TNF-alpha mediated selection of macrophage-resistant gene-regulatory tumor variants.
In vitro macrophage- or TNF-alpha-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-alpha 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-alpha binding capacity of the 3LL cell lines and their susceptibility towards macrophage- and TNF-alpha-mediated cytotoxicity, indicating that macrophage and TNF-alpha sensitivity may partially be regulated at the TNF-alpha receptor level. Further, the selected 3LL variants are gene-regulatory variants rather than cellular mutants, as upregulation of the TNF-alpha receptor by interferon-gamma (IFN-gamma) or 5'-azacytidine treatment resulted in an increased vulnerability of the selected 3LL variants to the killing activity of macrophages and TNF-alpha. The resistance of the 3LL variants to macrophage- and TNF-alpha-mediated cytotoxicity in vitro was reflected by a higher tumorigenic and metastatic potential in vivo. Therefore, the generation of TNF-alpha- and macrophage-resistant variants through immunoselection may contribute to the basic mechanisms of tumor progression and metastasis.
Remels
L
L
Laboratorium voor Algemene Biologie, Vrije Universiteit Brussel, Belgium.
Neirynck
A
A
Brys
L
L
Vercauteren
E
E
De Baetselier
P
P
D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D001374:Azacitidine