Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells

Johnson, Mahlon D.; Woodard, Ann; Kim, Paul; Frexes‐Steed, Maria

doi:10.3171/jns.2001.94.2.0293

Cited by 81 publications

(52 citation statements)

References 20 publications

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“…Inhibition of this pathway with selective MEK-1 inhibitors has shown diminished MAPK activity and associated inhibition in meningioma cell cultures. 32 Farnesyl transferase inhibitors, a class of chemotherapeutic agents that work by blocking farnesyl transferase and thereby inhibiting Ras localization and activation to the cytoplasmic surface of the receptor, are currently under investigation for a variety of hematological and solid tumors. These may hold promise for meningioma treatment as well, although several monotherapy trials using tipifarnib (Zarnestra) in gliomas have been disappointing to date.…”

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confidence: 99%

Recent developments in chemotherapy for meningiomas: a review

Moazzam

Wagle

Zada

2013

FOC

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Object Currently, few medical options exist for refractory and atypical/anaplastic meningiomas. New developments in chemotherapeutic options for meningiomas have been explored over the past decade. The authors review these recent developments, with an emphasis on emerging avenues for therapy, clinical efficacy, and adverse effects. Methods A review of the literature was performed to identify any studies exploring recent medical and chemotherapeutic agents that have been or are currently being tested for meningiomas. Results from included preclinical and human clinical trials were reviewed and summarized. Results Current guidelines recommend only 3 drugs that can be used to treat patients with refractory and highgrade meningiomas: hydroxyurea, interferon-α 2B, and Sandostatin long-acting release. Recent developments in the medical treatment of meningiomas have been made across a variety of pharmacological classes, including cytotoxic agents, hormonal agents, immunomodulators, and targeted agents toward a variety of growth factors and their signaling cascades. Promising avenues of therapy that are being evaluated for efficacy and safety include antagonists of platelet-derived growth factor receptor, epidermal growth factor receptor, vascular endothelial growth factor receptor, and mammalian target of rapamycin. Because malignant transformation in meningiomas is likely to be mediated by numerous processes interacting via a complex matrix of signals, combination therapies affecting multiple molecular targets are currently being explored and hold significant promise as adjuvant therapy options. Conclusions Improved understanding of the molecular mechanisms driving meningioma tumorigenesis and malignant transformation has resulted in the targeted development of more specific agents for chemotherapeutic intervention in patients with nonresectable, aggressive, and malignant meningiomas.

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confidence: 99%

Recent developments in chemotherapy for meningiomas: a review

Moazzam

Wagle

Zada

2013

FOC

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“…6 The MAPK cascade potentially plays an important role in meningioma growth; MAPK is activated in human meningioma cells and selective inhibition of MAPK phosphorylation/activation decreases meningioma cell proliferation. 7 Paclitaxel, a widely used taxane chemotherapeutic, stabilizes microtubules, leading to cell-cycle arrest and enhanced apoptosis. 8 Paclitaxel has been suggested to act via TLR4 in murine macrophages.…”

mentioning

confidence: 99%

Toll‐like receptor‐4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel

Tichomirowa

Theodoropoulou

Daly

et al. 2008

Intl Journal of Cancer

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Meningiomas are the second most common type of brain and CNS tumors by histology. Surgery and radiotherapy are main treatment options, but meningiomas may be impossible to adequately resect or may regrow after surgery. In spite of many experimental attempts, there is no generally accepted chemotherapeutic approach. We have studied in a series of meningiomas the expression of the Toll-like receptor 4 (TLR4), which apart from its major role as a key factor of the innate immune system, is believed to play a role in tumorigenesis. All meningiomas studied expressed TLR4 mRNA and protein at variable degree. Paclitaxel, a ligand of TLR4, exhibited a dose-and time-dependent growth suppression in both monolayer and spheroid meningioma cell cultures. The knockdown of TLR4 with siRNA in meningioma cell cultures abrogated the inhibitory effect of paclitaxel. The suppressive action of paclitaxel on meningioma cell growth was enhanced in the presence of fluvastatin or the mitogen-actvated protein kinase (ERK1/2) inhibitor PD98059. At least part of the growth suppressive effect was mediated by the induction of apoptosis in meningioma cells by paclitaxel alone or in combination with fluvastatin. In conclusion, our in vitro results suggest that paclitaxel alone or in combination with other inhibitors of cell growth (statins, MAPK inhibitors) could provide a potential tool for the treatment of TLR4 expressing meningiomas.

