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

Oncogene volume 32, pages 849–860 (2013)Cite this article

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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.

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Acknowledgements

We wish to thank Drs Janusz Rak, Peter Siegel and Julie St-Pierre (McGill University) for their helpful corrections and comments on the manuscript. We are also indebted to Dr Russell Jones (McGill University) for help with bone marrow transplantations and Dr Kathryn V Holmes (University of Colorado) for the monoclonal CC1 antibody. This work was supported by grants from the Canadian Institutes for Health Research (NB, LF and PB) and the Canadian Cancer Society Research Institute (LF). AA and ALN were recipients of post-doctoral fellowships from the Fonds de la Recherche en Santé du Québec (FRSQ). AA and CC received post-doctoral awards from the McGill Integrated Cancer Research Training Program funded by the Canadian Institutes for Health Research and the Fonds de la Recherche en Santé du Québec (FRSQ).

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Authors and Affiliations

  1. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada

    A Arabzadeh, C Chan, A-L Nouvion, V Breton, S Benlolo, L DeMarte, C Turbide & N Beauchemin

  2. Department of Surgery, McGill University, Montreal, Quebec, Canada

    C Chan, P Brodt & L Ferri

  3. Department of Oncology, McGill University, Montreal, Quebec, Canada

    P Brodt, L Ferri & N Beauchemin

  4. Department of Medicine, McGill University, Montreal, Quebec, Canada

    N Beauchemin

  5. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    N Beauchemin

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  1. A Arabzadeh
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Arabzadeh, A., Chan, C., Nouvion, AL. et al. Host-related carcinoembryonic antigen cell adhesion molecule 1 promotes metastasis of colorectal cancer. Oncogene 32, 849–860 (2013). https://doi.org/10.1038/onc.2012.112

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