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Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis

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Abstract

The discovery of the carcinoembryonic antigen (CEA) as a tumor marker for colorectal cancer some 50 years ago became the first step in the identification of a much larger family of 12 carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) with surprisingly diverse functions in cell adhesion, in intracellular and intercellular signaling, and during complex biological processes such as cancer progression, inflammation, angiogenesis, and metastasis. The development of proper molecular and biochemical tools and mouse models has enabled bidirectional translation of the CEACAM network biology. Indeed, CEACAM1, CEACAM5, and CEACAM6 are now considered valid clinical biomarkers and promising therapeutic targets in melanoma, lung, colorectal, and pancreatic cancers. These fascinating proteins illustrate how a better understanding of the CEACAM family of cell adhesion molecules reveals their functional link to the underlying disease and lead to new monitoring and targeting opportunities.

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References

  1. Gold, P., & Freedman, S. O. (1965). Specific carcinoembryonic antigens of the human digestive system. The Journal of Experimental Medicine, 122, 467–481.

    PubMed  CAS  Google Scholar 

  2. von Kleist, S., Chavanel, G., & Burtin, P. (1972). Identification of an antigen from normal human tissue that crossreacts with the carcinoembryonic antigen. Proceedings of the National Academy of Sciences of the United States of America, 69, 2492–2494.

    Google Scholar 

  3. Mach, J. P., & Pusztaszeri, G. (1972). Carcinoembroynic sntigen (CEA): Demonstration of a partial identity between CEA and a normal glycoprotein. Immunochemistry, 9, 1031–1034.

    PubMed  CAS  Google Scholar 

  4. MacSween, J. M., Warner, N. L., Bankhurst, A. D., & Mackay, I. R. (1972). Carcinoembryonic antigen in whole serum. British Journal of Cancer, 26(5), 356–360.

    PubMed  CAS  Google Scholar 

  5. Sorokin, J. J., Sugarbaker, P. H., Zamcheck, N., Pisick, M., Kupchik, H. Z., & Moore, F. (1974). Serial carcinoembryonic antigen assays. Use in detection of cancer recurrence. Journal of the American Medical Association, 228(1), 49–53.

    PubMed  CAS  Google Scholar 

  6. Shively, J. E., & Beatty, J. D. (1985). CEA-related antigens: Molecular biology and clinical significance. Critical Reviews in Oncology/Hematology, 2(4), 355–399.

    PubMed  CAS  Google Scholar 

  7. Oikawa, S., Nakazato, H., & Kosaki, G. (1987). Primary structure of human carcinoembryonic antigen (CEA) deduced from cDNA sequence. Biochemical and Biophysical Research Communications, 142(2), 511–518.

    PubMed  CAS  Google Scholar 

  8. Zimmermann, W., Ortlieb, B., Friedrich, R., & von Kleist, S. (1987). Isolation and characterization of cDNA clones encoding the human carcinoembryonic antigen reveal a highly conserved repeating structure. Proceedings of the National Academy of Sciences of the United States of America, 84(9), 2960–2964.

    PubMed  CAS  Google Scholar 

  9. Thompson, J. A., Pande, H., Paxton, R. J., Shively, L., Padma, A., Simmer, R. L., Todd, C. W., Riggs, A. D., & Shively, J. E. (1987). Molecular cloning of a gene belonging to the carcinoembryonic antigen gene family and discussion of a domain model. Proceedings of the National Academy of Sciences of the United States of America, 84(9), 2965–2969.

    PubMed  CAS  Google Scholar 

  10. Beauchemin, N., Benchimol, S., Cournoyer, D., Fuks, A., & Stanners, C. P. (1987). Isolation and characterization of full-length functional cDNA clones for human carcinoembryonic antigen. Molecular and Cellular Biology, 7(9), 3221–3230.

    PubMed  CAS  Google Scholar 

  11. Kuroki, M., Yamanaka, T., Matsuo, Y., Ohtani, T., Matsuo, Y., Minowada, J., Misumi, Y., Oikawa, S., Nakazato, H., & Matsuoka, Y. (1994). Characterization of a species of non-specific cross-reacting antigen (NCA) expressed by human monocytic cell lines: Structure and expression during cell differentiation. International Journal of Cancer, 56(6), 886–891.

    CAS  Google Scholar 

  12. Kuroki, M., Arakawa, F., Matsuo, Y., Oikawa, S., Nakazato, H., & Matsuoka, Y. (1991). Three novel molecular biliary glycoprotein cDNA isoforms deduced clones from a leukocyte library. Biochemical and Biophysical Research Communications, 176, 578–585.

    PubMed  CAS  Google Scholar 

  13. Barnett, T. R., Kretschmer, A., Austen, D. A., Goebel, S. J., Hart, J. T., Elting, J. J., & Kamarck, M. E. (1989). Carcinoembryonic antigens: Alternative splicing accounts for the multiple mRNAs that code for novel members of the carcinoembryonic antigen family. The Journal of Cell Biology, 108, 267–276.

    PubMed  CAS  Google Scholar 

  14. Hinoda, Y., Neumaier, M., Hefta, S. A., Drzeniek, Z., Wagener, C., Shively, L., Hefta, L. J. F., Shively, J. E., & Paxton, R. J. (1988). Molecular cloning of a cDNA coding for biliary glycoprotein I: Primary structure of a glycoprotein immunologically crossreactive with carcinoembryonic antigen. Proceedings of the National Academy of Sciences of the United States of America, 85, 6959–6963.

    PubMed  CAS  Google Scholar 

  15. Beauchemin, N., Draber, P., Dveksler, G., Gold, P., Gray-Owen, S., Grunert, F., et al. (1999). Redefined nomenclature for members of the carcinoembryonic antigen family. Experimental Cell Research, 252(2), 243–249.

    PubMed  CAS  Google Scholar 

  16. Kammerer, R., & Zimmermann, W. (2010). Coevolution of activating and inhibitory receptors within mammalian carcinoembryonic antigen families. BioMedCentral Biology, 8, 12–33.

    Google Scholar 

  17. Obrink, B. (1997). CEA adhesion molecules: Multifunctional proteins with signal-regulatory properties. Current Opinion in Cell Biology, 9(5), 616–626.

    PubMed  CAS  Google Scholar 

  18. Kuespert, K., Pils, S., & Hauck, C. R. (2006). CEACAMs: Their role in physiology and pathophysiology. Current Opinion in Cell Biology, 18(5), 565–571.

    PubMed  CAS  Google Scholar 

  19. Voges, M., Bachmann, V., Naujoks, J., Kopp, K., & Hauck, C. R. (2012). Extracellular IgC2 constant domains of CEACAMs mediate PI3K sensitivity during uptake of pathogens. PLoS One, 7(6), e39908.

    PubMed  CAS  Google Scholar 

  20. Kammerer, R., Rüttiger, L., Riesenberg, R., Schäuble, C., Krupar, R., Kamp, A., Sunami, K., Eisenried, A., Hennenberg, M., Grunert, F., Bress, A., Battaglia, S., Schrewe, H., Knipper, M., Schneider, M. R., & Zimmermann, W. (2012). Loss of mammal-specific tectorial membrane component carcinoembryonic antigen cell adhesion molecule 16 (CEACAM16) leads to hearing impairment at low and high frequencies. Journal of Biological Chemistry, 287(26), 21584–21598.

    PubMed  CAS  Google Scholar 

  21. McLellan, A. S., Fischer, B., Dveksler, G., Hori, T., Wynne, F., Ball, M., Okumura, K., Moore, T., & Zimmermann, W. (2005). Structure and evolution of the mouse pregnancy-specific glycoprotein (Psg) gene locus. BioMedCentral Genomics, 6, 4.

    Google Scholar 

  22. Waterhouse, R., Ha, C., & Dveksler, G. S. (2002). Murine CD9 is the receptor for pregnancy-specific glycoprotein 17. The Journal of Experimental Medicine, 195(2), 277–282.

    PubMed  CAS  Google Scholar 

  23. Ha, C. T., Waterhouse, R., Wessells, J., Wu, J. A., & Dveksler, G. S. (2005). Binding of pregnancy-specific glycoprotein 17 to CD9 on macrophages induces secretion of IL-10, IL-6, PGE2, and TGF-beta1. Journal of Leukocyte Biology, 77(6), 948–957.

    PubMed  CAS  Google Scholar 

  24. Horst, A. K., & Wagener, C. (2004). CEA-related CAMs. Human Experimental Pharmacology, 165, 283–341.

    CAS  Google Scholar 

  25. Gray-Owen, S. D., & Blumberg, R. S. (2006). CEACAM1: Contact-dependent control of immunity. Nature Reviews Immunology, 6, 433–446.

    PubMed  CAS  Google Scholar 

  26. Hefta, S. A., Hefta, L. J., Lee, T. D., Paxton, R. J., & Shively, J. E. (1988). Carcinoembryonic antigen is anchored to membranes by covalent attachment to a glycosylphosphatidylinositol moiety: Identification of the ethanolamine linkage site. Proceedings of the National Academy of Sciences of the United States of America, 85(13), 4648–4652.

    PubMed  CAS  Google Scholar 

  27. Sack, T. L., Gum, J. R., Low, M. G., & Kim, Y. S. (1988). Release of carcinoembryonic antigen from human colon cancer cells by phosphatidylinositol-specific phospholipase C. Journal of Clinical Investigation, 82(2), 586–593.

    PubMed  CAS  Google Scholar 

  28. Naghibalhossaini, F., & Stanners, C. P. (2004). Minimal mutations are required to effect a radical change in function in CEA family members of the Ig superfamily. Journal of Cell Science, 117(5), 761–769.

    PubMed  CAS  Google Scholar 

  29. Dery, K. J., Gaur, S., Gencheva, M., Yen, Y., Shively, J. E., & Gaur, R. K. (2011). Mechanistic control of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) splice isoforms by the heterogeneous nuclear ribonuclear proteins hnRNP L, hnRNP A1, and hnRNPM. Journal of Biological Chemistry, 286(18), 16039–16051.

    PubMed  CAS  Google Scholar 

  30. Turbide, C., Kunath, T., Daniels, E., & Beauchemin, N. (1997). Optimal ratios of biliary glycoprotein isoforms required for inhibition of colonic tumor cell growth. Cancer Research, 57(13), 2781–2788.

