Host-related carcinoembryonic antigen cell adhesion molecule 1 promotes metastasis of colorectal cancer

Abstract

Liver metastasis is the predominant cause of colorectal cancer (CRC)-related mortality in developed countries. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a cell adhesion molecule with reduced expression in early phases of CRC development and thus functions as a tumor growth inhibitor. However, CEACAM1 is upregulated in metastatic colon cancer, suggesting a bimodal role in CRC progression. To investigate the role of this protein in the host metastatic environment, Ceacam1-/-mice were injected intrasplenically with metastatic MC38 mouse CRC cells. A significant reduction in metastatic burden was observed in Ceacam1-/-compared with wild-type (WT) livers. Intravital microscopy showed decreased early survival of MC38 cells in Ceacam1-/-endothelial environment. Metastatic cell proliferation within the Ceacam1-/-livers was also diminished. Bone marrow-derived cell recruitment, attenuation of immune infiltrates and diminished CCL2, CCL3 and CCL5 chemokine production participated in the reduced Ceacam1-/-metastatic phenotype. Transplantations of WT bone marrow (BM) into Ceacam1-/-mice fully rescued metastatic development, whereas Ceacam1-/-BM transfer into WT mice showed reduced metastatic burden. Chimeric immune cell profiling revealed diminished recruitment of CD11b + Gr1 + myeloid-derived suppressor cells (MDSCs) to Ceacam1-/-metastatic livers and adoptive transfer of MDSCs confirmed the involvement of these immune cells in reduction of liver metastasis. CEACAM1 may represent a novel metastatic CRC target for treatment. © 2013 Macmillan Publishers Limited All rights reserved.