Journal
ONCOGENE
Volume 32, Issue 7, Pages 849-860Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.112
Keywords
CEACAM 1; metastasis; microenvironment; intravital microscopy; MDSC; colorectal cancer
Funding
- Canadian Institutes for Health Research
- Canadian Cancer Society Research Institute
- Fonds de la Recherche en Sante du Quebec (FRSQ)
- McGill Integrated Cancer Research Training Program
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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 Ceacaml-i- 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. Oncogene (2013) 32, 849-860; doi:10.1038/onc.2012.112; published online 2 April 2012
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