Die Expression der Signaltransduktionsfaktoren MAPK, Akt/PKB und des Transkriptionsfaktors CREB in gastroenteropankreatischen neuroendokrinen Tumoren

The molecular pathogenesis of gastro-entero-pancreatic tumors (GEP-NET) is for the most part unknown. Unlike in other tumors typical mutations in classic oncogenes like Ras, myc, Fos, Src and Jun or tumor suppressor genes like p53 and retinoblastoma susceptibility gene are not frequent in GEP-NET. In many tumors there has been detected the activation of cellular signal transduction pathways which mainly regulate growth, proliferation and differentiation of cells as well as inhibiting apoptosis. These functions are mediated by the MAPK pathway, the PI3/Akt pathway and the transcription factor CREB. Treatment options of GEP-NET are limited, especially when the tumor has already metastasized. Therefore the components of these signaling pathways and their downstream substrates present promising potential targets for antineoplastic drugs. The goal of this work was to immunohistochemically examine GEP-NET (insulinomas n=25, gastrinomas n=14, carcinoids n=20) concerning an increased expression and activation of MAPK (as part of the MAPK pathway), Akt (as part of the PI3/Akt pathway) and the transcription factor CREB. In comparison to the normal pancreas tissue most of the tumors showed a clear overexpression of MAPK, Akt and CREB. Besides there was detected an increased activation of these components, particularly of Akt and CREB. Assessing insulinomas, gastrinomas and carcinoids separately there were no significant differences in the expression and activation of MAPK, Akt and CREB.The results of this work suggest that MAPK, Akt and CREB as well as the involved signaling pathways contribute to the development of neuroendocrine tumors. The exact molecular implications remain unclear. Also to which extend the MAPK and Akt pathways and CREB are involved and interact in the development of tumors remains to be investigated.