    PubMed  CAS  Google Scholar 

  31. Gaur, S., Shively, J.E., Yen, Y., & Gaur, R.K. (2008). Altered splicing of CEACAM1 in breast cancer: Identification of regulatory sequences that control splicing of CEACAM1 into long or short cytoplasmic domain isoforms. Molecular Cancer, 7(46). doi:10.1186/1476-4598-1187-1146.

  32. Wang, L., Lin, S. H., Wu, W. G., Kemp, B. L., Walsh, G. L., Hong, W. K., & Mao, L. (2000). C-CAM1, a candidate tumor suppressor gene, is abnormally expressed in primary lung cancers. Clinical Cancer Research, 6(8), 2988–2993.

    PubMed  CAS  Google Scholar 

  33. Markel, G., Achdout, H., Katz, G., Ling, K. L., Salio, M., Gruda, R., Gazit, R., Mizrahi, S., Hanna, J., Gonen-Gross, T., Arnon, T. I., Lieberman, N., Stren, N., Nachmias, B., Blumberg, R. S., Steuer, G., Blau, H., Cerundolo, V., Mussaffi, H., & Mandelboim, O. (2004). Biological function of the soluble CEACAM1 protein and implications in TAP2-deficient patients. European Journal of Immunology, 34(8), 2138–2148.

    PubMed  CAS  Google Scholar 

  34. Draberova, L., Cerna, H., Brodska, H., Boubelik, M., Watt, S. M., Stanners, C. P., et al. (2000). Soluble isoforms of CEACAM1 containing the A2 domain: Increased serum levels in patients with obstructive jaundice and differences in 3-fucosyl-N-acetyl-lactosamine moiety. Immunology, 101(2), 279–287.

    PubMed  CAS  Google Scholar 

  35. Markel, G., Ortenberg, R., Seidman, R., Sapoznik, S., Koren-Morag, N., Besser, M. J., Bar, J., Shapira, R., Kubi, A., Nardini, G., Tessone, A., Treves, A. J., Winkler, E., Orenstein, A., & Schachter, J. (2010). Systemic dysregulation of CEACAM1 in melanoma patients. Cancer Immunology, Immunotherapy, 59, 215–230.

    PubMed  CAS  Google Scholar 

  36. Simeone, D. M., Baoan, J., Banerjee, M., Arumugham, T., Li, D., Anderson, M. A., Bamberger, A. M., Greenson, J., Brand, R. E., Ramachandran, V., & Logsdon, C. D. (2007). CEACAM1, a novel serum biomarker for pancreatic cancer. Pancreas, 34, 436–443.

    PubMed  CAS  Google Scholar 

  37. Tilki, D., Singer, B. B., Shariat, S. F., Behrend, A., Fernando, M., Irmak, S., Buchner, A., Hooper, A. T., Stief, C. G., Reich, O., & Ergün, S. (2010). CEACAM1: A novel urinary marker for bladder cancer detection. European Urology, 57(4), 648–654.

    PubMed  CAS  Google Scholar 

  38. Zhou, H., Fuks, A., Alcaraz, G., Bolling, T. J., & Stanners, C. P. (1993). Homophilic adhesion between Ig superfamily carcinoembryonic antigen molecules involves double reciprocal bonds. The Journal of Cell Biology, 122(4), 951–960.

    PubMed  CAS  Google Scholar 

  39. Thompson, J. A., Grunert, F., & Zimmermann, W. (1991). Carcinoembryonic antigen gene family: Molecular biology and clinical perspectives. Journal of Clinical Laboratory Analysis, 5, 344–366.

    PubMed  CAS  Google Scholar 

  40. Bjerner, J., Lebedin, Y., Bellanger, L., Kuroki, M., Shively, J. E., Varaas, T., Nustad, K., Hammarström, S., & Børmer, O. P. (2002). Protein epitopes in carcinoembryonic antigen. Report of the ISOBM TD8 workshop. Tumour Biology, 23(4), 249–262.

    PubMed  CAS  Google Scholar 

  41. Nap, M., Mollgard, K., Burtin, P., & Fleuren, G. J. (1988). Immunohistochemistry of carcino-embryonic antigen in the embryo, fetus and adult. Tumour Biology, 9(2–3), 145–153.

    PubMed  CAS  Google Scholar 

  42. Eades-Perner, A.-M., van der Putten, H., Hirth, A., Thompson, J., Neumaier, M., von Kleist, S., & Zimmermann, W. (1994). Mice transgenic for the human carcinoembryonic antigen gene maintain its spatiotemporal expression pattern. Cancer Research, 54, 4169–4176.

    PubMed  CAS  Google Scholar 

  43. Hammarstrom, S. (1999). The carcinoembryonic antigen (CEA) family: Structures, suggested functions and expression in normal and malignant tissues. Seminars in Cancer Biology, 9, 67–81.

    PubMed  CAS  Google Scholar 

  44. Jothy, S., Yuan, S. Y., & Shirota, K. (1993). Transcription of carcinoembryonic antigen in normal colon and colon carcinoma. In situ hybridization study and implication for a new in vivo functional model. American Journal of Pathology, 143(1), 250–257.

    PubMed  CAS  Google Scholar 

  45. Kodera, Y., Isobe, K., Yamauchi, M., Satta, T., Hasegawa, T., Oikawa, S., Kondoh, K., Akiyama, S., Itoh, K., Nakashima, I., & Taakagi, H. (1993). Expression of carcinoembryonic antigen (CEA) and nonspecific crossreacting antigen (NCA) in gastrointestinal cancer; the correlation with degree of differentiation. British Journal of Cancer, 68(1), 130–136.

    PubMed  CAS  Google Scholar 

  46. Tiernan, J. P., Perry, S. L., Verghese, E. T., West, N. P., Yeluri, S., Jayne, D. G., & Hughes, T. A. (2013). Carcinoembryonic antigen is the preferred biomarker for in vivo colorectal cancer targeting. British Journal of Cancer, 108(3), 662–667.

    PubMed  CAS  Google Scholar 

  47. Saadatmand, S., de Kruijf, E. M., Sajet, A., Dekker-Ensink, N. G., van Nes, J. G., Putter, H., Smit, V. T., van de Velde, C. J., Liefers, G. J., & Kuppen, P. J. (2013). Expression of cell adhesion molecules and prognosis in breast cancer. British Journal of Surgery, 100(2), 252–260.

    PubMed  CAS  Google Scholar 

  48. Scholzel, S., Zimmermann, W., Schwarzkopf, G., Grunert, F., Rogaczewski, B., & Thompson, J. (2000). Carcinoembryonic antigen family members CEACAM6 and CEACAM7 are differentially expressed in normal tissues and oppositely deregulated in hyperplastic colorectal polyps and early adenomas. American Journal of Pathology, 156(2), 595–605.

    PubMed  CAS  Google Scholar 

  49. Berling, B., Kolbinger, F., Grunert, F., Thompson, J. A., Brombacher, F., Buchegger, F., von Kleist, S., & Zimmermann, W. (1990). Cloning of a carcinoembryonic antigen gene family member expressed in leukocytes of chronic myeloid leukemia patients and bone marrow. Cancer Research, 50(20), 6534–6539.

    PubMed  CAS  Google Scholar 

  50. Hanenberg, H., Baumann, M., Quentin, I., Nagel, G., Grosse-Wilde, H., von Kleist, S., Gobel, U., Burdach, S., & Grunert, F. (1994). Expression of the CEA gene family members NCA-50/90 and NCA-160 (CD66) in childhood acute lymphoblastic leukemias (ALLs) and in cell lines of B-cell origin. Leukemia, 8(12), 2127–2133.

    PubMed  CAS  Google Scholar 

  51. Jantscheff, P., Terracciano, L., Lowy, A., Glatz-Krieger, K., Grunert, F., Micheel, B., Brumer, J., Laffer, U., Metzger, U., Herrmann, R., & Rachlitz, C. (2003). Expression of CEACAM6 in resectable colorectal cancer: A factor of independent prognostic significance. Journal of Clinical Oncology, 21, 3638–3646.

    PubMed  CAS  Google Scholar 

  52. Kim, K. S., Kim, J. T., Lee, S. J., Kang, M. A., Choe, I. S., Kang, Y. H., Kim, S. Y., Yeom, Y. I., Lee, Y. H., Kim, J. H., Kim, K. H., Kim, C. N., Kim, J. W., Nam, M. S., & Lee, H. G. (2013). Overexpression and clinical significance of carcinoembryonic antigen-related cell adhesion molecule 6 in colorectal cancer. Clinica Chimica Acta, 415, 12–19.

    CAS  Google Scholar 

  53. Blumenthal, R. D., Leon, E., Hansen, H.J., & Goldenberg, D.M. (2007). Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers. BioMedCentral Cancer, 7, 2. doi:10.1186/1471-2407-1187-1182.

  54. Frangsmyr, L., Baranov, V., Prall, F., Yeung, M. M., Wagener, C., & Hammarstrom, S. (1995). Cell- and region-specific expression of biliary glycoprotein and its messenger RNA in normal human colonic mucosa. Cancer Research, 55, 2963–2967.

    PubMed  CAS  Google Scholar 

  55. Prall, F., Nollau, P., Neumaier, M., Haubeck, H. D., Drzeniek, Z., Helmchen, U., Loning, T., & Wagener, C. (1996). CD66a (BGP), an adhesion molecule of the carcinoembryonic antigen family, is expressed in epithelium, endothelium, and myeloid cells in a wide range of normal human tissues. Journal of Histochemistry and Cytochemistry, 44(1), 35–41.

    PubMed  CAS  Google Scholar 

  56. Sundberg, U., & Obrink, B. (2002). CEACAM1 isoforms with different cytoplasmic domains show different localization, organization and adhesive properties in polarized epithelial cells. Journal of Cell Science, 115(Pt 6), 1273–1284.

    PubMed  CAS  Google Scholar 

  57. Sundberg, U., Beauchemin, N., & Obrink, B. (2004). The cytoplasmic domain of CEACAM1-L controls its lateral localization and the organization of desmosomes in polarized epithelial cells. Journal of Cell Science, 117(pt 7), 1091–1104.

    PubMed  CAS  Google Scholar 

  58. Neumaier, M., Paululat, S., Chan, A., Matthaes, P., & Wagener, C. (1993). Biliary glycoprotein, a potential human cell adhesion molecule, is down-regulated in colorectal carcinomas. Proceedings of the National Academy of Sciences of the United States of America, 90, 10744–10748.

