Pathogenesis of intracranial tumors
Our experience and findings on the pathomechanisms of pituitary adenomas are also transferred to other types of intracranial tumors such as meningiomas and craniopharyngiomas. Both types of tumors are thought to be hormone-dependent due to the intratumoral expression of multiple hormone receptors. However, neither anti-hormone nor any other form of medical therapy has been successfully applied in these tumors, which still have to be removed by surgery or have to be treated by irradiation. However, for critically located meningiomas and for craniopharyngiomas a medical therapy would be desirable due to the side effects of surgery and irradiation. In particular, surgical removal or fractionated irradiation of craniopharyngiomas very often damage surrounding hypothalamic tissue leading to disturbances of hypothalamic-hypophyseal interactions and severe disorders of the central regulation of energy homoeostasis and water balance inducing adipositas and diabetes insipidus.
We have a long tradition in studying the aberrant expression of different factors or receptors in meningiomas and have tried to develop novel pharmacological treatment concepts for this kind of tumors. In a recent study we have demonstrated that similar as in pituitary adenomas (see project: Immune-endocrine interactions in pituitary physiology and pathophysiology), meningiomas express Tlr4. Taxol, an anti-tumoral agent acting through interfering with intracellular microtubli structures and/or through Tlr4, was able to suppress meningioma cell proliferation in both monolayer and spheroid cell culture. The effect was mediated through Tlr4 as confirmed after down-regulation of Tlr4 by specific siRNA. Whether our findings will serve as a basis for the development of a medical treatment concept for meningiomas needs to be studied. Other ongoing investigations are dealing with the role of angiogenic factors (VEGF, PDGF) as well as their receptors and signaling pathways for the progression of meningiomas.
Research groups involved:
Roland Goldbrunner, M.D., Dept. of Neurosurgery, University of Munich, Germany
Manfred Lange, M.D., Dept. of Neurosurgery, Clinic Villingen-Schwenningen, Germany
Jürgen Honegger, M.D., Dept. of Neurosurgery, University of Tübingen, Germany
Thomas Arzberger, M.D., Dept. of Neuropathology, University of Munich, Germany
Labeur M, Refojo D, Wölfel B, Stalla J, Vargas V, Theodoropoulou M, Buchfelder M, Paez-Pereda M, Arzt E, Stalla GK (2008) Interferon-gamma inhibits cellular proliferation and ACTH production in corticotroph tumor cells through a novel janus kinases-signal transducer and activator of transcription 1/nuclear factor-kappa B inhibitory signaling pathway. J Endocrinol 199(2):177-89
Schneider HJ, Sievers C, Klotsche J, Böhler S, Pittrow D, Lehnert H, Wittchen HU, Stalla GK (2008) Prevalence of low male testosterone levels in primary care in Germany: cross-sectional results from the DETECT study. Clin Endocrinol (Oxf). (Epub ahead of print)
Tichomirowa MA, Theodoropoulou M, Daly AF, Yassouridis A, Hansen S, Lu J, Lange M, Goldbrunner RH, Stalla GK, Renner U (2008) Toll-like receptor-4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel. Int J Cancer. 123(8):1956-63
Meyer S, Haist M, Schaefer S, Ivan D, Ittner JR, Nawroth PP, Plöckinger U, Stalla GK, Tuschy U, Weber MM, Weise A, Pfützner A, Habbe N, Kann PH (2008) Association of COLIA1 Sp1 polymorphism with the effect of subcutaneously injected recombinant hGH in GH-deficient adults. Pharmacogenomics 9(8):1017-26
Tichomirowa MA*, Theodoropoulou M*, Daly AF, Hansen S, Lu J, Lange M, Goldbrunner RH, Stalla GK, Renner U (submitted) Toll-like receptor-4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel. Int J Cancer (*equal contribution)