Liver metastasis of pancreatic cancer: the hepatic microenvironment impacts differentiation and self-renewal capacity of pancreatic ductal epithelial cells
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Hendrike Knaack1, Lennart Lenk2, Lisa-Marie Philipp1, Lauritz Miarka1, Sascha Rahn1, Fabrice Viol3, Charlotte Hauser4, Jan-Hendrik Egberts4, Jan-Paul Gundlach4, Olga Will5, Sanjay Tiwari5, Wolfgang Mikulits6, Udo Schumacher7, Jan G. Hengstler8 and Susanne Sebens1
1Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany
2Department of Pediatrics, UKSH Campus Kiel, Kiel, Germany
3Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
4Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, UKSH Campus Kiel, Kiel, Germany
5Molecular Imaging North Competence Center, Clinic of Radiology and Neuroradiology, CAU and UKSH Campus Kiel, Kiel, Germany
6Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
7Centre of Experimental Medicine, Department of Anatomy and Experimental Morphology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
8Leibniz Research Centre for Working Environment and Human Factors (IfADo), Technical University Dortmund, Dortmund, Germany
Susanne Sebens, email: [email protected]
Keywords: pancreatic ductal adenocarcinoma; cancer stem cell; EMT; epithelial-mesenchymal-transition; hepatic microenvironment
Received: December 13, 2017 Accepted: July 21, 2018 Published: August 03, 2018
Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at advanced stages with the liver as the main site of metastases. The hepatic microenvironment has been shown to determine outgrowth of liver metastases. Cancer stem cells (CSCs) are essential for initiation and maintenance of tumors and acquisition of CSC-properties has been linked to Epithelial-Mesenchymal-Transition. Thus, this study aimed at elucidating whether and how the hepatic microenvironment impacts stemness and differentiation of disseminated pancreatic ductal epithelial cells (PDECs). Culture of premalignant H6c7-kras and malignant Panc1 PDECs together with hepatocytes and hepatic stellate cells (HSC) promoted self-renewal capacity of both PDEC lines. This was indicated by higher colony formation compared to cells cocultured with hepatocytes and hepatic myofibroblasts. Different Panc1 colony types derived from an HSC-enriched coculture were expanded and characterized revealing that holoclones exhibited an enhanced colony formation ability, elevated and exclusive expression of the CSC-marker Nestin and a more pronounced mesenchymal phenotype compared to paraclones. Moreover, Panc1 holoclone cells showed an increased tumorigenic potential in vivo leading to formation of undifferentiated tumors in 7/10 animals, while inoculation of paraclone cells only led to formation of tumors in 2/10 animals being smaller in number and size. Holoclone tumors were characterized by elevated expression of mesenchymal markers, complete loss of E-cadherin expression and high expression of Nestin. Finally, Etanercept-mediated TNF-α blocking partly reversed the mesenchymal CSC-phenotype of Panc1 holoclone cells. Overall, these data provide evidence that the hepatic microenvironment determines stemness and differentiation of PDECs, thereby substantially contributing to liver metastases of PDAC.
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