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

Abstract

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.

In vitro testing to a panel of potential chemotherapeutics and current concepts of chemotherapy in benign meningiomas

“…Interestingly, TLR4 immunoreactivity positively correlated with the antiproliferative response to TAX. A dose-related toxicity might limit its acceptability; therefore, combination of TAX with other agents enhancing its antiproliferative activity can permit the use of this drug in lower concentrations [35]. In line with our observations, Tichomirowa et al did not observe correlations between the response to TAX and benign meningioma variants.…”

“…The likely candidate for transmitting paclitaxel signalling is Toll-like receptor-4 (TLR4) [34]. Tichomirowa et al [35] evaluated 21 meningiomas (19 of them benign) which expressed TLR4 mRNA and protein at variable degree. TAX exhibited dose-and time-dependent growth suppression in the meningioma cell cultures [35].…”

“…Tichomirowa et al [35] evaluated 21 meningiomas (19 of them benign) which expressed TLR4 mRNA and protein at variable degree. TAX exhibited dose-and time-dependent growth suppression in the meningioma cell cultures [35]. Interestingly, TLR4 immunoreactivity positively correlated with the antiproliferative response to TAX.…”

Recent developments in chemotherapy for meningiomas: a review

“…Results thus far are derived from in vitro studies only, and show favorable results. 15,33 Tichomirowa et al 73 recently published an in vitro study in which an entirely novel strategy of inducing apoptosis in meningioma cells via inhibition of Toll-like receptor 4 with paclitaxel was used. The meningioma cell cultures used in this experiment exhibited dose-and time-dependent growth suppression following paclitaxel treatment, which was further amplified following addition of a statin medication.…”

Regression of a meningioma during paclitaxel and bevacizumab therapy for breast cancer

“…Part of the observed effect is secondary to induction of apoptosis. 9 These data suggest that paclitaxel may be an option for treatment of meningiomas, particularly those highly expressing TLR4. Our report of regression of a meningioma using a regimen containing paclitaxel adds to this support.…”