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“…Nonetheless, in our previous studies, cerebrospinal fluid, which activates STAT3 and stimulates meningioma cell proliferation, promoted STAT3 phosphorylation that could be detected in meningioma cells at 72 h following treatment suggesting phospho-STAT3 maintenance or stability in at least some in vitro conditions. Furthermore, extensive phosphorylation of p44/42 MAPK and Akt was detected in frozen tissue (1,3,6). Thus, in cases of extensive cellular activation, phospho-STAT3 may be stable and reliably detected in tissue frozen relatively promptly following surgical extirpation.…”

Section: Discussionmentioning

confidence: 89%

“…However, the identity and role of these pathways in the early recurrence of WHO and Simpson grade I/II meningiomas have not yet been established. Previous studies have demonstrated that the MAPK kinase (Raf-1)-MEK1-p44/42 MAPK/ERK cascade and the PI3K-PKB/Akt-mTOR and JAK1-STAT3 pathways are variably activated in certain grades of meningiomas (1)(2)(3)9,20,21); however, whether this activation of any given pathway is a predictor of recurrence remains unknown. The present study evaluated whether phosphorylation/activation of STAT3 is a predictor of recurrence.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies by our group and others have identified several key signaling pathways that are activated in meningiomas, including the mitogen-activated protein kinase (MAPK) kinase kinase-MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK1)-p44/42 MAPK cascade and the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt)-mammalian target of rapamycin (mTOR) and JAK1-STAT3 pathways, which regulate the proliferation of meningiomas (1,2,(3)(4)(5) and appear to be activated, in part, by components of the cerebrospinal fluid (6) and/or paracrine effects that activate receptor/kinases, such as the epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptor/kinases, in meningiomas (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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STAT3 activation and risk of recurrence in meningiomas

2017

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Abstract. Several studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) is associated with initiation, progression and metastasis of numerous types of malignancy. However, the role of the Janus kinase-interleukin 6-STAT3 signaling pathway in the pathogenesis and recurrence of meningiomas is unknown. The present study evaluated STAT3 activation by western blotting and immunohistochemistry and assessed its association with Ki-67 labeling in 13 cases of meningioma in which frozen tissue and ≥5.5-year follow-up information were available, and in formalin-fixed meningioma tissues from 14 cases with an 8.4-year follow-up. The results of the western blot analysis indicated that STAT3 phosphorylation was markedly higher in grade II meningiomas compared with that in grade I, with mean densitometric values of 8.6 and 1.7 following normalization to actin, respectively. High STAT3 phosphorylation/activation was identified in 2 of 3 recurrent World Health Organization (WHO) grade I meningiomas and 0 of 3 non-recurrent meningiomas. Strong STAT3 phosphorylation/activation signal was also found in 2 of 4 recurrent grade II meningiomas and 1 of 3 non-recurrent cases. According to the immunohistochemistry results, phospho-STAT3 was not increased in WHO grade II tumors compared with that in grade I tumors, and was not significantly different between recurrent and non-recurrent cases. Ki-67 labeling was significantly increased in grade II vs. grade I tumors, and was also significantly increased in recurrent compared with non-recurrent grade I meningiomas. The results of the current study suggest that, while detection of phosphorylated/activated STAT3 may be useful in isolated cases, identifying activation may be of little value in predicting recurrence.

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Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells

Abstract: The findings indicate that MAPK is constitutively expressed in leptomeningeal and meningioma cells and transduces mitogenic signals of PDGF, contributing to the growth of human meningiomas.

Cited by 81 publications

References 20 publications

Recent developments in chemotherapy for meningiomas: a review

Recent developments in chemotherapy for meningiomas: a review

Toll‐like receptor‐4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel

STAT3 activation and risk of recurrence in meningiomas

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