The expression of ‘steroid superfamily’ receptors in meningiomas

Abstract

The meningioma is a tumour that arises from the cells that form a fibrous membrane covering the brain. They account for around 15% of intracranial tumours and about 7% of all people dying from brain tumours. These tumours occur more frequently in women than in men and this has lead to the suggestion that oestrogens have a role in their development and growth. Studies a decade ago with antioestrogens have proved inconclusive and therefore a medical therapy based on anti-endocrine treatment has not been developed. Radiotherapy or surgery is still the only means of treatment. With the latter in mind, we have re-visited the ‘endocrine hypothesis’ by performing the most extensive screening study so far performed for members of the ‘superfamily’ of steroid receptors. RNA was extracted from around 140 tumours and reverse transcription-PCR was performed. This analysis revealed that the ERα, ERβ, AR, PR, GRα, GRβ, PPARα, PPARβ, PPARγ was expressed in, 6%, 0%, 56%, 26% 83%, 0%, 46%, 91%, and 13% of the tumour samples, respectively. Our recent studies, as well as those of some other groups, have indicated that glucocorticoids reduce apoptotic cell death in response to chemotherapeutic agents. Given that glucocorticoid receptors are expressed in so may tumours and the fact that glucocorticoids are given to patients prior to radiotherapy, we have tested whether these steroid hormones modulate cell death. When added alone, the glucocorticoid, dexamethasone (100nM), reduced cellular metabolic activity by 25%, as measured by the redox sensitive dye, WST-1. The glucocorticoid receptor antagonist RU486, at a concentration of 10µM, was able to reverse this effect. Classical apoptosis was observed to be induced in meningioma cultures by the addition of the HMG-CoA enzyme inhibitor, Fluvastatin (10µM). Prior treatment of meningioma cultures with dexamethasone for 24h before exposure to Fluvastatin for 72h reduced the extent of apoptotic cell death observed. As these experiments with glucocorticoids are preliminary, extrapolation to the treatment scenario is not yet justified. We are therefore currently extending these studies by combining glucocorticoid pre-treatment of meningioma cultures with subsequent gamma irradiation.