    PubMed  CAS  Google Scholar 

  59. Rosenberg, M., Nédellec, P., Jothy, S., Fleiszer, D., Turbide, C., & Beauchemin, N. (1993). The expression of mouse biliary glycoprotein, a carcinoembryonic antigen-related gene, is down-regulated in malignant mouse tissues. Cancer Research, 53, 4938–4945.

    PubMed  CAS  Google Scholar 

  60. Busch, C., Hanssen, T. A., Wagener, C., & Obrink, B. (2002). Down-regulation of CEACAM1 in human prostate cancer: Correlation with loss of cell polarity, increased proliferation rate, and Gleason grade 3 to 4 transition. Human Pathology, 33(3), 290–298.

    PubMed  CAS  Google Scholar 

  61. Cruz, P. V., Wakai, T., Shirai, Y., Yokoyama, N., & Hatakeyama, K. (2005). Loss of carcinoembryonic antigen-related cell adhesion molecule 1 expression is an adverse prognostic factor in hepatocellular carcinoma. Cancer, 104(2), 354–360.

    PubMed  CAS  Google Scholar 

  62. Huang, J., Simpson, J. F., Glackin, C., Riethorf, L., Wagener, C., & Shively, J. E. (1998). Expression of biliary glycoprotein (CD66a) in normal and malignant breast epithelial cells. Anticancer Research, 18(5A), 3203–3212.

    PubMed  CAS  Google Scholar 

  63. Nittka, S., Gunther, J., Ebisch, C., Erbersdobler, A., & Neumaier, M. (2004). The human tumor suppressor CEACAM1 modulates apoptosis and is implicated in early colorectal tumorigenesis. Oncogene, 23(58), 9306–9313.

    PubMed  CAS  Google Scholar 

  64. Kunath, T., Ordonez-Garcia, C., Turbide, C., & Beauchemin, N. (1995). Inhibition of colonic tumor cell growth by biliary glycoprotein. Oncogene, 11(11), 2375–2382.

    PubMed  CAS  Google Scholar 

  65. Hsieh, J.-T., Luo, W., Song, W., Wang, Y., Kleinerman, D. I., Van, N. T., & Lin, S.-H. (1995). Tumor suppressive role of an androgen-regulated epithelial cell adhesion molecule (C-CAM) in prostate carcinoma cell revealed by sense and antisense approaches. Cancer Research, 55, 190–197.

    PubMed  CAS  Google Scholar 

  66. Thies, A., Moll, I., Berger, J., Wagener, C., Brummer, J., Schulze, H. J., Brunner, G., & Schumacher, U. (2002). CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. Journal of Clinical Oncology, 20(10), 2530–2536.

    PubMed  CAS  Google Scholar 

  67. Laack, E., Nikbakht, H., Peters, A., Kugler, C., Jasiewicz, Y., Edler, L., Brummer, J., Schumacher, U., & Hossfeld, D. K. (2002). Expression of CEACAM1 in adenocarcinoma of the lung: A factor of independent prognostic significance. Journal of Clinical Oncology, 20, 4279–4284.

    PubMed  Google Scholar 

  68. Zhou, C. J., Liu, B., Zhu, K. X., Zhang, Q. H., Zhang, T. G., Xu, W. H., Wang, H. B., Yu, W. H., Qu, Y. D., Wang, H. J., Wu, H. L., Sun, S. Z., & Guo, J. Q. (2009). The different expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and possible roles in gastric carcinomas. Pathology Research and Practice, 205(7), 483–489.

    CAS  Google Scholar 

  69. Liu, W., Wei, W., Winer, D., Bamberger, A. M., Bamberger, C., Wagener, C., Ezzat, S., & Asa, S. L. (2007). CEACAM1 impedes thyroid cancer growth but promotes invasiveness: A putative mechanism for early metastases. Oncogene, 26, 2747–2758.

    PubMed  Google Scholar 

  70. Oliveira-Ferrer, L., Tilki, D., Ziegeler, G., Hauschild, J., Loges, S., Irmak, S., Kilic, E., Huland, H., Friedrich, M., & Ergun, S. (2004). Dual role of carcinoembryonic antigen-related cell adhesion molecule 1 in angiogenesis and invasion of human urinary bladder cancer. Cancer Research, 64(24), 8932–8938.

    PubMed  CAS  Google Scholar 

  71. Fiori, V., Magnani, M., & Cianfriglia, M. (2012). The expression and modulation of CEACAM1 and tumor cell transformation. Annali dell’Intituto Superiore di Sanita, 48(2), 161–171.

    CAS  Google Scholar 

  72. Ieda, J., Yokoyama, S., Tamura, K., Takifuji, K., Hotta, T., Matsuda, K., Oku, Y., Nasu, T., Kiriyama, S., Yamamoto, N., Makamura, Y., Shively, J. E., & Yamaue, H. (2011). Re-expression of CEACAM1 long cytoplasmic domain isoform is associated with invasion and migration of colorectal cancer. International Journal of Cancer, 129(6), 1351–1361.

    CAS  Google Scholar 

  73. Tilki, D., Irmak, S., Oliveira-Ferrer, L., Hauschild, J., Miethe, K., Atakaya, H., Hammerer, P., Friedrich, M. G., Schuch, G., Galalae, R., Stief, C. G., Kilic, E., Hurland, H., & Ergun, S. (2006). CEA-related cell adhesion molecule-1 is involved in angiogenic switch in prostate cancer. Oncogene, 25, 4965–4974.

    PubMed  CAS  Google Scholar 

  74. Thirunavukarasu, P., Sukumar, S., Sathaiah, M., Mahan, M., Pragatheeshwar, K. D., Pingpank, J. F., Zeh, H., 3rd, Bartels, C. J., Lee, K. K., & Bartlett, D. L. (2011). C-stage in colon cancer: Implications of carcinoembryonic antigen biomarker in staging, prognosis, and management. Journal of the National Cancer Institute, 103(8), 689–697.

    PubMed  Google Scholar 

  75. Clarke, P., Mann, J., Simpson, J. F., Rickard-Dickson, K., & Primus, F. J. (1998). Mice transgenic for human carcinoembryonic antigen as a model for immunotherapy. Cancer Research, 58(7), 1469–1477.

    PubMed  CAS  Google Scholar 

  76. Thompson, J. A., Eades-Perner, A. M., Ditter, M., Muller, W. J., & Zimmermann, W. (1997). Expression of transgenic carcinoembryonic antigen (CEA) in tumor-prone mice: An animal model for CEA-directed tumor immunotherapy. International Journal of Cancer, 72(1), 197–202.

    CAS  Google Scholar 

  77. Johnson, R. L., & Fleet, J. C. (2013). Animal models of colorectal cancer. Cancer and Metastasis Reviews, 32(1–2), 39–61.

    PubMed  Google Scholar 

  78. Chan, C. H., Cook, D., & Stanners, C. P. (2006). Increased colon tumor susceptibility in azoxymethane treated CEABAC transgenic mice. Carcinogenesis, 27(9), 1909–1916.

    PubMed  CAS  Google Scholar 

  79. Nambiar, P. R., Girnun, G., Lillo, N. A., Guda, K., Whiteley, H. E., & Rosenberg, D. W. (2003). Preliminary analysis of azoxymethane induced colon tumors in inbred mice commonly used as transgenic/knockout progenitors. International Journal of Oncology, 22, 145–150.

    PubMed  CAS  Google Scholar 

  80. Ilantzis, C., Jothy, S., Alpert, L. C., Draber, P., & Stanners, C. P. (1997). Cell-surface levels of human carcinoembryonic antigen are inversely correlated with colonocyte differentiation in colon carcinogenesis. Laboratory Investigation, 76, 703–716.

    PubMed  CAS  Google Scholar 

  81. Benchimol, S., Fuks, A., Jothy, S., Beauchemin, N., Shirota, K., & Stanners, C. P. (1989). Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell, 57(2), 327–334.

    PubMed  CAS  Google Scholar 

  82. Jessup, J. M., Kim, J. C., Thomas, P., Ishii, S., Ford, R., Shively, J. E., Durbin, H., Stanners, C. P., Fuks, A., Zhou, H., Hansen, H. J., Goldenberg, D. M., & Steele, G., Jr. (1993). Adhesion to carcinoembryonic antigen by human colorectal carcinoma cells involves at least two epitopes. International Journal of Cancer, 55(2), 262–268.

    CAS  Google Scholar 

  83. Charbonneau, J., & Stanners, C. P. (1999). Role of carbohydrate structures in CEA-mediated intercellular adhesion. Cell Adhesion and Communication, 7(3), 233–244.

    PubMed  CAS  Google Scholar 

  84. Eidelman, F. J., Fuks, A., DeMarte, L., Taheri, M., & Stanners, C. P. (1993). Human carcinoembryonic antigen, an intercellular adhesion molecule, blocks fusion and differentiation of rat myoblasts. The Journal of Cell Biology, 123(2), 467–475.

    PubMed  CAS  Google Scholar 

  85. Ilantzis, C., DeMarte, L., Screaton, R. A., & Stanners, C. P. (2002). Deregulated expression of the human tumor marker CEA and CEA family member CEACAM6 disrupts tissue architecture and blocks colonocyte differentiation. Neoplasia, 4(2), 151–163.

    PubMed  CAS  Google Scholar 

  86. Ordonez, C., Screaton, R. A., Ilantzis, C., & Stanners, C. P. (2000). Human carcinoembryonic antigen functions as a general inhibitor of anoikis. Cancer Research, 60(13), 3419–3424.

    PubMed  CAS  Google Scholar 

  87. Camacho-Leal, P., Zhai, A. B., & Stanners, C. P. (2007). A co-clustering model involving alpha5beta1 integrin for the biological effects of GPI-anchored human carcinoembryonic antigen (CEA). Journal of Cell Physiology, 211(3), 791–802.

    CAS  Google Scholar 

  88. Saeland, E., Belo, A. I., Mongera, S., van Die, I., Meijer, G. A., & van Kooyk, Y. (2012). Differential glycosylation of MUC1 and CEACAM5 between normal mucosa and tumour tissue of colon cancer patients. International Journal of Cancer, 131(1), 117–128.

