Article
Selectin binding is essential for peritoneal carcinomatosis in pancreatic cancer
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Published: | May 20, 2011 |
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Introduction: Binding of tumor cells to selectins expressed on the luminal surface of endothelial cells is a crucial event in haematogeneous metastasis formation. We analyzed the functional role of E- and P-selectins in peritoneal dissemination of pancreatic adenocarcinoma.
Materials and methods: A novel E- and P-selectin-deficient mouse strain (k.o.) was established and the mice were inoculated intraperitoneally (i.p.) with 1x106 human pancreatic cancer cells (PaCa5061). For assessment of tumor growth in-vivo, MR-imaging was conducted repeatedly. Expression of E- and P-selectin on cultivated and embedded human peritoneum and selectin ligand expression of PaCa5061 was assessed using flow-cytometry, immunohistochemistry and immunofluorescence. Inhibition of selectin binding was determined by blocking the main selectin ligands CA19-9 and CD15s with monoclonal antibodies. A dynamic flow chamber was established for assessment of the physiological relevance of tumor cell binding on mesothelial monolayer and selectins.
Results: Thirty-three percent of the selectin k.o. mice showed i.p. tumor spots whereas 100% in the wild-type group displayed massive tumor growth (P = 0.005). MR-imaging revealed significant differences in average tumor diameter of the tumor masses between the two groups. In addition, selectin k.o. mice showed a dramatically prolonged overall-survival (Figure 1 [Fig. 1]).
PaCa5061 cells showed more intense binding to E-selectin than to P-selectin in flow-cytometry, immunohistochemistry and immunofluorescence which is being mainly conferred by CA19-9 and could be inhibited dose dependent by a monoclonal antibody. Flow chamber experiments showed direct adhesion of PaCa5061 to mesothelial monolayer at low shear rates, firm adhesion cells to E-selectin while P-selectin conferred only weak adhesive effects. E-selectin expression was clearly detectable in non-stimulated human mesothelial cells both in-vivo and in-vitro, while P-selectin expression was low.
Conclusion: We identified molecular interaction partners for metastatic spread in the peritoneum, unraveling new potential therapeutic targets. In addition, this adhesive mechanism might operate in the intra-peritoneal spread of other malignancies as well.