Richard Drexler1,2, Mirco Küchler3,4, Kim C Wagner3,4, Tim Reese3,4, Bernd Feyerabend5, Moritz Kleine6, Karl J Oldhafer7,8. 1. Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany. richard.drexler@semmelweis-hamburg.de. 2. Division of HPB Surgery, Department of Surgery, Asklepios Hospital Barmbek, Hamburg, Germany. richard.drexler@semmelweis-hamburg.de. 3. Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany. 4. Division of HPB Surgery, Department of Surgery, Asklepios Hospital Barmbek, Hamburg, Germany. 5. MVZ Hanse Histologikum GmbH, Hamburg, Germany. 6. Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany. 7. Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany. k.oldhafer@asklepios.com. 8. Division of HPB Surgery, Department of Surgery, Asklepios Hospital Barmbek, Hamburg, Germany. k.oldhafer@asklepios.com.
Abstract
PURPOSE: The Hippo pathway has broadened in cancer research in the past decade and revealed itself to be an important driver for tumorigenesis and metastatic spread. In this study, we investigated the clinical relevance of the Hippo pathway with regard to metastatic invasion, patients' outcome and histopathological features. METHODS: Protein expression of components of the Hippo pathway were analyzed by immunohistochemistry (IHC) using paraffin-embedded tissue from 103 patients who had been diagnosed with pancreatic ductal adenocarcinoma and had undergone surgery. Results were correlated with clinicopathological data, disease-free and overall survival. RESULTS: Immunohistochemistry studies in pancreatic tumour tissues revealed a significant upregulation of MST1, MST2, pLATS, pYAP and 14-3-3, representing the active Hippo pathway, in non-metastasized patients (p < 0.01). In turn, the pathway is more inactive in metastasized patients and relating liver metastases as LATS1, LATS2, YAP, transcriptional factors TEAD2 and TEAD3 were upregulated in these patients (p < 0.01). A higher pYAP expression was associated with a favorable OS and DFS. CONCLUSION: The Hippo pathway is inactive in metastasized patients releasing the pro-metastatic and proliferative potential of the pathway. Furthermore, our study underlines the prognostic relevance of the Hippo pathway as a shift in the balance towards the inactive pathway predicts an unfavorable OS and DFS.
PURPOSE: The Hippo pathway has broadened in cancer research in the past decade and revealed itself to be an important driver for tumorigenesis and metastatic spread. In this study, we investigated the clinical relevance of the Hippo pathway with regard to metastatic invasion, patients' outcome and histopathological features. METHODS: Protein expression of components of the Hippo pathway were analyzed by immunohistochemistry (IHC) using paraffin-embedded tissue from 103 patients who had been diagnosed with pancreatic ductal adenocarcinoma and had undergone surgery. Results were correlated with clinicopathological data, disease-free and overall survival. RESULTS: Immunohistochemistry studies in pancreatic tumour tissues revealed a significant upregulation of MST1, MST2, pLATS, pYAP and 14-3-3, representing the active Hippo pathway, in non-metastasized patients (p < 0.01). In turn, the pathway is more inactive in metastasized patients and relating liver metastases as LATS1, LATS2, YAP, transcriptional factors TEAD2 and TEAD3 were upregulated in these patients (p < 0.01). A higher pYAP expression was associated with a favorable OS and DFS. CONCLUSION: The Hippo pathway is inactive in metastasized patients releasing the pro-metastatic and proliferative potential of the pathway. Furthermore, our study underlines the prognostic relevance of the Hippo pathway as a shift in the balance towards the inactive pathway predicts an unfavorable OS and DFS.
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