    CAS  Google Scholar 

  89. van Gisbergen, K. P., Aarnoudse, C. A., Meijer, G. A., Geijtenbeek, T. B., & van Kooyk, Y. (2005). Dendritic cells recognize tumor-specific glycosylation of carcinoembryonic antigen on colorectal cancer cells through dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin. Cancer Research, 65(13), 5935–5944.

    PubMed  Google Scholar 

  90. Engering, A., Geijtenbeek, T. B., van Vliet, S. J., Wijers, M., van Liempt, E., Demaurex, N., Lanzavecchia, A., Fransen, J., Figdor, C. G., Piguet, V., & van Kooyk, Y. (2002). The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. Journal of Immunology, 168(5), 2118–2126.

    CAS  Google Scholar 

  91. Stern, N., Markel, G., Arnon, T. I., Gruda, R., Wong, H., Gray-Owen, S. D., & Mandelboim, O. (2005). Carcinoembryonic antigen (CEA) inhibits NK killing via interaction with CEA-related cell adhesion molecule 1. Journal of Immunology, 174(11), 6692–6701.

    CAS  Google Scholar 

  92. Conaghan, P., Ashraf, S., Tytherleigh, M., Wilding, J., Tchilian, E., Bicknell, D., Mortensen, N. J., & Bodmer, W. (2008). Targeted killing of colorectal cancer cell lines by a humanised IgG1 monoclonal antibody that binds to membrane-bound carcinoembryonic antigen. British Journal of Cancer, 98(7), 1217–1225.

    PubMed  CAS  Google Scholar 

  93. Zheng, C., Feng, J., Lu, D., Wang, P., Xing, S., Coll, J. L., Yang, D., & Yan, X. (2011). A novel anti-CEACAM5 monoclonal antibody, CC4, suppresses colorectal tumor growth and enhances NK cells-mediated tumor immunity. PLoS One, 6(6), e21146.

    PubMed  CAS  Google Scholar 

  94. Berinstein, N. L. (2002). Carcinoembryonic antigen as a target for therapeutic anticancer vaccines: A review. Journal of Clinical Oncology, 20(8), 2197–2207.

    PubMed  CAS  Google Scholar 

  95. Hodge, J. W., Poole, D. J., Aarts, W. M., Gómez Yafal, A., Gritz, L., & Schlom, J. (2003). Modified vaccinia virus Ankara recombinants are as potent as vaccinia recombinants in diversified prime and boost vaccine regimens to elicit therapeutic antitumor responses. Cancer Research, 63(22), 7942–7949.

    PubMed  CAS  Google Scholar 

  96. Gulley, J. L., Arlen, P. M., Tsang, K. Y., Yokokawa, J., Palena, C., Poole, D. J., Remondo, C., Cereda, V., Jones, J. L., Pazdur, M. P., Higgins, J. P., Hodge, J. W., Steinberg, S. M., Kotz, H., Dahut, W. L., & Schlom, J. (2008). Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma. Clinical Cancer Research, 14(10), 3060–3069.

    PubMed  CAS  Google Scholar 

  97. Sakakibara, M., Kanto, T., Hayakawa, M., Kuroda, S., Miyatake, H., Itose, I., Miyazaki, M., Kakita, N., Higashitani, K., Matsubara, T., Hiramatsu, N., Kasahara, A., Takehara, T., & Hayashi, N. (2011). Comprehensive immunological analyses of colorectal cancer patients in the phase I/II study of quickly matured dendritic cell vaccine pulsed with carcinoembryonic antigen peptide. Cancer Immunology, Immunotherapy, 60(11), 1565–1575.

    PubMed  CAS  Google Scholar 

  98. Hong, X., Dong, T., Hu, J., Yi, T., Li, W., Zhang, Z., Lin, S., & Niu, W. (2013). Synergistical toll-like receptors activated dendritic cells induce antitumor effects against carcinoembryonic antigen-expressing colon cancer. International Journal of Colorectal Disease, 28(1), 25–33.

    PubMed  Google Scholar 

  99. Crosti, M., Longhi, R., Consogno, G., Melloni, G., Zannini, P., & Protti, M. P. (2006). Identification of novel subdominant epitopes on the carcinoembryonic antigen recognized by CD4+ T cells of lung cancer patients. Journal of Immunology, 176(8), 5093–5099.

    CAS  Google Scholar 

  100. Abdul-Wahid, A., Huang, E. H., Lu, H., Flanagan, J., Mallick, A. I., & Gariépy, J. (2012). A focused immune response targeting the homotypic binding domain of the carcinoembryonic antigen blocks the establishment of tumor foci in vivo. International Journal of Cancer, 131(12), 2839–2851.

    CAS  Google Scholar 

  101. Orava, E. W., Abdul-Wahid, A., Huang, E. H., Mallick, A. I., & Gariépy, J. (2013). Blocking the attachment of cancer cells in vivo with DNA aptamers displaying anti-adhesive properties against the carcinoembryonic antigen. Molecular Oncology, S1574–7891(13), 00061–00066. doi:10.1016/j.molonc.2013.1003.1005.

    Google Scholar 

  102. Wilmanns, C., Steinhauer, S., Großmann, J., Schmitt-Gräff, A., & Ruf, G. (2012). Cooperate concept of metastasis: Site-specific requirement of activated differentiation and dynamic deterioration. Cancer and Metastasis Reviews, 31(1–2), 269–276.

    PubMed  CAS  Google Scholar 

  103. Spelt, L., Andersson, B., Nilsson, J., & Andersson, R. (2012). Prognostic models for outcome following liver resection for colorectal cancer metastases: A systematic review. European Journal of Surgical Oncology, 38(1), 16–24.

    PubMed  CAS  Google Scholar 

  104. Thomas, P., Forse, R. A., & Bajenova, O. (2011). Carcinoembryonic antigen (CEA) and its receptor hnRNP M are mediators of metastasis and the inflammatory response in the liver. Clinical & Experimental Metastasis, 28(8), 923–932.

    CAS  Google Scholar 

  105. Edmiston, K. H., Gangopadhyay, A., Shoji, Y., Nachman, A. P., Thomas, P., & Jessup, J. M. (1997). In vivo induction of murine cytokine production by carcinoembryonic antigen. Cancer Research, 57(19), 4432–4436.

    PubMed  CAS  Google Scholar 

  106. Jessup, J. M., Laguinge, L., Lin, S., Samara, R., Aufman, K., Battle, P., Frantz, M., Edmiston, K. H., & Thomas, P. (2004). Carcinoembryonic antigen induction of IL-10 and IL-6 inhibits hepatic ischemic/reperfusion injury to colorectal carcinoma cells. International Journal of Cancer, 111(3), 332–337.

    CAS  Google Scholar 

  107. Gangopadhyay, A., Bajenova, O., Kelly, T. M., & Thomas, P. (1996). Carcinoembryonic antigen induces cytokine expression in Kuppfer cells: Implications for hepatic metastasis from colorectal cancer. Cancer Research, 56, 4805–4810.

    PubMed  CAS  Google Scholar 

  108. Samara, R. N., Laguinge, L. M., & Jessup, J. M. (2007). Carcinoembryonic antigen inhibits anoikis in colorectal carcinoma cells by interfering with TRAIL-R2 (DR5) signaling. Cancer Research, 67(10), 4774–4782.

    PubMed  CAS  Google Scholar 

  109. Li, Y., Cao, H., Jiao, Z., Pakala, S. B., Sirigiri, D. N., Li, W., Kumar, R., & Mishra, L. (2010). Carcinoembryonic antigen interacts with TGF-β receptor and inhibits TGF-β signaling in colorectal cancers. Cancer Research, 70(20), 8159–8168.

    PubMed  CAS  Google Scholar 

  110. Massagué, J. (2008). TGFbeta in cancer. Cell, 134(2), 215–230.

    PubMed  Google Scholar 

  111. Blumenthal, R. D., Hansen, H. J., & Goldenberg, D. M. (2005). Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (carcinoembryonic antigen). Cancer Research, 65(19), 8809–8817.

    PubMed  CAS  Google Scholar 

  112. Maraqa, L., Cummings, M., Peter, M. B., Shaaban, A. M., Horgan, K., Hanby, A. M., & Speirs, V. (2008). Carcinoembryonic antigen cell adhesion molecule 6 predicts breast cancer recurrence following adjuvant tamoxifen. Clinical Cancer Research, 14(2), 405–411.

    PubMed  CAS  Google Scholar 

  113. Lewis-Wambi, J. S., Cunliffe, H. E., Kim, H. R., Willis, A. L., & Jordan, V. C. (2008). Overexpression of CEACAM6 promotes migration and invasion of oestrogen-deprived breast cancer cells. European Journal of Cancer, 44(12), 1770–1779.

    PubMed  CAS  Google Scholar 

  114. Witzens-Harig, M., Hose, D., Jünger, S., Pfirschke, C., Khandelwal, N., Umansky, L., Seckinger, A., Conrad, H., Brackertz, B., Rème, T., Gueckel, B., Meißner, T., Hundemer, M., Ho, A.D., Rossi, J.F., Neben, K., Bernhard, H., Goldschmidt, H., Klein, B., & Beckhove, P. (2013). Tumor cells in multiple myeloma patients inhibit myeloma-reactive T cells through carcinoembryonic-antigen-related cell adhesion molecule-6. Blood, 121, 4493–4503.

  115. Kobayashi, M., Miki, Y., Ebina, M., Abe, K., Mori, K., Narumi, S., Suzuki, T., Sato, I., Maemondo, M., Endo, C., Inoue, A., Kumamoto, H., Kondo, T., Yamada-Okabe, H., Nukiwa, T., & Sasano, H. (2012). Carcinoembryonic antigen-related cell adhesion molecules as surrogate markers for EGFR inhibitor sensitivity in human lung adenocarcinoma. British Journal of Cancer, 107(10), 1745–1753.

    PubMed  CAS  Google Scholar 

  116. Duxbury, M. S., Ito, H., Zinner, M. J., Ashley, S. W., & Whang, E. E. (2004). CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells. Oncogene, 23(2), 465–473.

    PubMed  CAS  Google Scholar 

  117. Duxbury, M. S., Ito, H., Benoit, E., Waseem, T., Ashley, S. W., & Whang, E. E. (2004). A novel role for carcinoembryonic antigen-related cell adhesion molecule 6 as a determinant of gemcitabine chemoresistance in pancreatic adenocarcinoma cells. Cancer Research, 64(11), 3987–3993.

