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Die Bedeutung Von Integrin α3 Und Integrin αV für Die Metastasierung Des Humanen Pankreaskarzinoms in Vivo
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Die Bedeutung Von Integrin α3 Und Integrin αV für Die Metastasierung Des Humanen Pankreaskarzinoms in Vivo
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Dissertation
Die Bedeutung Von Integrin α3 Und Integrin αV für Die Metastasierung Des Humanen Pankreaskarzinoms in Vivo
2023
Overview
Background:The development of intraperitoneal metastases from pancreatic ductal adenocarcinoma (PDAC) drastically minimizes therapeutic options. Integrins are key players in the interaction of PDAC cells with mesothelial cells and the extracelular matrix (ECM) components of the submesothelial layer, which is important for the initiation and progression of intraperitoneal (IP) candriomaloisis. In particular, integrin alpha 3 (ITGA3), which binds to various ECM ligands, is highly upregulated in PDAC. Its functional relevance in PDAC however, is largely unknown.Methods:A stable shRNA mediated ITGA3 knockdown was established in three PDAC cell lines. In xenograft models, the spread of IP carcinomatosis was analysed upon intraperitoneal injection of these knockdown vs. negative control cells. In addition, sustained ITGAS knockdown and possible (counter) regulation of other integrin subunits due to ITGA3 reduction was studied in cell lines and in IP carcinomatosis tumour samples. Peritoneal metastases were also analyzed by next generation sequencing and compared with differential gene expression data from patients diagnosed with PDAC. Using the stable tumour cell lines, the effects of ITGAS on key steps of peritoneal metastasis formation were further characterized in vitroResults:The knockdown of ITGA3 led to significantly improved overall survival due to reduced development of IP carcinomatosis and decreased malignant ascites formation in two of three xenograft models. Overlapping gene expression data from patients and the two PDAC cell lines with survival benefit identified ITGAS to be a regulator of genes relevant for tumour progression, eg. CEACAM6. In addition, ITGAS was found to be involved in different steps of peritoneal spread in wirst as demonstrated by reduced adhesion, proliferation, invasion and colony forming potential due to ITGA3 knockdown.Conclusion:High ITGAS expression levels in PDAC have a delrimental impact on survival and progression of IP carcinomatosis. ITGA3 as a part of the leukocyte adhesion cascade is significantly involved in peritoneal metastasis of PDAC. Thus, it represents a promising target for future therapies.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798383030363
