Abstract 5172: Role of CEACAM1 on cancer cell endothelial adhesion and liver metastasis in vivo

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Abstract Background: There are emerging data to suggest that tumor over-expression of the carcinoembryonic antigen-related cell adhesion molecules (CEACAM1, 5 and 6) may influence cancer metastasis; however, the mechanisms for this are unclear. CEACAM1 was shown to bind homotypically to itself and heterotypically to CEACAM5 and CEACAM6. Since CEACAM1 is the only known CEACAM family member expressed on the hepatic endothelium, we hypothesized that CEACAM1 promotes cancer metastasis by directly mediating binding between circulating tumor cells and the sinusoidal endothelium. Methods: Using intra-vital microscopy (IVM), a physiologically relevant model system to assess the early stages of liver metastasis in vivo, we have compared the hepatic endothelial adhesion of intra-splenically injected MC38 cells (mouse colon cancer cell line with minimal CEACAM1 expression) between Ceacam1+/+ and Ceacam1−/− mice. A CEACAM1-negative population of MC38 cells (MC38-null) was sorted out by FACS using specific anti-CEACAM1 antibodies. MC38-null cells were then infected with retroviruses produced from ψ2 packaging cells carrying pLXSN-CEACAM1 expression construct and infected cells were selected using neomycin-containing media. A CEACAM1-positive population of MC38 cells (MC38-CC1) was sorted out by FACS using specific anti-CEACAM1 antibodies. The migratory ability of MC38-null and MC38-CC1 cells were compared by IVM in Ceacam1+/+ mice as mentioned above. Liver metastasis assays were performed by means of intra-splenic injection of MC38 cells into the Ceacam1+/+ and Ceacam1−/− mice. Data expressed as mean ± SEM, student t-test determined significance (*p<0.05). Results: By using IVM, we observed a 3-fold decrease in hepatic sinusoidal endothelial adhesion of intra-splenically injected MC38-null cells in Ceacam1−/− mice compared to Ceacam1 +/+ mice (0.8±0.2 vs 2.5±0.3 adhered cells)*. Forced expression of CEACAM1 in MC38 cells however did not significantly increase hepatic endothelial adhesion in the Ceacam1+/+ mice (2.7±0.9 adhered MC38-CC1 cells vs 2.5±0.2 adhered MC38-null cells). Development of liver metastasis after intra-splenic injection of MC38-null cells was significantly reduced in the Ceacam1−/− mice (81% reduction in comparison to Ceacam1+/+ mice)*. Conclusion: Sinusoidal endothelial cell, but not cancer cell, CEACAM1 expression supports liver metastasis by increasing the adherence of circulating tumor cells to hepatic endothelium. Further investigation will be required to dissect the exact mechanism of how endothelial CEACAM1 influence hepatic endothelial adhesion of cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5172.