    PubMed  CAS  Google Scholar 

  118. Duxbury, M. S., Ito, H., Benoit, E., Ashley, S. W., & Whang, E. E. (2004). CEACAM6 is a determinant of pancreatic adenocarcinoma cellular invasiveness. British Journal of Cancer, 91(7), 1384–1390.

    PubMed  CAS  Google Scholar 

  119. Duxbury, M. S., Matros, E., Clancy, T., Bailey, G., Doff, M., Zinner, M. J., Ashley, S. W., Maitra, A., Redston, M., & Whang, E. E. (2005). CEACAM6 is a novel biomarker in pancreatic adenocarcinoma and PanIN lesions. Annals of Surgery, 241(3), 491–496.

    PubMed  Google Scholar 

  120. Duxbury, M. S., Ito, H., Ashley, S. W., & Whang, E. E. (2004). CEACAM6 as a novel target for indirect type 1 immunotoxin-based therapy in pancreatic adenocarcinoma. Biochemical and Biophysical Research Communications, 317(3), 837–843.

    PubMed  CAS  Google Scholar 

  121. Strickland, L. A., Ross, J., Williams, S., Ross, S., Romero, M., Spencer, S., Erickson, R., Sutcliffe, J., Verbeke, C., Polakis, P., van Bruggen, N., & Koeppen, H. (2009). Preclinical evaluation of carcinoembryonic cell adhesion molecule (CEACAM) 6 as potential therapy target for pancreatic adenocarcinoma. The Journal of Pathology, 218(3), 380–390.

    PubMed  CAS  Google Scholar 

  122. Oikawa, S., Inuzuka, C., Kuroki, M., Arakawa, F., Matsuoka, Y., Kosaki, G., & Nakazato, H. (1991). A specific heterotypic cell adhesion activity between members of carcinoembryonic antigen family, W272 and NCA, is mediated by N-domains. Journal of Biological Chemistry, 266(13), 7995–8001.

    PubMed  CAS  Google Scholar 

  123. Kuroki, M., Abe, H., Imakiirei, T., Liao, S., Uchida, H., Yamauchi, Y., et al. (2001). Identification and comparison of residues critical for cell-adhesion activities of two neutrophil CD66 antigens, CEACAM6 and CEACAM8. Journal of Leukocyte Biology, 70(4), 543–550.

    PubMed  CAS  Google Scholar 

  124. Obrink, B. (1991). C-CAM (cell-CAM 105)—A member of the growing immunoglobulin superfamily of cell adhesion proteins. Bioessays, 13(5), 227–234.

    PubMed  CAS  Google Scholar 

  125. Klaile, E., Vorontsova, O., Sigmundsson, K., Müller, M. M., Singer, B. B., Ofverstedt, L. G., Svensson, S., Skoglund, U., & Obrink, B. (2009). The CEACAM1 N-terminal Ig domain mediates cis- and trans-binding and is essential for allosteric rearrangements of CEACAM1 microclusters. The Journal of Cell Biology, 187(4), 553–567.

    PubMed  CAS  Google Scholar 

  126. Watt, S. M., Teixeira, A. M., Zhou, G. Q., Doyonnas, R., Zhang, Y., Grunert, F., et al. (2001). Homophilic adhesion of human CEACAM1 involves N-terminal domain interactions: Structural analysis of the binding site. Blood, 98(5), 1469–1479.

    PubMed  CAS  Google Scholar 

  127. Tan, K., Zelus, B. D., Meijers, R., Liu, J. H., Bergelson, J. M., Duke, N., Zhang, R., Joachimiak, A., Holmes, K. V., & Wang, J. H. (2002). Crystal structure of murine sCEACAM1a[1, 4]: A coronavirus receptor in the CEA family. EMBO Journal, 21(9), 2076–2086.

    PubMed  CAS  Google Scholar 

  128. Scheffrahn, I., Singer, B. B., Sigmundsson, K., Lucka, L., & Obrink, B. (2005). Control of density-dependent, cell state-specific signal transduction by the cell adhesion molecule CEACAM1, and its influence on cell cycle regulation. Experimental Cell Research, 307(2), 427–435.

    PubMed  CAS  Google Scholar 

  129. Lucka, L., Fernando, M., Grunow, D., Kannicht, C., Horst, A. K., Nollau, P., & Wagener, C. (2005). Identification of Lewis X structures of the cell adhesion molecule CEACAM1 from human granulocytes. Glycobiology, 15(1), 87–100.

    PubMed  CAS  Google Scholar 

  130. Lawson, E. L., Mills, D. R., Brilliant, K. E., & Hixson, D. C. (2012). The transmembrane domain of CEACAM1-4S is a determinant of anchorage independent growth and tumorigenicity. PLoS One, 7(1), e29606.

    PubMed  CAS  Google Scholar 

  131. Margolis, R. N., Taylor, S. I., Seminara, D., & Hubbard, A. L. (1988). Identification of pp 120, an endogenous substrate for the hepatocyte insulin receptor tyrosine kinase, as an integral membrane glycoprotein of the bile canalicular domain. Proceedings of the National Academy of Sciences of the United States of America, 85, 7256–7259.

    PubMed  CAS  Google Scholar 

  132. Afar, D. E., Stanners, C. P., & Bell, J. C. (1992). Tyrosine phosphorylation of biliary glycoprotein, a cell adhesion molecule related to carcinoembryonic antigen. Biochimica et Biophysica Acta, 1134(1), 46–52.

    PubMed  CAS  Google Scholar 

  133. Brümmer, J., Neumaier, M., Göpfert, C., & Wagener, C. (1995). Association of pp 60c-src with biliary glycoprotein (CD66a), an adhesion molecule of the carcinoembryonic antigen family downregulated in colorectal carcinomas. Oncogene, 11, 1649–1655.

    PubMed  Google Scholar 

  134. Skubitz, K. M., Campbell, K. D., Ahmed, K., & Skubitz, A. P. (1995). CD66 family members are associated with tyrosine kinase activity in human neutrophils. Journal of Immunology, 155(11), 5382–5390.

    CAS  Google Scholar 

  135. Najjar, S. M., Accili, D., Philippe, N., Jernberg, J., Margolis, R., & Taylor, S. I. (1993). pp 120/ecto-ATPase, an endogenous substrate of the insulin receptor tyrosine kinase, is expressed as two variably spliced isoforms. Journal of Biological Chemistry, 268(2), 1201–1206.

    PubMed  CAS  Google Scholar 

  136. Formisano, P., Najjar, S. M., Gross, C. N., Philippe, N., Oriente, F., Kern-Buell, C. L., Accili, D., & Gorden, P. (1995). Receptor-mediated internalization of insulin. Potential role of pp 120/HA4, a substrate of the insulin receptor kinase. Journal of Biological Chemistry, 270(41), 24073–24077.

    PubMed  CAS  Google Scholar 

  137. Abou-Rjaily, G. A., Lee, S. J., May, D., Al-Share, Q. Y., Ruch, R. J., Neumaier, M., Kalthoff, H., Lin, S. H., & Najjar, S. M. (2004). CEACAM1 modulates epidermal growth factor receptor-mediated cell proliferation. Journal of Clinical Investigation, 114, 944–952.

    PubMed  CAS  Google Scholar 

  138. Beauchemin, N., Kunath, T., Robitaille, J., Chow, B., Turbide, C., Daniels, E., & Veillette, A. (1997). Association of biliary glycoprotein with protein tyrosine phosphatase SHP-1 in malignant colon epithelial cells. Oncogene, 14, 783–790.

    PubMed  CAS  Google Scholar 

  139. Huber, M., Izzi, L., Grondin, P., Houde, C., Kunath, T., Veillette, A., & Beauchemin, N. (1999). The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells. Journal of Biological Chemistry, 274(1), 335–344.

    PubMed  CAS  Google Scholar 

  140. Müller, M. M., Klaile, E., Vorontsova, O., Singer, B. B., & Obrink, B. (2009). Homophilic adhesion and CEACAM1-S regulate dimerization of CEACAM1-L and recruitment of SHP-2 and c-Src. The Journal of Cell Biology, 187(4), 569–581.

    PubMed  Google Scholar 

  141. Edlund, M., Wikstrom, K., Toomik, R., Ek, P., & Obrink, B. (1998). Characterization of protein kinase C-mediated phosphorylation of the short cytoplasmic domain isoform of C-CAM. FEBS Letters, 425(1), 166–170.

    PubMed  CAS  Google Scholar 

  142. Fournes, B., Sadekova, S., Turbide, C., Létourneau, S., & Beauchemin, N. (2001). The CEACAM1-L Ser503 residue is crucial for inhibition of colon cancer cell tumorigenicity. Oncogene, 20(2), 219–230.

    PubMed  CAS  Google Scholar 

  143. Poy, M. N., Yang, Y., Rezaei, K., Fernstrom, M. A., Lee, A. D., Kido, Y., Erickson, S. K., & Najjar, S. M. (2002). CEACAM1 regulates insulin clearance in liver. Nature Genetics, 30(3), 270–276.

    PubMed  Google Scholar 

  144. Li, Y., & Shively, J. E. (2013). CEACAM1 regulates Fas-mediated apoptosis in Jurkat T-cells via its interaction with β-catenin. Experimental Cell Research. doi:10.1016/j.yexcr.2013.1002.1020.

    Google Scholar 

  145. Fiset, A., Xu, E., Marette, A., Pelletier, G., Siminovitch, K. A., Olivier, M., Beauchemin, N., & Faure, R. (2007). Compartmentalized CDK2 is connected with SHP-1 and β-catenin and regulates insulin internalization. Cell Signalling, 23(5), 911–919.

    Google Scholar 

  146. Li, C., Chen, C. J., & Shively, J. E. (2009). Mutational analysis of the cytoplasmic domain of CEACAM1-4L in humanized mammary glands reveals key residues involved in lumen formation: Stimulation by Thr-457 and inhibition by Ser-461. Experimental Cell Research, 315(7), 1225–1233.

    PubMed  CAS  Google Scholar 

  147. Hunter, I., Sawa, H., Edlund, M., & Obrink, B. (1996). Evidence for regulated dimerization of cell–cell adhesion molecule (C-CAM) in epithelial cells. Biochemical Journal, 320(Pt 3), 847–853.

