Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-α1) are strongly expressed in human gliomas

Wiesenhofer, Bettina; Stockhammer, Günther; Kostron, Herwig; Maier, Hans; Hinterhuber, Hartmann; Humpel, Christian

doi:10.1007/pl00007416

Cited by 78 publications

(53 citation statements)

References 42 publications

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“…Thus, the targeted expression of gas1 using the gfa2 promoter to drive its expression is an interesting approach to treat gliomas, because Gas1 blocks the proliferative action of GDNF, which is implicated in glioma cell migration and proliferation. 39,64 Also, it is reported that Gas1 antagonizes the Shh pathway, 34,65 which is involved in brain tumor formation and tumor growth. 66,67 Moreover, Gas1 inhibits cell proliferation and induces cell death (apoptosis and/or autophagy) even in the absence of active p53.…”

Section: Discussionmentioning

confidence: 99%

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

et al. 2007

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The targeted expression of transgenes is one of the principal goals of gene therapy, and it is particularly relevant for the treatment of brain tumors. In this study, we examined the effect of the overexpression of human gas1 (growth arrest specific 1) and human p53 cDNAs, both under the transcriptional control of a promoter of the human glial fibrillary acidic protein (gfa2), employing adenoviral expression vectors, in glioma cells. We showed that the targeted overexpression of gas1 and p53 (AdSGas1 and AdSp53, respectively) in rat glioma cells (C6) reduced the number of viable cells and induced apoptosis. Moreover, the adenovirally targeted expression of these genes also reduced tumor growth in vivo. Unexpectedly, there was no additive effect when both gas1 and p53 were simultaneously expressed in the same cells using a bicistronic adenoviral vector. We suggest that Gas1 does not act in combination with p53 in the C6 and U373 glioma cell lines, inducing apoptosis and cell cycle arrest. Our results indicate that the targeted expression of tumor suppressor genes (gas1 and p53) regulated by the gfa2 promoter, together with adenoviral vectors may provide an interesting approach for adjuvant selective glioma gene therapy.

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Section: Discussionmentioning

confidence: 99%

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

et al. 2007

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“…Previous reports have shown that GDNF also affects the survival of cancer cells and their proliferation in gliomas (Wiesenhofer et al 2000b) and enhances the metastasis ) and invasion potential (Kikuchi 2004, Ito et al 2005, Qiao et al 2009, Lu et al 2010) of pancreatic cancer. GDNF and its receptor are expressed in human cancers such as gliomas (Wiesenhofer et al 2000a). It has also been reported that GDNF is overexpressed at the transcript level in non-small-cell lung carcinomas (Garnis et al 2005).…”

Section: Introductionmentioning

confidence: 98%

GDNF increases cell motility in human colon cancer through VEGF–VEGFR1 interaction

Huang

Chen

Chiu

et al. 2013

Endocrine-Related Cancer

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Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor, has been shown to affect cancer cell metastasis and invasion. However, the molecular mechanisms underlying GDNF-induced colon cancer cell migration remain unclear. GDNF is found to be positively correlated with malignancy in human colon cancer patients. The migratory activities of two human colon cancer cell lines, HCT116 and SW480, were found to be enhanced in the presence of human GDNF. The expression of vascular endothelial growth factor (VEGF) was also increased in response to GDNF stimulation, along with VEGF mRNA expression and transcriptional activity. The enhancement of GDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Our results also showed that the expression of VEGF receptor 1 (VEGFR1) was increased in response to GDNF stimulation, whereas GDNF-induced cancer cell migration was reduced by a VEGFR inhibitor. The GDNF-induced VEGF expression was regulated by the p38 and PI3K/Akt signaling pathways. Treatment with GDNF increased nuclear hypoxia-inducible factor 1 a (HIF1a) accumulation and its transcriptional activity in a time-dependent manner. Moreover, GDNF increased hypoxia responsive element (HRE)-containing VEGF promoter transcriptional activity but not that of the HRE-deletion VEGF promoter construct. Inhibition of HIF1a by a pharmacological inhibitor or dominant-negative mutant reduced the GDNF-induced migratory activity in human colon cancer cells. These results indicate that GDNF enhances the migration of colon cancer cells by increasing VEGF-VEGFR interaction, which is mainly regulated by the p38, PI3K/Akt, and HIF1a signaling pathways.

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“…23 Furthermore, both genes are strongly expressed in human glioma. 24 Within each type of MEN 2, there are variations between members of the same family regarding the presence of 1 or several of the features of the disease and the age at onset. 25,26 Variations in phenotypes within the same family suggest a role for genetic modifiers, which may also work through quantitative effect.…”

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confidence: 99%

Genetic analysis of RET, GFRα1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A

Gil

Azañedo

Pollán

et al. 2002

Intl Journal of Cancer

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Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germline missense mutations in the RET proto-oncogene. This locus encodes a receptor tyrosine kinase whose activation requires the formation of a multimeric receptor complex including GDNF as a ligand and GFR␣1 as a coreceptor. In order to explore the role of RET, GFR␣1 and GDNF genes in the variation of phenotypes observed in MEN2A families, we analysed germline mutations of these genes in 4 unrelated Spanish MEN2A families (23 cases studied). We found 2 novel variants corresponding to a single change in position ؉ 47 (intron 12) of RET and position ؉22 (intron 7) of GFR␣1. Furthermore, we observed strong cosegregation between 2 polymorphisms of RET [G691S (exon 11) and S904S (TCC-TCG, exon 15) (100%, Fisher's exact test, p< 0.001)]. More interestingly, we found that these polymorphisms occurred at a significantly high frequency in patients with age at onset < 20 years old (Kruskal-Wallis's and Fisher's exact test, p ‫؍‬ 0.007). These findings suggest that the G691S and S904S variants of RET may somehow play a role on the age of onset of MEN 2A.

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Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-α1) are strongly expressed in human gliomas

Cited by 78 publications

References 42 publications

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

GDNF increases cell motility in human colon cancer through VEGF–VEGFR1 interaction

Genetic analysis of RET, GFRα1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A

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