolvimento de tumores secundários. Novas perspectivas terapêuticas surgem com a identificação de células-tronco em gliomas, as quais apresentam alto potencial tumorigênico e maior resistência à radioterapia e quimioterapia. A hipótese das células-tronco tumorais sugere que a transformação de células-tronco e/ou progenitores neurais do cerebelo está envolvida no desenvolvimento do meduloblastoma. Portanto, analisar alterações genéticas e moleculares envolvidas nesse processo é de grande importância na pesquisa básica e aplicada ao câncer. Nesse sentido, discutimos o possível envolvimento de vias de sinalização bioquímica críticas a ambos os processos de

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“…(d,e,f,g) U-251MG cells were plated as above, followed by lysis with RIPA buer with the addition of 1% SDS, SDS ± PAGE of equivalent migrogram of lysate and Western blot analysis with mAb anti-paxillin (d), or rabbit anti-a5 IgG (f) stripping and re-probing with mAb anti-actin (e,g) (Shibanuma et al, 1994). Moreover, it has been reported that TGF-b1 is synthesized by some tumors, such as malignant astrocytomas (Kjellman et al, 2000). As our laboratory has been studying the integrin-mediated signaling pathways that promote malignant astrocytoma cell invasion (Gladson, 1999;Wang et al, 2000), we investigated the regulation of paxillin by TGF-b1 in malignant astrocytoma cells.…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 up-regulates paxillin protein expression in malignant astrocytoma cells: requirement for a fibronectin substrate

et al. 2001

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Cytokines can in¯uence the interactions between members of the integrin cell adhesion receptor family and the extracellular matrix thereby potentially aecting cell function and promoting cell adhesion, growth and migration of malignant astrocytoma tumor cells. As malignant astrocytoma cells synthesize TGF-b1 in vivo, we analysed the eects of TGF-b1 on signaling events associated with integrin receptor ligation, focusing on the eects on paxillin, a phosphorylated adaptor protein, that acts as a scaold for signaling molecules recruited to focal adhesions. TGF-b1-stimulation of primary astrocytes and serum-starved U-251MG malignant astrocytoma cells attached to ®bronectin induced a substantial increase in the levels of paxillin protein (®vefold increase at 2.0 ng/ml) in a dose-and timedependent manner compared to the levels observed on plating onto ®bronectin in the absence of stimulation. In the astrocytoma cells, this resulted in an increase in the pool of tyrosine-phosphorylated paxillin, although it did not appear to alter the extent of phosphorylation of the paxillin molecules. In contrast, in primary astrocytes the protein levels were upregulated in the absence of a parallel increase in phosphorylation. The TGF-b1-stimulated increase in paxillin levels required ligation of the ®bronectin receptor, as it was not induced when the cells were plated onto vitronectin, collagen or laminin. The increase in the pool of paxillin on TGFb1 stimulation of the ®bronectin-plated astrocytoma cells was associated with an increase in translation, but was not associated with an increase in the steady-state levels of paxillin mRNA. Stimulation with TGF-b1 on a ®bronectin substrate increased subsequent attachment and spreading of U-251MG cells onto ®bronectin and, to a lesser extent, vitronectin, but not collagen. Our results indicate that physiologic levels of TGF-b1 stimulate the expression of paxillin protein at the level of translation through a process that requires engagement of the ®bronectin receptor, and promotes attachment and spreading of malignant astrocytoma cells on ®bronectin.Oncogene (2001) 20, 7976 ± 7986.

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Expression of TGF-β isoforms, TGF-β receptors, and SMAD molecules at different stages of human glioma

Cited by 195 publications

References 18 publications

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

Aberrant signaling pathways in medulloblastomas: a stem cell connection

TGF-β1 up-regulates paxillin protein expression in malignant astrocytoma cells: requirement for a fibronectin substrate

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