Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp--/rag2-- mice

TY - JOUR

T1 - Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp--/rag2-- mice

AU - Gebauer, Florian

AU - Wicklein, Daniel

AU - Stübke, Katrin

AU - Nehmann, Nina

AU - Schmidt, Anna

AU - Salamon, Johannes

AU - Peldschus, Kersten

AU - Nentwich, Michael Fabian

AU - Adam, Gerhard

AU - Tolstonog, Genrich

AU - Bockhorn, Maximilian

AU - Izbicki, Jakob R

AU - Wagener, Christoph

AU - Schumacher, Udo

PY - 2013/5/1

Y1 - 2013/5/1

N2 - 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.

AB - 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.

KW - Adenocarcinoma

KW - Animals

KW - Cell Line, Tumor

KW - Disease Models, Animal

KW - E-Selectin

KW - Flow Cytometry

KW - Humans

KW - Immunohistochemistry

KW - Mice

KW - Mice, Inbred Strains

KW - Mice, Knockout

KW - P-Selectin

KW - Pancreatic Neoplasms

KW - Peritoneal Neoplasms

KW - Selectins

KW - Transplantation, Heterologous

KW - Tumor Markers, Biological

U2 - 10.1136/gutjnl-2011-300629

DO - 10.1136/gutjnl-2011-300629

M3 - SCORING: Journal article

C2 - 22490524

VL - 62

SP - 741

EP - 750

JO - GUT

JF - GUT

SN - 0017-5749

IS - 5

ER -