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Carcinoembryonic antigen-stimulated THP-1 macrophages activate endothelial cells and increase cell–cell adhesion of colorectal cancer cells

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Abstract

The liver is the most common site for metastasis by colorectal cancer, and numerous studies have shown a relationship between serum carcinoembryonic antigen (CEA) levels and metastasis to this site. CEA activates hepatic macrophages or Kupffer cells via binding to the CEA receptor (CEA-R), which results in the production of cytokines and the up-regulation of endothelial adhesion molecules, both of which are implicated in hepatic metastasis. Since tissue macrophages implicated in the metastatic process can often be difficult to isolate, the aim of this study was to develop an in vitro model system to study the complex mechanisms of CEA-induced macrophage activation and metastasis. Undifferentiated, human monocytic THP-1 (U-THP) cells were differentiated (D-THP) to macrophages by exposure to 200 ng/ml phorbol myristate acetate (PMA) for 18 h. Immunohistochemistry showed two CEA-R isoforms present in both U- and D-THP cells. The receptors were localized primarily to the nucleus in U-THP cells, while a significant cell-surface presence was observed following PMA-differentiation. Incubation of D-THP-1 cells with CEA resulted in a significant increase in tumor necrosis factor-alpha (TNF-α) release over 24 h compared to untreated D-THP-1 or U-THP controls confirming the functionality of these cell surface receptors. U-THP cells were unresponsive to CEA. Attachment of HT-29 cells to human umbilical vein endothelial cells significantly increased at 1 h after incubation with both recombinant TNF-α and conditioned media from CEA stimulated D-THP cells by six and eightfold, respectively. This study establishes an in vitro system utilizing a human macrophage cell line expressing functional CEA-Rs to study activation and signaling mechanisms of CEA that facilitate tumor cell attachment to activated endothelial cells. Utilization of this in vitro system may lead to a more complete understanding of the expression and function of CEA-R and facilitate the design of anti-CEA-R therapeutic modalities that may significantly diminish the metastatic potential of CEA overexpressing colorectal tumors.

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Acknowledgement

Supported by the Smithwlck Funds, Department of Surgery, Boston Medical Center and NIH grant CA74941 (PT).

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Authors and Affiliations

  1. Department of Surgery, Boston University School of Medicine, 700 Albany Street, Room W402, Boston, MA, 02118, USA

    Cary B. Aarons, Stanley Heydrick, Karen L. Reed, James M. Becker & Arthur F. Stucchi

  2. Department of Pathology, Boston University School of Medicine, Boston, MA, 02118, USA

    Charles Andrews

  3. Department of Pharmacology, Boston University School of Medicine, Boston, MA, 02118, USA

    Kristen N. Bushell

  4. Department of Surgery, Creighton University Medical School, Omaha, NE, 68178, USA

    Olga Bajenova & Peter Thomas

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  1. Cary B. Aarons
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  2. Olga Bajenova
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  9. Arthur F. Stucchi
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Correspondence to Arthur F. Stucchi.

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Aarons, C.B., Bajenova, O., Andrews, C. et al. Carcinoembryonic antigen-stimulated THP-1 macrophages activate endothelial cells and increase cell–cell adhesion of colorectal cancer cells. Clin Exp Metastasis 24, 201–209 (2007). https://doi.org/10.1007/s10585-007-9069-7

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  • DOI: https://doi.org/10.1007/s10585-007-9069-7

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