Summary
Both experimental and clinical data show evidence of a correlation between elevated blood levels of carcinoembryonic antigen (CEA) and the development of liver metastases from colorectal carcinomas. However, a cause–effect relationship between these two observations has not been demonstrated. For this reason, we developed a new experimental model to evaluate the possible role of circulating CEA in the facilitation of liver metastases. A CEA-negative subclone from the human colon carcinoma cell line CO115 was transfected either with CEA-cDNA truncated at its 3′ end by the deletion of 78 base pairs leading to the synthesis of a secreted form of CEA or with a full-length CEA-cDNA leading to the synthesis of the entire CEA molecule linked to the cell surface by a GPI anchor. Transfectants were selected either for their high CEA secretion (clone CO115-2C2 secreting up to 13 μg CEA per 106 cells within 72 h) or for their high CEA membrane expression (clone CO115-5F12 expressing up to 1 × 106 CEA molecules per cell). When grafted subcutaneously, CO115-2C2 cells gave rise to circulating CEA levels that were directly related to the tumour volume (from 100 to 1000 ng ml–1 for tumours ranging from 100 to 1000 mm3), whereas no circulating CEA was detectable in CO115 and CO115-5F12 tumour-bearing mice. Three series of nude mice bearing a subcutaneous xenograft from either clone CO115-2C2 or the CO115-5F12 transfectant, or an untransfected CO115 xenograft, were further challenged for induction of experimental liver metastases by intrasplenic injection of three different CEA-expressing human colorectal carcinoma cell lines (LoVo, LS174T or CO112). The number and size of the liver metastases were shown to be independent of the circulating CEA levels induced by the subcutaneous CEA secreting clone (CO115-2C2), but they were directly related to the metastatic properties of the intrasplenically injected tumour cells.
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References
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: 327–334.
Buchegger, F., Mach, J. P., Pèlegrin, A., Gillet, M., Vogel, C. A., Buclin, T., Ryser, J. E., Delaloye, B. & Bischof-Delaloye, A. (1995). Radiolabeled chimeric anti-CEA monoclonal antibody compared with the original mouse monoclonal antibody for surgically treated colorectal carcinoma. J Nucl Med 36: 420–429.
Carrel, S., Sordat, B. & Merenda, C. (1976). Establishment of a cell line (CO115) from a human colon carcinoma transplanted into nude mice. Cancer Res 36: 3978–3984.
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 Res 57: 4432–4436.
Folli, S., Pèlegrin, A., Chalandon, Y., Yo, X., Buchegger, F., Lejeune, F. & Mach, J-P (1993). Tumor Necrosis Factor can enhance radio-antibody uptake in human colon carcinoma xenografts by selective increase of vascular permeability. Int J Cancer 53: 829–836.
Gangopadhyay, A., Bajenova, O., Kelly, T. M. & Thomas, P. (1996). Carcinoembryonic antigen induces cytokine expression in kupffer cells: implications for hepatic metastasis from colorectal cancer. Cancer Res 56: 4805–4810.
Giavazzi, R., Campbell, D. E., Jessup, J. M., Cleary, K. & Fidler, I. J. (1986). Metastatic behaviour of tumor cells isolated from primary and metastatic human colorectal carcinomas implanted into different sites in nude mice. Cancer Res 46: 1928–1933.
Hammarstrom, S., Shively, J. E., Paxton, R. J., Beatty, B. G., Larson, A., Ghosh, R., Bormer, O., Buchegger, F., Mach, J-P, Burtin, P., Seguin, P., Darbouret, B., Degorce, F., Sertour, J., Jolu, J-P, Fuks, A., Kalthoff, H., Schmiegel, W., Arndt, R., Kloppel, G., von Kleist, S., Grunert, F., Schwarz, K., Matsuoka, Y., Kuroki, M., Wagener, C., Weber, T., Yachi, A., Imai, K., Hishikawa, N. & Tsujisaki, M. (1989). Antigenic sites in carcinoembryonic antigen. Cancer Res 49: 4852–4858.
Hardman, N., Lee Gill, L., de Winter, R. F. J., Wagner, K., Hollis, M., Businger, F., Ammaturo, D., Buchegger, F., Mach, J-P & Heusser, C. (1989). Generation of a recombinant human-mouse chimaeric monoclonal antibody directed against human carcinoembryonic antigen. Int J Cancer 44: 424–433.
Hashino, J., Fukuda, Y., Oikawa, S., Nakazato, H. & Nakanishi, T. (1994). Metastatic potential in nude mice of Chinese hamster ovary cells expressing human carcinoembryonic antigen. Biochem Biophys Res Commun 200: 1748–1753.
