Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp−−/rag2−− mice
- Florian Gebauer1,2,3,
- Daniel Wicklein1,3,
- Katrin Stübke1,
- Nina Nehmann1,
- Anna Schmidt1,
- Johannes Salamon1,4,
- Kersten Peldschus4,
- Michael Fabian Nentwich1,2,
- Gerhard Adam4,
- Genrich Tolstonog5,
- Maximilian Bockhorn2,
- Jakob R Izbicki2,
- Christoph Wagener3,
- Udo Schumacher1
- 1Institute of Anatomy and Experimental Morphology and University Cancer Center Hamburg (UCCH), University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
- 2Department of General, Visceral and Thoracic Surgery, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
- 3Institute of Clinical Chemistry, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
- 4Department of Radiology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
- 5Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany
- Correspondence to Dr Daniel Wicklein, Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany;
Contributors Study concept and design: US, JRI, MB, CW, DW, FG; acquisition of data: FG, DW, KS, NN, AS, JS, KP, GA, GT; analysis and interpretation of data: FG, DW, JS, MFN, US, CW; drafting of the manuscript: DW, FG, US, CW; obtained funding: US, JRI, CW.
- Revised 27 February 2012
- Accepted 29 February 2012
- Published Online First 5 April 2012
Background and objective E- and P-selectins expressed on the luminal surface of mesodermally derived endothelial cells play a crucial role in the formation of haematogenous metastases in a number of malignancies. As peritoneal mesothelial cells are also derived form the mesoderm, it was hypothesised that selectins are also of importance in peritoneal tumour spread.
Methods Immunohistochemistry was used to identify selectin expression on normal human peritoneum and isolated mesothelial cells. E- and P-selectin interactions with human pancreatic adenocarcinoma cells were investigated in dynamic flow assays and flow cytometry; the latter was also used to determine the main selectin ligands on pancreatic adenocarcinoma cell lines PaCa 5061, BxPC-3 and PaCa 5072, and selectin expression on human mesothelial cells. All cell lines were xenografted into the peritoneum of E- and P-selectin-deficient pfp/rag2 mice and selectin wild-type controls. Peritoneal carcinomatosis was quantified using MRI or a scoring system.
Results E- and P-selectin were constitutively expressed on human mesothelial and endothelial cells in the peritoneum. PaCa 5061 and BxPC-3 cells interacted with E- and P-selectins in dynamic flow assays and flow cytometry, with CA19-9 (Sialyl Lewis a) being the main E-selectin ligand. For xenografted PaCa 5061 and BxPC-3 cells, peritoneal metastasis was significantly reduced in E- and P-selectin double knockout mice compared with wild-type pfp/rag2 animals. In contrast, PaCa 5072 cells were almost devoid of selectin binding sites and no intraperitoneal tumour growth was observed.
Conclusion Interactions of tumour cells with peritoneal selectins play an important role in the peritoneal spread of pancreatic adenocarcinoma.
- Peritoneal carcinomatosis/metastasis of pancreatic adenocarcinoma
- Pancreatic tumours
- abdominal surgery
- gastrointestinal cancer
- abdominal MRI
- abdominal pain
- biliary strictures
- diverticular disease
- cell biology
FG and DW contributed equally to this work.
Funding This study was supported by the Landesexzellenzinitiative Hamburg Nanotechnology in Medicine (NAME).
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.