    PubMed  CAS  Google Scholar 

  148. Edlund, M., Blikstad, I., & Obrink, B. (1996). Calmodulin binds to specific sequences in the cytoplasmic domain of C-CAM and down-regulates C-CAM self-association. Journal of Biological Chemistry, 271(3), 1393–1399.

    PubMed  CAS  Google Scholar 

  149. Jin, L., Li, Y., Chen, C. J., Sherman, M. A., Le, K., & Shively, J. E. (2008). Direct interaction of tumor suppressor CEACAM1 with beta-catenin: Interaction of key residues in the long cytoplasmic domain. Experimental Biology & Medicine (Maywood), 233(7), 849–859.

    CAS  Google Scholar 

  150. Houde, C., Roy, S., Leung, N., Nicholson, D. W., & Beauchemin, N. (2003). The cell adhesion molecule CEACAM1-L is a substrate of caspase-3-mediated cleavage in apoptotic mouse intestinal cells. Journal of Biological Chemistry, 278(19), 16929–16935.

    PubMed  CAS  Google Scholar 

  151. Leung, N., Turbide, C., Balachandra, B., Marcus, V., & Beauchemin, N. (2008). Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1(−/−) mice. Oncogene, 27(36), 4943–4953.

    PubMed  CAS  Google Scholar 

  152. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646–674.

    PubMed  CAS  Google Scholar 

  153. Najjar, S. M. (2002). Regulation of insulin action by CEACAM1. Trends in Endocrinology and Metabolism, 13, 240–245.

    PubMed  CAS  Google Scholar 

  154. Pollak, M. (2008). Insulin and insulin-like growth factor signalling in neoplasia. Nature Reviews. Cancer, 8(12), 915–928.

    PubMed  CAS  Google Scholar 

  155. Poy, M. N., Ruch, R. J., Fernstrom, M. A., Okabayashi, Y., & Najjar, S. M. (2002). Shc and CEACAM1 interact to regulate the mitogenic action of insulin. Journal of Biological Chemistry, 277(2), 1076–1084.

    PubMed  CAS  Google Scholar 

  156. Xu, E., Leung, N., Dubois, M. J., Charbonneau, A., Streichert, T., Elcheby, M., Turbide, C., Lévy, E., Beauchemin, N., & Marette, A. (2009). Targeted disruption of Ceacam1 promotes diet-induced hepatic steatosis and insulin resistance. Endocrinology, 150, 3503–3512.

    PubMed  CAS  Google Scholar 

  157. Lee, S. J., Heinrich, G., Fedorova, L., Al-Share, Q. Y., Ledford, K. J., Fernstrom, M. A., McInerney, M. F., Erickson, S. K., Gatto-Weis, C., & Najjar, S. M. (2008). Development of nonalcoholic steatohepatitis in insulin-resistant liver-specific S503A carcinoembryonic antigen-related cell adhesion molecule 1 mutant mice. Gastroenterology, 135(6), 2084–2095.

    PubMed  CAS  Google Scholar 

  158. Najjar, S. M., Yang, Y., Dai, T., Fernström, M. A., Lee, S. J., DeAngelis, A. M., Abou Rjaily, G. A., Al-Share, Q. Y., Dai, T., Miller, T. A., Ratnam, S., Ruch, R. J., Smith, S., Lin, S. H., Beauchemin, N., & Oyarce, A. M. (2005). Insulin acutely decreases hepatic fatty acid synthase activity. Cell Metabolism, 2(1), 43–53.

    PubMed  CAS  Google Scholar 

  159. Flavin, R., Peluso, S., Nguyen, P. L., & Loda, M. (2010). Fatty acid synthase as a potential therapeutic target in cancer. Future Oncology, 6(4), 551–562.

    PubMed  CAS  Google Scholar 

  160. Lee, W. (2011). The CEACAM1 expression is decreased in the liver of severely obese patients with or without diabetes. Diagnostic Pathology, 6, 40.

    PubMed  Google Scholar 

  161. Sun, B., & Karin, M. (2012). Obesity, inflammation, and liver cancer. Journal of Hepatology, 56(3), 704–713.

    PubMed  CAS  Google Scholar 

  162. Janakiram, N. B., Mohammed, A., & Rao, C. V. (2011). Role of lipoxins, resolvins, and other bioactive lipids in colon and pancreatic cancer. Cancer and Metastasis Reviews, 30(3–4), 507–523.

    PubMed  CAS  Google Scholar 

  163. Cathcart, M. C., Lysaght, J., & Pidgeon, G. P. (2011). Eicosanoid signalling pathways in the development and progression of colorectal cancer: Novel approaches for prevention/intervention. Cancer and Metastasis Reviews, 30(3–4), 363–385.

    PubMed  CAS  Google Scholar 

  164. Higashiyama, S., Abraham, J. A., Miller, J., Fiddes, J. C., & Klagsbrun, M. (1991). A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science, 251(4996), 936–939.

    PubMed  CAS  Google Scholar 

  165. Díaz, B., Yuen, A., Iizuka, S., Higashiyama, S., & Courtneidge, S. A. (2013). Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. The Journal of Cell Biology, 201(2), 279–292.

    PubMed  Google Scholar 

  166. Kammerer, R., Hahn, S., Singer, B. B., Luo, J. S., & von Kleist, S. (1998). Biliary glycoprotein (CD66a), a cell adhesion molecule of the immunoglobulin superfamily, on human lymphocytes: Structure, expression and involvement in T cell activation. European Journal of Immunology, 28(11), 3664–3674.

    PubMed  CAS  Google Scholar 

  167. Singer, B. B., Scheffrahn, I., Heymann, R., Sigmundsson, K., Kammerer, R., & Obrink, B. (2002). Carcinoembryonic antigen-related cell adhesion molecule 1 expression and signaling in human, mouse, and rat leukocytes: Evidence for replacement of the short cytoplasmic domain isoform by glycosylphosphatidylinositol-linked proteins in human leukocytes. Journal of Immunology, 168(10), 5139–5146.

    CAS  Google Scholar 

  168. Morales, V. M., Christ, A., Watt, S. M., Kim, H. S., Johnson, K. W., Utku, N., Texieira, A. M., Mizoguchi, A., Mizoguchi, E., Russell, G. J., Russell, S. E., Bhan, A. K., Freeman, G. J., & Blumberg, R. S. (1999). Regulation of human intestinal intraepithelial lymphocyte cytolytic function by biliary glycoprotein (CD66a). Journal of Immunology, 163(3), 1363–1370.

    CAS  Google Scholar 

  169. Nakajima, A., Iijima, H., Neurath, M. F., Nagaishi, T., Nieuwenhuis, E. E., Raychowdhury, R., Glickman, J., Blau, D. M., Russell, S., Holmes, K. V., & Blumberg, R. S. (2002). Activation-induced expression of carcinoembryonic antigen-cell adhesion molecule 1 regulates mouse T lymphocyte function. Journal of Immunology, 168(3), 1028–1035.

    CAS  Google Scholar 

  170. Nagaishi, T., Iijima, H., Nakajima, A., Chen, D., & Blumberg, R. S. (2006). Role of CEACAM1 as a regulator of T cells. Annals of the New York Academy of Sciences, 1072, 155–175.

    PubMed  CAS  Google Scholar 

  171. Chen, C. J., & Shively, J. E. (2004). The cell–cell adhesion molecule CEACAM1 inhibits IL-2 production and proliferation in human T-cell by association with activated Src homology protein-1 and down-regulates IL-2 receptor. Journal of Immunology, 172, 3544–3552.

    CAS  Google Scholar 

  172. Chen, D., Iijima, H., Nagaishi, T., Nakajima, A., Russell, S., Raychowdhury, R., Morales, V., Rudd, C. W., Utku, N., & Blumberg, R. S. (2004). Carcinoembryonic antigen-related cellular adhesion molecule 1 isoforms alternatively inhibit and costimulate human T cell function. Journal of Immunology, 172, 3535–3543.

    CAS  Google Scholar 

  173. Chen, Z., Chen, L., Qiao, S. W., Nagaishi, T., & Blumberg, R. S. (2008). Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits proximal TCR signaling by targeting ZAP-70. Journal of Immunology, 180, 6085–6093.

    CAS  Google Scholar 

  174. Nagaishi, T., Pao, L., Lin, S. H., Iijima, H., Kaser, A., Qiao, S. W., Chen, Z., Glickman, J., Najjar, S. M., Nakajima, A., Neel, B. G., & Blumberg, R. S. (2006). SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms. Immunity, 25, 769–781.

    PubMed  CAS  Google Scholar 

  175. Chen, L., Chen, Z., Baker, K., Halvorsen, E. M., da Cunha, A. P., Flak, M. B., Gerber, G., Huang, Y. H., Hosomi, S., Arthur, J. C., Dery, K. J., Nagaishi, T., Beauchemin, N., Holmes, K. V., Ho, J. W., Shively, J. E., Jobin, C., Onderdonk, A. B., Bry, L., Weiner, H. L., Higgins, D. E., & Blumberg, R. S. (2012). The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction. Immunity, 37(5), 930–946.

    PubMed  CAS  Google Scholar 

  176. Arthur, J. C., & Jobin, C. (2013). The complex interplay between inflammation, the microbiota and colorectal cancer. Gut Microbes, 4(3), 253–258.

    Google Scholar 

  177. Moller, M. J., Kammerer, R., Grunert, F., & von Kleist, S. (1996). Biliary glycoprotein (BGP) expression on T cells and on a natural-killer-cell sub-population. International Journal of Cancer, 65(6), 740–745.

    CAS  Google Scholar 

  178. Markel, G., Wolf, D., Hanna, J., Gazit, R., Goldman-Wohl, D., Lavy, Y., Yagel, S., & Mandelboim, O. (2002). Pivotal role of CEACAM1 protein in the inhibition of activated decidual lymphocyte functions. Journal of Clinical Investigation, 110, 943–953.

    PubMed  CAS  Google Scholar 

  179. Kammerer, R., Riesenberg, R., Weiler, C., Lohtmann, J., Schleypen, J., & Zimmermann, W. (2004). The tumour suppressor gene CEACAM1 is completely but reversibly downregulated in renal cell carcinoma. The Journal of Pathology, 204, 258–267.

