Spannungsabhangige Ionenkanale in Humanen Hirntumorzellen
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Spannungsabhangige Ionenkanale in Humanen Hirntumorzellen

Spannungsabhangige Ionenkanale in Humanen Hirntumorzellen


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About the Book

Inhalt dieser Arbeit ist die Analyse spannungsabhangiger Na+-, Ca2+- und K+-Kanale an Hirntumorzellen unterschiedlicher Herkunft. Zum ersten Mal wird ein Vergleich zellphysiologischer Eigenschaften von Gliomen (Astrozytomen), Meningeomen, Medulloblastomen und neuronalen Tumoren durchgefuhrt. Zellinien von Astrozytomen (1321N1 und A172) weisen nach mehrtagigem Entzug von Serum und der Applikation von Nervenwachstumsfaktor (NGF) eine hohe und stabile Expression spannungsabhangiger Na+-Strome auf. Die Hochregulation dieser Strome geht einher mit morphologischen Veranderungen der Astrozytomzellen, insbesondere Zellrundung und Auslauferbildung. NGF beeinflusst ausserdem die funktionellen Eigenschaften der Na+-Kanale sowohl in Astrozytom- als auch in Neuroblastomzellen. Daraus lasst sich ableiten, dass NGF in Verbindung mit autokriner Stimulation spannungsabhangige Na+-Kanale in Astrozytomzellen reguliert. Ausserdem scheint der modulatorische Effekt von NGF auf die Eigenschaften der Na+-Kanale ein generelles Phanomen in neuroektodermalen Tumorzellen zu sein. Spannungsabhangige Na+-Kanale wurden weiterhin in Zellen eines Neurozytoms, eines dysembryoblastischen neuroepithelialen Tumors (DNT) sowie einem Medulloblastom nachgewiesen. Alle Meningeome, ein Gangliogliom, ein Teil der Astrozytome (2 von 8), ein weiteres Medulloblastom und eine Medulloblastomzellinie zeigten jedoch keine Na+-Kanalexpression. Die Medulloblastomzellinie MHH-MED-3 war durch spannungsabhangige Ca2+-Kanale charakterisiert. In langsamwachsenden Tumorzellen - Astrozytomzellen nach Serumentzug und neuronalen Tumorzellen (Neurozytom, DNT) - wurde die hochste Dichte an Na+-Stromen gefunden. Die Na+-Strome aller untersuchten Tumorzellen waren mindestens zu 85% durch 100-300 nM des spezifischen Inhibitors Tetrodotoxin hemmbar. Die Variabilitat funktioneller Eigenschaften der Na+-Strome in Astrozytom- und Neuroblastomzellen wurde auch in Neurozytomzellen nachgewiesen. Medulloblastome als maligne und Meningeome als benigne Vertreter von Hirntumoren sind durch eine unterschiedliche Expression von K+- Kanalen charakterisiert. Wahrend in Medulloblastomzellen insbesondere spannungsabhangige K+-Kanale (KV-Kanale) vorkommen, exprimieren Meningeomzellen v.a. Ca2+-aktivierte K+-Kanale grosser Leitfahigkeit (BKCa-Kanale). In Astrozytomzellen sind beide Kanaltypen vorhanden. Experimente an Meningeom- und Astrozytomkulturen unter Verwendung von K+-Kanalinhibitoren sprechen fur eine proliferationsfordernde Rolle von KV- jedoch nicht von BKCa-Kanalen. Die weitere Charakterisierung von BKCa-Kanalen an Meningeomzellen ergab einen regulatorischen (inhibitorischen) Effekt des Zytoskeletts auf die Kanalaktivitat. Diese Zytoskelett-Abhangigkeit deutet moglicherweise auf eine Rolle der BKCa- Kanale bei der Migration oder bei der Beantwortung mechanischer Reize hin. Aufgrund ihrer hohen Expression und dynamischen Regulation in Hirntumorzellen konnen spannungsabhangige Ionenkanale als Indikatoren fur die Untersuchung wichtiger tumorbiologischer Mechanismen dienen, wie der Proliferation, Differenzierung, Apoptose und Invasivitat. The present work contains an analysis of voltage-dependent Na+-, Ca2+- and K+-channels in brain tumor cells of different origin. For the first time cellular physiological properties of gliomas (astrocytomas), meningiomas, medulloblastomas and neuronal tumors are compared. Cell lines of astrocytomas (1321N1 and A172) show a consistent high expression of voltage-gated Na+-currents after serum deprivation and treatment with nerve growth factor (NGF). The upregulation of these currents is accompanied by morphological changes that are characterized by cell rounding and outgrowth of cellular processes. NGF modulates functional properties of Na+-channels in both astrocytoma and neuroblastoma cells. From this it is concluded that NGF controls voltage- gated Na+-channels in astrocytoma cells by autocrine stimulation. Furthermore, the modulatory effect of NGF on Na+-channel properties seems to be a general phenomenon in neural tumor cells. Voltage-gated Na+-channels were also found in cells of a neurocytoma, a dysembryoblastic neuroepithelial tumor (DNT) and a medulloblastoma. All meningiomas, a ganglioglioma, six of eight astrocytomas, another medulloblastoma and a medulloblastoma cell line did not express functional Na+-channels. The medulloblastoma cell line MHH-MED-3 was characterized by voltage-gated Ca2+-channels. Slow growing tumor cells - astrocytoma cells during serum deprivation and neuronal tumor cells of the neurocytoma and the DNT - showed the highest density of Na+-currents. The specific inhibitor tetrodotoxin blocked the Na+- currents by at least 85% in all tumor cells. Single neurocytoma cells displayed differences in functional properties of their Na+-currents as observed in astrocytoma and neuroblastoma cells. Medulloblastomas as malignant and meningiomas as benign brain tumors are characterized by a different expression of K+-channels. While medulloblastoma cells show voltage-gated K+-channels (KV-channels), meningeoma cells express predominantly large conductance Ca2+- activated K+-channels (BKCa-channels). Both channel types were regularly found in astrocytoma cells. Experiments on meningioma and astrocytoma cultures using K+-channel inhibitors suggest that KV- but not BKCa-channels support proliferation. The further characterization of BKCa-channels in meningioma cells provided evidence for controlling channel activity by the cytoskeleton. This suggest a possible role of BKCa-channels in cellular migration or in response to mechanical stimulation. Because of their high expression and dynamic regulation in brain tumor cells voltage-dependent ion channels may serve as indicators for other tumor-relevant mechanisms, such as proliferation, differentiation, apoptosis and invasion.


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Product Details
  • ISBN-13: 9783897228214
  • Publisher: Logos Verlag Berlin
  • Publisher Imprint: Logos Verlag Berlin
  • Height: 210 mm
  • No of Pages: 99
  • Spine Width: 0 mm
  • Width: 145 mm
  • ISBN-10: 3897228211
  • Publisher Date: 30 Dec 2001
  • Binding: Paperback
  • Language: German
  • Returnable: N
  • Weight: 750 gr


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