Zurück

ID: 128 (Conflict of Interest: K)

Die Rolle von MMP-3 in der Tumorentstehung und -progression des Pankreaskarzinoms

N.Voss1, A.Martin2, D. K.Bartsch3, V.Fendrich4, J.Waldmann5
1Universitätsklinikum Hamburg-Eppendorf, Hamburg
2Uniklinik Köln, Köln
3Universitätsklinikum Marburg , Marburg
4Schön Klinik Eilbek, Hamburg
5MIVENDO Klinik , Hamburg

Einleitung

Pancreatic cancer is still a malignant disease with a poor prognosis. 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 tumour invasiveness. EMT is a physiologial 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 tumour 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.

Material und Methoden

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-makrers E-Cadherin, Vimentin, Snail, Collagen and MMP-3. Tissue samples of human PDACs and normal pancreas were analysed for MMP-3 expression. Expression data was correlated to overall-survival using a log-rank-test.

Ergebnisse

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 upon introduction of 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 to a lesser degree than transgenic mice. 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.

Schlussfolgerung

For the first time we demonstrated that MMP-3 activation in combination with 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 might be considered as a possible target for prevention and control of metastasis.