Der Stellenwert des Sonic Hedgehog Signalweges bei neuroendokrinen Lungentumoren

Die wesentliche Fragestellung dieser Arbeit bezog sich darauf, welche EMT Signalwege bei den neuroendokrinen Lungentumoren eine signifikante Rolle spielen, und somit als mögliches therapeutisches Ziel von Bedeutung sind. Dazu wurde mittels der IHC die Aktivität der EMT Signalwege SHH, SMO, PTCH1, Tw...

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Bibliographic Details
Main Author: Grups, Joana Donata Regina
Contributors: Kirschbaum, Andreas (Prof. Dr. med.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2020
Online Access:PDF Full Text
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The core question of this study was to clarify which EMT signaling pathways play a significant role in neuroendocrine lung tumors and are therefore of importance as a possible therapeutic target. Thus, the activity of the EMT signaling pathways SHH, SMO, PTCH1, Twist, Vimentin, Snail 1 and E-Cadherin in typical and atypical lung carcinomas was investigated using IHC. Histological samples of 20 patients with secured lung NET were used for IHC analysis. Out of the available 20 samples, there were 9 TC and 11 AC. In addition, these samples were used to investigate whether the established IHC staining method can be replaced by PCR to differentiate between TC and AC. It has been shown, in 19 of the 20 patients, that the hedgehog signaling pathway (SHH) was ubiquitously activated in the tumor tissue of lung NET. This could be a starting point for the development of new antitumor drugs based on SHH inhibitors in the future. In all 20 NET patients examined, it was also proven that the PTCH 1 complex was still present but its activity was suppressed. This is due to the intracellular detection of SMO, which is directed by PTCH 1 in healthy cells, but was positive in 80% of the cases studied. Thus, the activation of SHH seems to occur via a second, PTCH 1 independent pathway. The high percentage of SMO detection in the examined lung NET makes this component of the EMT signaling pathway a potential target for future antitumor therapy. The non-activity of Twist in all 20 patients however shows, that, like PTCH 1, it is not a decisive signaling pathway in the development or progression of pulmonary NET. This is also confirmed by the low expression of vimentin in 2 of the 20 patients. E-Cadherin was not affected in almost all (19/20) NET patients. In conclusion, E-Cadherin, as well as vimentin and twist, is only of minor importance in the tumorigenesis of NET, since it was not suppressed. Results have also shown, that PCR of the IHC is not superior in differentiating a TC from an AC or did not lead to better results in the cases examined here. Using growth curves of the bronchial carcinoma cell line CRL-8515, EMT signaling pathway inhibitors were investigated in vitro for their antitumor effect. Unfortunately, the in vitro influence of the tested EMT inhibitors on the growth behavior of the bronchial carcinoma cell line CRL-5815 did not show any significant effects, so that no therapeutic approaches can be derived from this. This work shows, that substances directed against the SHH signaling pathway or SMO can be an antitumor therapy for advanced NET of the lung. Vismodegib, the first SHH signaling pathway inhibitor approved by the FDA for the treatment of small cell lung cancer, could therefore also be used for the AC of the lung. In order to verify this, future investigations in the xenograft mouse model would be useful.