    PubMed  CAS  Google Scholar 

  180. Hosomi, S., Chen, Z., Baker, K., Chen, L., Huang, Y.H., Olszak, T., Zeissig, S., Wang, J.H., Mandelboim, O., Beauchemin, N., Lanier, L.L., & Blumberg, R.S. (2013). CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling. European Journal of Immunology. doi:10.1002/eji.201242676.

  181. Chen, Z., Chen, L., Baker, K., Olszak, T., Zeissig, S., Huang, Y. H., Mandelboim, O., Beauchemin, N., Lanier, L. L., & Blumberg, R. S. (2011). CEACAM1 dampens anti-tumor immunity by downregulation of NKG2D ligand expression on tumor cells and NKG2D function on NK cells. The Journal of Experimental Medicine, 208(13), 2633–2640.

    PubMed  CAS  Google Scholar 

  182. Chen, T., Zimmermann, W., Parker, J., Chen, I., Maeda, A., & Bolland, S. (2001). Biliary glycoprotein (BGPa, CD66a, CEACAM1) mediates inhibitory signals. Journal of Leukocyte Biology, 70(2), 335–340.

    PubMed  CAS  Google Scholar 

  183. Greicius, G., Severinson, E., Beauchemin, N., Obrink, B., & Singer, B. (2003). CEACAM1 is a potent regulator of B cell receptor complex-induced activation. Journal of Leukocyte Biology, 74, 126–134.

    PubMed  CAS  Google Scholar 

  184. Lobo, E. O., Zhang, Z., & Shively, J. E. (2009). Pivotal advance: CEACAM1 is a negative coreceptor for the B cell receptor and promotes CD19-mediated adhesion of B cells in a PI3K-dependent manner. Journal of Leukocyte Biology, 86(2), 205–218.

    PubMed  CAS  Google Scholar 

  185. Satoh, Y., Hayashi, T., Takahashi, T., Itoh, F., Adachi, M., Fukui, M., Kuroki, M., Kuroki, M., Imai, K., & Hinoda, Y. (2002). Expression of CD66a in multiple myeloma. Journal of Clinical Laboratory Analysis, 16(2), 79–85.

    PubMed  CAS  Google Scholar 

  186. Skubitz, K. M., Ducker, T. P., & Goueli, S. A. (1992). CD66 monoclonal antibodies recognize a phosphotyrosine-containing protein bearing a carcinoembryonic antigen cross-reacting antigen on the surface of human neutrophils. Journal of Immunology, 148(3), 852–860.

    CAS  Google Scholar 

  187. Botling, J., Oberg, F., & Nilsson, K. (1995). CD49f (alpha 6 integrin) and CD66a (BGP) are specifically induced by retinoids during human monocytic differentiation. Leukemia, 9(12), 2034–2041.

    PubMed  CAS  Google Scholar 

  188. Pan, H., & Shively, J. E. (2010). Carcinoembryonic antigen-related cell adhesion molecule-1 regulates granulopoiesis by inhibition of granulocyte colony-stimulating factor receptor. Immunity, 33(4), 620–631.

    PubMed  CAS  Google Scholar 

  189. Singer, B. B., Klaile, E., Scheffrahn, I., Müller, M. M., Kammerer, R., Reutter, W., Obrink, B., & Lucka, L. (2005). CEACAM1 (CD66a) mediates delay of spontaneous and Fas ligand-induced apoptosis in granulocytes. European Journal of Immunology, 35(6), 1949–1959.

    PubMed  CAS  Google Scholar 

  190. Yu, Q., Chow, E. M., Wong, H., Gu, J., Mandelboim, O., Gray-Owen, S. D., & Ostrowski, M. A. (2006). CEACAM1 (CD66a) promotes human monocyte survival via a phosphatidylinositol 3-kinase- and AKT-dependent pathway. Journal of Biological Chemistry, 281(51), 39179–39193.

    PubMed  CAS  Google Scholar 

  191. Kammerer, R., Stober, D., Singer, B. B., Obrink, B., & Reimann, J. (2001). Carcinoembryonic antigen-related cell adhesion molecule 1 on murine dendritic cells is a potent regulator of T cell stimulation. Journal of Immunology, 166(11), 6537–6544.

    CAS  Google Scholar 

  192. van Gisbergen, K. P., Ludwig, I. S., Geijtenbeek, T. B., & van Kooyk, Y. (2005). Interactions of DC-SIGN with Mac-1 and CEACAM1 regulate contact between dendritic cells and neutrophils. FEBS Letters, 579(27), 6159–6168.

    PubMed  Google Scholar 

  193. Bogoevska, V., Horst, A., Klampe, B., Lucka, L., Wagener, C., & Nollau, P. (2006). CEACAM1, an adhesion molecule of human granulocytes, is fucosylated by fucosyltransferase IX and interacts with DC-SIGN of dendritic cells via Lewis X residues. Glycobiology, 16(3), 197–209.

    PubMed  CAS  Google Scholar 

  194. Nonaka, M., Ma, B. Y., Murai, R., Nakamura, N., Baba, M., Kawasaki, N., Hodohara, K., Asano, S., & Kawasaki, T. (2008). Glycosylation-dependent interactions of C-type lectin DC-SIGN with colorectal tumor-associated Lewis glycans impair the function and differentiation of monocyte-derived dendritic cells. Journal of Immunology, 180(5), 3347–3356.

    CAS  Google Scholar 

  195. Schumann, D., Chen, C. J., Kaplan, B., & Shively, J. E. (2001). Carcinoembryonic antigen cell adhesion molecule 1 directly associates with cytoskeleton proteins actin and tropomyosin. Journal of Biological Chemistry, 276(50), 47421–47433.

    PubMed  CAS  Google Scholar 

  196. Sadekova, S., Lamarche-Vane, N., Li, X., & Beauchemin, N. (2000). The CEACAM1-L glycoprotein associates with the actin cytoskeleton and localizes to cell–cell contact through activation of Rho-like GTPases. Molecular Biology of the Cell, 11(1), 65–77.

    PubMed  CAS  Google Scholar 

  197. Chen, C. J., Kirshner, J., Sherman, M. A., Hu, W., Nguyen, T., & Shively, J. E. (2007). Mutation analysis of the short cytoplasmic domain of the cell–cell adhesion molecule CEACAM1 identifies residues that orchestrate actin binding and lumen formation. Journal of Biological Chemistry, 282(8), 5749–5760.

    PubMed  CAS  Google Scholar 

  198. Ebrahimnejad, A., Flayeh, R., Unteregger, G., Wagener, C., & Brummer, J. (2000). Cell adhesion molecule CEACAM1 associates with paxillin in granulocytes and epithelial and endothelial cells. Experimental Cell Research, 260(2), 365–373.

    PubMed  CAS  Google Scholar 

  199. Klaile, E., Muller, M. M., Kannicht, C., Singer, B. B., & Lucka, L. (2005). CEACAM1 functionally interacts with filamin A and exerts a dual role in the regulation of cell migration. Journal of Cell Science, 118, 5513–5524.

    PubMed  CAS  Google Scholar 

  200. Muller, M. M., Singer, B. B., Klaile, E., Obrink, B., & Lucka, L. (2005). Transmembrane CEACAM1 affects integrin-dependent signaling and regulates extracellular matrix protein-specific morphology and migration of endothelial cells. Blood, 105(10), 3925–3934.

    PubMed  Google Scholar 

  201. Brummer, J., Ebrahimnejad, A., Flayeh, R., Schumacher, U., Loning, T., Bamberger, A. M., & Wagener, C. (2001). cis Interaction of the cell adhesion molecule CEACAM1 with integrin beta(3). American Journal of Pathology, 159(2), 537–546.

    PubMed  CAS  Google Scholar 

  202. Ebrahimnejad, A., Streichert, T., Nollau, P., Horst, A. K., Wagener, C., Bamberger, A. M., & Brummer, J. (2004). CEACAM1 enhances invasion and migration of melanocytic and melanoma cells. American Journal of Pathology, 165, 1781–1787.

    PubMed  CAS  Google Scholar 

  203. Briese, J., Schulte, H. M., Bamberger, C. M., Löning, T., & Bamberger, A. M. (2006). Expression pattern of osteopontin in endometrial carcinoma: Correlation with expression of the adhesion molecule CEACAM1. International Journal of Gynecology and Pathology, 25(2), 161–169.

    Google Scholar 

  204. Kluger, H. M., Hoyt, K., Bacchiocchi, A., Mayer, T., Kirsch, J., Kluger, Y., Sznol, M., Ariyan, S., Molinaro, A., & Halaban, R. (2011). Plasma markers for identifying patients with metastatic melanoma. Clinical Cancer Research, 17(8), 2417–2425.

    PubMed  CAS  Google Scholar 

  205. Ergün, S., Kilic, N., Ziegeler, G., Hansen, A., Nollau, P., Götze, J., Wurmbach, J. H., Horst, A., Weil, J., Fernando, M., & Wagener, C. (2000). CEA-related cell adhesion molecule 1 (CEACAM1): A potent angiogenic factor and a major effector of vascular endothelial growth factor (VEGF). Molecular Cell, 5, 311–320.

    PubMed  Google Scholar 

  206. Horst, A. K., Wulf, D. I., Dabelstein, J., Schumacher, U., Sander, H., Turbide, C., Brummer, J., Meinertz, T., Beauchemin, N., & Wagener, C. (2006). Carcinoembryonic antigen-related cell adhesion molecule 1 modulates vascular remodeling in vitro and in vivo. Journal of Clinical Investigation, 116(6), 1596–1605.

    PubMed  CAS  Google Scholar 

  207. Nouvion, A. L., Oubaha, M., LeBlanc, S., Davis, E. C., Jastrow, H., Kammerer, R., Breton, V., Turbide, C., Ergun, S., Gratton, J. P., & Beauchemin, N. (2010). CEACAM1: A key regulator of vascular permeability. Journal of Cell Science, 123(24), 4221–4230.

    PubMed  CAS  Google Scholar 

  208. Gerstel, D., Wegwitz, F., Jannasch, K., Ludewig, P., Scheike, K., Alves, F., Beauchemin, N., Deppert, W., Wagener, C., & Horst, A. K. (2011). CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation. Oncogene, 30(41), 4275–4288.

