Die Rolle von MMP-3 in der Entstehung und Progression des Pankreaskarzinoms
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Philipps-Universität Marburg
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Abstract
Pancreatic cancer is still a malignant disease with a poor prognosis. Due to a relative 5-year-survival rate of under 5% and failure of significant achievements in therapy it will likely rise in the list of tumor deaths in the following years.
In recent studies, changes in the „micro-environment“ of pancreatic ductal adenocarcinomas (PDACs) have become of particular interest especially in matters of resistance to radio- and chemotherapy and invasion and metastasis. Desmoplastic stroma reaction attending chronic pancreatitis is very similar to the changes in tumor initiation, -progress and -metastasis in PDACs. Because of these similarities, epithelial-mesenchymal transition (EMT) is considered as reasonable explanation for tumor invasiveness. EMT is a physiological process in embryogenesis and wound healing and represents a process in which epithelial cells gain mesenchymal features like motility. But it also leads to pathological changes in sustained tissue damage or tumor metastasis.
For this reason MMP-3, a key proteine of the extracellular matrix (ECM) and reactive stroma, should get detected in human PDACs and its prognostic value was examined. For the first time we generated Ela-1-tTA/tet-MMP-3-mice with a selective tetracyclin dependent activation in pancreatic acinar cells and aditionally induced chronic pancreatitis by daily caerulein injections to evaluate this risk factor for PDACs. As control we used mice without transgene activation as well as mice without induced chronic pancreatitis. The effect of MMP-3 activation on fibrosis, ADMs, EMT, PanINs and PDACs after two and five months was analyzed by histopathological and immunohistochemical evaluation and by Realtime-PCR for ADM-markers Amylase and CK-19 and EMT-markers E-Cadherin, Vimentin, Snail, Collagen and MMP-3.
We could demonstrate a higher MMP-3-expression in human PDACs in comparison to normal and pancreatitis tissue. In addition we found MMP-3-overexpression in pT4-tumours. There was no evidence for MMP-3 as possible prognostic marker for postoperative survival.
Furthermore Ela-1-tTA/tet-MMP-3-mice showed significant increase of fibrotic changes, ADMs and rise of EMT-markers especially combined with chronic pancreatitis. MMP-3 activation without chronic pancreatitis had no significant effect on fibrosis or EMT. In contrast control-mice with induced chronic pancreatitis only also showed ADMs, Ki-67-positive cell nuclei and fibrotic changes. All these results were most significant after five months duration. MMP-3 activation combined with chronic pancreatitis did not lead to PanINs or invasive PDACs.
It could be shown that MMP-3 is overexpressed in human PDACs and that higher tumor stages are correlated with higher MMP-3 levels. For the first time it is revealed that MMP-3 activation and chronic pancreatitis lead to intense fibrosis and measurable EMT and that inflammation is a major factor. The abscence of PanINs and PDACs after a duration of five months could imply the necessity of oncogenes and longtime exposition for the development of neoplastic lesions. Nevertheless MMP-3 is an initiator of EMT and key player in ECM and should be considered as a possible target for prevention and control of metastasis. To make this possible, it is necessary to investigate in detail the function of MMPs in PDACs and moreover their differentiation in physiological and neoplastic changes.
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Created: 2022Issued: 2022-02-17Updated: 2022-02-17
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Medizin
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Philipps-Universität Marburg
Language
ger
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DoctoralThesis
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610
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Voß, Nina: Die Rolle von MMP-3 in der Entstehung und Progression des Pankreaskarzinoms. : Philipps-Universität Marburg 2022-02-17. DOI: https://doi.org/10.17192/z2022.0137.
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This item has been published with the following license: In Copyright