INCREASED TUMORIGENICITY OF HUMAN KERATINOCYTES HARBORING HUMAN PAPILLOMAVIRUS TYPE-16 IS ASSOCIATED WITH RESISTANCE TO ENDOGENOUS TUMOR NECROSIS FACTOR-ALPHA-MEDIATED GROWTH LIMITATION

The aim of this study was to evaluate the relationship between tumorig enicity of cell sublines derived from weakly tumorigenic SKv-e and SKv -I keratinocytes harboring human papillomavirus type 16 (HPV16) and th eir susceptibility to autocrine growth limitation mediated by tumor ne crosis factor-alpha (TNF-alpha). These sublines displayed different in vitro proliferative potential which correlated with tumorigenicity in nu/nu mice. Recombinant TNF-alpha inhibited in vitro growth of weakly tumorigenic parental SKv cell lines while it did not affect prolifera tion of their respective highly tumorigenic sublines. Resistance to TN F-alpha correlated with both increased in vitro proliferation and tumo rigenicity. Anti-TNF-alpha antibodies (Ab) significantly increased in vitro proliferation of weakly tumorigenic parental SKv cells up to the levels of their highly tumorigenic sublines. Growth of highly tumorig enic SKv cells was not affected. On the other hand, proliferation of S Kv cells was affected neither by transforming growth factor-beta (TGF- beta) nor by anti-TGF-beta Ab. All SKv cell sublines tested spontaneou sly released TNF-alpha, as evaluated by a specific radioimmunoassay; h owever, the levels of the endogenous cytokine were not related to thei r proliferative potential and tumorigenicity. An increased resistance to the anti-proliferative effect of TNF-alpha may be associated with d ecreased expression of TNF-alpha receptors (TNF-alpha R) inasmuch as e valuation of I-125-TNF-alpha binding and Northern-blot analysis of TNF -alpha R-specific mRNA showed that highly tumorigenic SKv cell subline s expressed significantly lower numbers of TNF-alpha R than their resp ective parental cells. These results show that an increased tumorigeni city of HPV16-harboring SKv keratinocytes may be, at least partially, due to escape from autocrine TNF-alpha-mediated growth limitation. (C) 1994 Wiley-Liss, Inc.