Neuropeptides in neurological tumours

Allen, Janet M.; Hoyle, N. R.; Yeats, J.C.; Ghatei, Mohammad A.; Thomas, D. G. T.; Bloom, Stephen R.

doi:10.1007/bf00165179

Cited by 25 publications

(21 citation statements)

References 21 publications

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“…Despite the data showing that substance P may act as a mitogen, our data clearly indicate that TAC1 is down-regulated and hypermethylated in f45% of the grade 3 to 4 gliomas. Interestingly, decreased levels of TAC1-encoded peptides like substance P in primary glioma samples has been reported (46). The exact role of TAC1 in primary human gliomas will, therefore, require additional study; however, the net effect of its reduced expression may depend on the local environment of the tumor.…”

Section: Discussionmentioning

confidence: 99%

Epigenomic Profiling Reveals Novel and Frequent Targets of Aberrant DNA Methylation-Mediated Silencing in Malignant Glioma

et al. 2006

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Malignant glioma is the most common central nervous system tumor of adults and is associated with a significant degree of morbidity and mortality. Gliomas are highly invasive and respond poorly to conventional treatments. Gliomas, like other tumor types, arise from a complex and poorly understood sequence of genetic and epigenetic alterations. Epigenetic alterations leading to gene silencing, in the form of aberrant CpG island promoter hypermethylation and histone deacetylation, have not been thoroughly investigated in brain tumors, and elucidating such changes is likely to enhance our understanding of their etiology and provide new treatment options. We used a combined approach of pharmacologic inhibition of DNA methylation and histone deacetylation, coupled with expression microarrays, to identify novel targets of epigenetic silencing in glioma cell lines. From this analysis, we identified >160 genes up-regulated by 5-aza-2 ¶-deoxycytidine and trichostatin A treatment. Further characterization of 10 of these genes, including the putative metastasis suppressor CST6, the apoptosis-inducer BIK, and TSPYL5, whose function is unknown, revealed that they are frequent targets of epigenetic silencing in glioma cell lines and primary tumors and suppress glioma cell growth in culture. Furthermore, we show that other members of the TSPYL gene family are epigenetically silenced in gliomas and dissect the contribution of individual DNA methyltransferases to the aberrant promoter hypermethylation events. These studies, therefore, lay the foundation for a comprehensive understanding of the full extent of epigenetic changes in gliomas and how they may be exploited for therapeutic purposes. (Cancer Res 2006; 66(15): 7490-501)

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Section: Discussionmentioning

confidence: 99%

Epigenomic Profiling Reveals Novel and Frequent Targets of Aberrant DNA Methylation-Mediated Silencing in Malignant Glioma

et al. 2006

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“…In human brain biopsies of glioma patients, the presence of the neuropeptide SP as well as the presence of tachykinin NK 1 receptors have been observed (Allen et al, 1985;Henning et al, 1995). Nine out of 12 astrocytomas and 10 out of 10 glioblastomas were positive for SP receptors, with an increasing percentage of tachykinin NK 1 receptor expression in tumours possessing the most malignant phenotype (Henning et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, astrocytoma and glioblastoma contain significant levels of high affinity receptors for SP and their increase in expression correlate with the most malignant phenotype (Henning et al, 1995). Moreover, the presence of the SP itself has been documented in human malignant glioma tissues (Allen et al, 1985).In the last decades a wide range of antagonists highly specific and selective for human tachykinin NK 1 receptors have been described with heterogeneous chemical structures and types of pharmacological antagonism (Quartara and Maggi, 1998). Summary Astrocytes harbour functional receptors to many neurotransmitters, including substance P (SP), an undecapeptide belonging to the tachykinin family of peptide transmitters.…”

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Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

