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TNF-α mediated selection of macrophage-resistant gene-regulatory tumor variants

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Abstract

In vitro macrophage-or TNF-α-mediated selection procedures on 3LL tumor cells have led to the selection of 3LL variants manifesting a highly reduced sensitivity towards the cytotoxic effects of both TNF-α and tumoricidal macrophages, while retaining the parental sensitivity to the cytolytic activity of (i) H2O2, (ii) macrophage-ADCC reactions and (iii) NK cells. A correlation was observed between the TNF-α binding capacity of the 3LL cell lines and their susceptibility towards macrophage-and TNF-α-mediated cytotoxicity, indicating that macrophage and TNF-α sensitivity may partially be regulated at the TNF-α receptor level. Further, the selected 3LL variants are gene-regulatory variants rather than cellular mutants, as upregulation of the TNF-α receptor by interferon-gamma (IFN-γ) or 5′-azacytidine treatment resulted in an increased vulnerability of the selected 3LL variants to the killing activity of macrophages and TNF-α. The resistance of the 3LL variants to macrophage-and TNF-αmediated cytotoxicityin vitro was reflected by a higher tumorigenic and metastatic potentialin vivo. Therefore, the generation of TNF-α-and macrophage-resistant variants through immunoselection may contribute to the basic mechanisms of tumor progression and metastasis.

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  1. Laboratorium voor Algemene Biologie, Instituut voor Moleculaire Biologie, Vrije Universiteit Brussel, Sint Genesius Rode, Paardenstraat 65, B-1640, Belgium

    Linda Remels, Anne Neirynck, Lea Brys, Eddy Vercauteren & Patrick De Baetselier

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  1. Linda Remels
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  2. Anne Neirynck
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  5. Patrick De Baetselier
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Remels, L., Neirynck, A., Brys, L. et al. TNF-α mediated selection of macrophage-resistant gene-regulatory tumor variants. Clin Exp Metast 7, 493–506 (1989). https://doi.org/10.1007/BF01753810

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  • DOI: https://doi.org/10.1007/BF01753810

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