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Patient survival in pancreatic ductal adenocarcinoma: correlation with changes on molecular basis
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths in western industrialized nations. The low 5-year survival rate of 18.8% 21 can be explained by the lack of diagnostic options and therapeutic strategies. Therefore, research into prognostic and therapeutic...
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| Format: | Doctoral Thesis |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2023
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| Online Access: | PDF Full Text |
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| Summary: | Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths in western industrialized nations. The low 5-year survival rate of 18.8% 21 can be explained by the lack of diagnostic options and therapeutic strategies. Therefore, research into prognostic and therapeutic approaches is becoming increasingly important. Changes at the molecular level have been observed in tumor cells and the tumor microenvironment. However, only few data are available showing the impact of these changes on patient survival. The focus of this work was to generate survival data from 91 PDAC patients treated in our department.
For this purpose, exosomes were purified from patient samples. Their size and concentration were measured using nano-flow cytometry (FCM). However, the determined distribution could not be linked to an overall survival pattern.
From our data, the median survival is 21 months after diagnosis of Pancreatic cancer (PC). Patients assigned to the short-term survival group (≤21 months) were predominantly of high tumor stage according to the 2017 UICC-TNM (Union for International 64 Cancer Control; tumor, node, metastasis) classification.
PCR and Western Blotting were used to display the expression patterns of tetraspanins CD9 and CD81 in EVs derived from pancreatic tumor cells.
For both CD9 and CD81, an inverse correlation was shown between strong expression levels and poor prognosis of PDAC patients after complete surgical resection (R0). However, only the CD9 data could show a significant difference, while for future projects a larger cohort of patients would be interesting for CD81 to obtain significant results.
PCR followed by immunohistochemical staining was used to describe the distribution pattern and expression levels of ADAM8, PRMT1 and TLR-7 in tumor cells its surrounding stromal cells from over 70 PDAC patients.
In addition, the amount of ADAM8+ neutrophils in the postcapillary venules in PDAC sections was quantified. Remarkably, the amount of ADAM8+ neutrophils could be correlated with post-operative patient survival time. In contrast, no linkage could be shown between survival time and overall ADAM8 expression levels.
While high PRMT1 protein expression levels were shown to be favorable for the prognostic outcome of patients, TLR-7 was over-expressed in samples from patients with short survival time.
From our observations, we conclude that changes in tumor cells and their micromilieu-specific stromal cells at the molecular level have a remarkable impact on the overall survival of PDAC patients.
Therefor they show prognostic potential and could be an interesting target for therapeutic approaches. |
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| DOI: | 10.17192/z2024.0041 |