    PubMed  CAS  Google Scholar 

  209. Horst, A., Bickert, T., Brewig, N., Schumacher, U., Beauchemin, N., Fleischer, B., Wagener, C., & Ritter, U. (2009). CEACAM1+ myeloid cells control angiogenesis in inflammation. Blood, 113(26), 6726–6736.

    PubMed  CAS  Google Scholar 

  210. Lu, R., Kujawski, M., Pan, H., & Shively, J. E. (2012). Tumor angiogenesis mediated by myeloid cells is negatively regulated by CEACAM1. Cancer Research, 72(9), 2239–2250.

    PubMed  CAS  Google Scholar 

  211. Samineni, S., Zhang, Z., & Shively, J. E. (2013). Carcinoembryonic antigen-related cell adhesion molecule 1 negatively regulates granulocyte colony-stimulating factor production by breast tumor-associated macrophages that mediate tumor angiogenesis. International Journal of Cancer 133(2), 394–407.

    Google Scholar 

  212. Arabzadeh, A., Chan, C., Nouvion, A. L., Breton, V., Benlolo, S., DeMarte, L., Turbide, C., Brodt, P., Ferri, L., & Beauchemin, N. (2012). Host-related carcinoembryonic antigen cell adhesion molecule 1 promotes metastasis of colorectal cancer. Oncogene, 32(7), 849–860.

    PubMed  Google Scholar 

  213. Sappino, A. P., Buser, R., Seguin, Q., Fernet, M., Lesne, L., Gumy-Pause, F., Reith, W., Favaudon, V., & Mandriota, S. J. (2012). The CEACAM1 tumor suppressor is an ATM and p53-regulated gene required for the induction of cellular senescence by DNA damage. Oncogenesis, 1, e7.

    PubMed  Google Scholar 

  214. Klaile, E., Kukalev, A., Obrink, B., & Müller, M. M. (2008). PDIP38 is a novel mitotic spindle-associated protein that affects spindle organization and chromosome segregation. Cell Cycle, 7(20), 3180–3186.

    PubMed  CAS  Google Scholar 

  215. Klaile, E., Müller, M. M., Kannicht, C., Otto, W., Singer, B. B., Reutter, W., Obrink, B., & Lucka, L. (2007). The cell adhesion receptor carcinoembryonic antigen-related cell adhesion molecule 1 regulates nucleocytoplasmic trafficking of DNA polymerase delta-interacting protein 38. Journal of Biological Chemistry, 282(36), 26629–26640.

    PubMed  CAS  Google Scholar 

  216. Terahara, K., Yoshida, M., Taguchi, F., Igarashi, O., Nochi, T., Gotoh, Y., Yamamoto, T., Tsunetsugu-Yokota, Y., Beauchemin, N., & Kiyono, H. (2009). Expression of newly identified secretory CEACAM1(a) isoforms in the intestinal epithelium. Biochemical and Biophysical Research Communications, 383(3), 340–346.

    PubMed  CAS  Google Scholar 

  217. Kirshner, J., Hardy, J., Wilczynski, S., & Shively, J. E. (2004). Cell–cell adhesion molecule CEACAM1 is expressed in normal breast and milk and associates with beta1 integrin in a 3D model of morphogenesis. Journal of Molecular Histology, 35(3), 287–299.

    PubMed  CAS  Google Scholar 

  218. Zhang, H., Eisenried, A., Zimmermann, W., & Shively, J. E. (2013). Role of CEACAM1 and CEACAM20 in an in vitro model of prostate morphogenesis. PLoS One, 8(1), e53359.

    PubMed  CAS  Google Scholar 

  219. Huang, J., Hardy, J. D., Sun, Y., & Shively, J. E. (1999). Essential role of biliary glycoprotein (CD66a) in morphogenesis of the human mammary epithelial cell line MCF10F. Journal of Cell Science, 112(23), 4193–4205.

    PubMed  CAS  Google Scholar 

  220. Alegre, M. L., Shiels, H., Thompson, C. B., & Gajewski, T. F. (1998). Expression and function of CTLA-4 in Th1 and Th2 cells. Journal of Immunology, 161(7), 3347–3356.

    CAS  Google Scholar 

  221. Riley, J. L. (2009). PD-1 signaling in primary T cells. Immunological Reviews, 229(1), 114–125.

    PubMed  CAS  Google Scholar 

  222. Sapoznik, S., Hammer, O., Ortenberg, R., Besser, M. J., Ben-Moshe, T., Schachter, J., & Markel, G. (2012). Novel anti-melanoma immunotherapies: Disarming tumor escape mechanisms. Clinical and Developmental Immunology, 2012, 818214.

    PubMed  Google Scholar 

  223. Curran, M. A., Montalvo, W., Yagita, H., & Allison, J. P. (2010). PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proceedings of the National Academy of Sciences of the United States of America, 107(9), 4275–4280.

    PubMed  CAS  Google Scholar 

  224. (2013). Inhibiting CTLA-4 and PD-1 Boosts Response. Cancer Discovery. doi:10.1158/2159-8290.CD-NB2013-076.

  225. Ortenberg, R., Sapir, Y., Raz, L., Hershkovitz, L., Ben Arav, A., Sapoznik, S., Barshack, I., Avivi, C., Berkun, Y., Besser, M. J., Ben-Moshe, T., Schachter, J., & Markel, G. (2012). Novel immunotherapy for malignant melanoma with a monoclonal antibody that blocks CEACAM1 homophilic interactions. Molecular Cancer Therapy, 11(6), 1300–1310.

    CAS  Google Scholar 

  226. Liu, J., Di, G., Wu, C. T., Hu, X., & Duan, H. (2013). Development and evaluation of a novel anti-colorectal cancer monoclonal antibody, WL5. Biochemical and Biophysical Research Communications, 432(2), 370–377.

    PubMed  CAS  Google Scholar 

  227. Humphries, M. J. (1999). Towards a structural model of an integrin. Biochemical Society Symposia, 65, 63–78.

    CAS  Google Scholar 

  228. Singer, B. B., Scheffrahn, I., Kammerer, R., Suttorp, N., Ergun, S., & Slevogt, H. (2010). Deregulation of the CEACAM expression pattern causes undifferentiated cell growth in human lung adenocarcinoma cells. PLoS One, 5(1), e8747.

    PubMed  Google Scholar 

  229. Jantscheff, P., Nagel, G., Thompson, J., von Kleist, S., Embleton, M. J., Price, M. R., & Grunert, F. (1996). A CD66a-specific, activation-dependent epitope detected by recombinant human single chain fragments (scFvs) on CHO transfectants and activated granulocytes. Journal of Leukocyte Biology, 59(6), 891–901.

    PubMed  CAS  Google Scholar 

  230. Chan, C. H., & Stanners, C. P. (2004). Novel mouse model for carcinoembryonic antigen-based therapy. Molecular Therapy, 9, 775–785.

    PubMed  CAS  Google Scholar 

  231. Leung, N., Turbide, C., Marcus, V., Jothy, S., & Beauchemin, N. (2006). Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) contributes to progression of colon tumors. Oncogene, 25, 5527–5536.

    PubMed  CAS  Google Scholar 

  232. Gu, A., Zhang, Z., Zhang, N., Tsark, W., & Shively, J. E. (2010). Generation of human CEACAM1 transgenic mice and binding of Neisseria Opa protein to their neutrophils. PLoS One, 5(4), e10067.

    PubMed  Google Scholar 

  233. Hauck, W., Nédellec, P., Turbide, C., Stanners, C. P., Barnett, T. R., & Beauchemin, N. (1994). Transcriptional control of the human biliary glycoprotein gene, a CEA gene family member down-regulated in colorectal carcinomas. European Journal of Biochemistry, 223, 529–541.

    PubMed  CAS  Google Scholar 

  234. Shimada, R., Iinuma, H., Akahane, T., Horiuchi, A., & Watanabe, T. (2012). Prognostic significance of CTCs and CSCs of tumor drainage vein blood in Dukes’ stage B and C colorectal cancer patients. Oncology Reports, 27(4), 947–953.

    PubMed  Google Scholar 

  235. Gemei, M., Mirabelli, P., Di Noto, R., Corbo, C., Iaccarino, A., Zamboli, A., Troncone, G., Galizia, G., Lieto, E., Del Vecchio, L., & Salvatore, F. (2013). CD66c is a novel marker for colorectal cancer stem cell isolation, and its silencing halts tumor growth in vivo. Cancer, 119(4), 729–738.

    PubMed  CAS  Google Scholar 

  236. Zengin, E., Chalajour, F., Gehling, U. M., Ito, W. D., Treede, H., Lauke, H., Weil, J., Reichenspurner, H., Kilic, N., & Ergun, S. (2006). Vascular wall resident progenitor cells: A source for postnatal vasculogenesis. Development, 133(8), 1543–1551.

    PubMed  CAS  Google Scholar 

  237. Profumo, V., & Gandellini, P. (2013). MicroRNAs: Cobblestones on the road to cancer metastasis. Critical Reviews in Oncogenesis, 18(4), 341–355.

    PubMed  Google Scholar 

  238. Tran, R., Kashmiri, S. V., Kantor, J., Greiner, J. W., Pestka, S., Shively, J. E., & Schlom, J. (1988). Correlation of DNA hypomethylation with expression of carcinoembryonic antigen in human colon carcinoma cells. Cancer Research, 48(20), 5674–5679.

    PubMed  CAS  Google Scholar 

  239. Kim, M. S., Lee, J., & Sidransky, D. (2010). DNA methylation markers in colorectal cancer. Cancer and Metastasis Reviews, 29(1), 181–206.

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank the members of the Beauchemin laboratory for the frank discussions and exciting years of research. We are also greatly indebted to Drs. Phil Gold, Bjorn Obrink, Janusz Rak, Carlos Chan, and Josie Ursini-Siegel for their insightful comments and suggestions. We have tried to be as inclusive as possible and we apologize to authors in the field whose work may not have been cited in this review. NB is funded by the Canadian Institutes of Health Research and the Cancer Research Society Inc. AA is a fellow of the Fonds de Recherche du Québec-Santé and the McGill Integrated Cancer Research Training Program.

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Beauchemin, N., Arabzadeh, A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev 32, 643–671 (2013). https://doi.org/10.1007/s10555-013-9444-6

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