et al. 2000

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Malignant astrocytomas or glioblastomas represent the most common type of primary brain tumour in adults (Salcman and Kaplan, 1986;Hochberg and Pruitt, 1987). High-grade malignant gliomas are inevitably lethal neoplasms and the median survival of patients treated with standard cytoreductive surgery and postoperative radiotherapy is in the range of 1 year. Likewise chemotherapy is of limited effectiveness in the treatment of these tumours and other therapeutic approaches must be explored. Glioblastomas are sensitive to several hormones and growth factors. The presence of receptors for epidermal growth factor, platelet-derived growth factor, insulin-like growth factor-I/II as well as for glucocorticoid, androstenedione and progesterone in malignant gliomas, has been described (Shapiro et al, 1995). Recently, neurotransmitters/neuropeptides have also been found to regulate astrocytoma growth (Sharif, 1998).Substance P (SP), an undecapeptide of the tachykinin family of neuropeptides, is released both in the central and peripheral nervous systems, playing a well established role in neuronal transmission, vasodilatation and motor responses (Maggi et al, 1993). Tachykinins exert their actions through activation of G-protein coupled receptors, labelled NK 1 , NK 2 , NK 3 ; SP is the preferential endogenous ligand for the tachykinin NK 1 receptor (Maggi et al, 1993;Otsuka and Toshioka, 1993). In various astrocytic/glial brain tumour-derived cell lines, the presence of tachykinin NK 1 receptor strictly correlates with the effect of SP and/or NKA in increasing DNA synthesis and cellular proliferation Sharif et al, 1996;Palma et al, 1999a). In addition, SP can control many other glial responses such as taurine release, secretion of various cytokines (e.g. interleukin (IL)-6, IL-8, transforming growth factor-β, leukaemia inhibitory factor, granulocyte-macrophage colony stimulating factor) which are thought to be relevant for glioma progression (Gitter et al, 1994;Palma et al, 1995;Palma and Manzini, 1998). In a large number of these studies, the human astrocytoma grade III U373 MG cell line, which expresses a high level of functional tachykinin NK 1 receptor (Lee et al, 1992;Palma et al, 1999b) but not tachykinin NK 2 or NK 3 receptors (Heuillet et al, 1993), were used.The role of SP in glioma activities may be ascribed to a pathological use of normal signal transduction pathways occurring in reactive astrocytes. In fact, SP activates phospholipase C and stimulates the release of IL-6 and prostaglandin E 2 from human fetal astrocytes in culture (Palma et al, 1997), and there is evidence for an up-regulation of this receptor by reactive proliferating astrocytes after transection of the optic nerve (Mantyh et al, 1989). Moreover, SP-immunoreactive astrocytes have been observed in multiple sclerosis plaques (Kostyk et al, 1989) and in the forebrains of human infants (Michel et al, 1986). Interestingly, the involvement of tachykinin NK 1 receptor and SP in glioma progression was not only supported by the functional in vitro stud...

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“…Moreover, SPimmunoreactive astrocytes were observed in multiple sclerosis plaques (Kostyk et al, 1989) and in the forebrains of human infants (Michel et al, 1986). Interestingly, high expression of SP receptors (Henning et al, 1995), as well as the presence of the SP itself, (Allen et al, 1985) has been described in human malignant gliomas such as astrocytomas and glioblastomas. These observations suggest a possible role of tachykinin NK 1 Rs in supporting the development and growth of human astrocytomas.…”

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confidence: 95%

Substance P activates responses correlated with tumour growth in human glioma cell lines bearing tachykinin NK1 receptors

et al. 1998

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SummaryThe neuropeptide substance P (SP), by stimulating tachykinin NK 1 receptors (NK 1 R), triggers a number of biological responses in human glioma cells which are potentially relevant for tumour growth. First, radioligand binding studies demonstrated the presence of tachykinin NK 1 R on SNB-19, DBTRG-05 MG and U373 MG, but not on U138 MG and MOG-G-GCM human glioma cell lines. Second, application of SP or neurokinin A (NKA) to NK 1 R + glioma cell lines increased the secretion of interleukin 6 (IL-6) and potentiated IL-6 secretion induced by IL-1β. SP also up-regulated the release of transforming growth factor β1 (TGF-β1) by the U373 MG glioma cell line. Third, SP induced new DNA synthesis and enhanced the proliferation rate of NK 1 R + , but not of NK 1 R -glioma cell lines. Also, NKA stimulated the proliferation and cytokine secretion in NK 1 R + glioma cell lines. All the stimulant effects of SP/NKA on NK 1 R + glioma cell lines were completely blocked by a specific tachykinin NK 1 R antagonist, MEN 11467. These data support the potential use of tachykinin NK 1 R antagonist for controlling the proliferative rate of human gliomas.

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Neuropeptides in neurological tumours

Cited by 25 publications

References 21 publications

Epigenomic Profiling Reveals Novel and Frequent Targets of Aberrant DNA Methylation-Mediated Silencing in Malignant Glioma

Epigenomic Profiling Reveals Novel and Frequent Targets of Aberrant DNA Methylation-Mediated Silencing in Malignant Glioma

Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

Substance P activates responses correlated with tumour growth in human glioma cell lines bearing tachykinin NK1 receptors

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