Hostetter, R. B., Augustus, L. B., Mankarious, R., Chi, K. F., Fan, D., Toth, C., Thomas, P. & Jessup, J. M. (1990). Carcinoembryonic antigen as a selective enhancer of colorectal cancer metastasis. J Natl Cancer Inst 82: 380–385.
Jessup, J. M., Petrick, A. T., Toth, C. A., Ford, R., Meterissian, S., O’Hara, C. J., Steele, G. Jr & Thomas, P. (1993a). Carcinoembryonic antigen: enhancement of liver colonisation through retention of human colorectal carcinoma cells. Br J Cancer 67: 464–470.
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 (1993b). Adhesion to carcinoembryonic antigen by human colorectal carcinoma cells involves at least two epitopes. Int J Cancer 55: 262–268.
Kozlowski, J. M., Fidler, I. J., Campbell, D., Xu, Z., Kaighn, M. E. & Hart, I. R. (1984). Metastatic behavior of human tumor cell lines grown in the nude mouse. Cancer Res 44: 3522–3529.
Landuzzi, L., Frabetti, F., Rossi, I., Griffoni, C., De Giovanni, C., Nicoletti, G., Nanni, P., Miniero, R., Palmieri, G., Santoni, A. & Lollini, P. L. (1996). Expression of transduced carcinoembryonic antigen gene in human rhabdomyosarcoma inhibits metastasis. Cancer Res 56: 4503–4508.
Liotta, L. A., Saidel, M. G. & Kleinerman, J. (1976). The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res 36: 889–894.
Lucha, P. A. Jr, Rosen, L., Olenwine, J. A., Reed, J. F. 3rd, Riether, R. D., Stasik, J. J. Jr & Khubchandani, I. T. (1997). Value of carcinoembryonic antigen monitoring in curative surgery for recurrent colorectal carcinoma. Dis Colon Rectum 40: 145–149.
Mach, J-P, Carrel, S., Merenda, C., Sordat, B. & Cerottini, J-C (1974). In vivo localisation of radiolabelled antibodies to carcinoembryonic antigen in human colon carcinoma grafted into nude mice. Nature 248: 704–706.
Oikawa, S., Inuzuka, C., Kuroki, M., Matsuoka, Y., Kosaki, G. & Nakazato, H. (1989). Cell adhesion activity of non-specific cross-reacting antigen (NCA) and carcinoembryonic antigen (CEA) expressed on cho cell surface: homophilic and heterophilic adhesion. Biochem Biophys Res Commun 164: 39–45.
Pèlegrin, A., Terskikh, A., Hayoz, D., Chalandon, Y., Olsson, N. O., Folli, S., Buchegger, F., Kromer, B., Schwarz, K., Martin, M., Martin, F. & Mach, J-P (1992). Human carcinoembryonic antigen cDNA expressed in rat carcinoma cells can function as target antigen for tumor localization of antibodies in nude rats and as rejection antigen in syngeneic rats. Int J Cancer 52: 110–119.
Pignatelli, M., Durbin, H. & Bodmer, W. F. (1990). Carcinoembryonic antigen functions as an accessory adhesion molecule mediating colon epithelial cell-collagen interactions. Proc Natl Acad Sci USA 87: 1541–1545.
Terskikh, A., Mach, J. P. & Pèlegrin, A. (1993). Marked increase in the secretion of a fully antigenic recombinant carcinoembryonic antigen obtained by deletion of its hydrophobic tail. Mol Immunol 30: 921–927.
Thomas, P., Gangopadhyay, A., Steele, G. Jr, Andrews, C., Nakazato, H., Oikawa, S. & Jessup, J. M. (1995). The effect of transfection of the CEA gene on the metastatic behavior of the human colorectal cancer cell line MIP-101. Cancer Lett 92: 59–66.
Tibbetts, L. M., Doremus, C. M., Tzanakakis, G. N. & Vezeridis, M. P. (1993). Liver metastases with 10 human colon carcinoma cell lines in nude mice and association with carcinoembryonic antigen production. Cancer 71: 315–321.
Toth, C. A. & Thomas, P. (1992). Liver endocytosis and Kupffer cells. Hepatology 16: 255–266.
Zhou, H., Fuks, A. & Stanners, C. P. (1990). Specificity of intercellular adhesion mediated by various members of the immunoglobulin supergene family. Cell Growth Differ 1: 209–215.
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. J Cell Biol 122: 951–960.
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Leconte, A., Garambois, V., Ychou, M. et al. Involvement of circulating CEA in liver metastases from colorectal cancers re-examined in a new experimental model. Br J Cancer 80, 1373–1379 (1999). https://doi.org/10.1038/sj.bjc.6690531
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DOI: https://doi.org/10.1038/sj.bjc.6690531
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