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Lack of FasL-mediated killing leads to in vivo tumor promotion in mouse Lewis lung cancer

  1. Author:
    Lee, J. K.
    Sayers, T. J.
    Back, T. C.
    Wigginton, J. M.
    Wiltrout, R. H.

  2. Author Address

    Natl Inst Hlth, Natl Genome Res Inst, 5 Nokbun Dong, Seoul 122701, South Korea Natl Inst Hlth, Natl Genome Res Inst, Seoul 122701, South Korea NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA NCI, Expt Immunol Lab, Frederick, MD 21702 USA NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA Lee JK Natl Inst Hlth, Natl Genome Res Inst, 5 Nokbun Dong, Seoul 122701, South Korea
    1. Year: 2003
  2. Journal: Apoptosis
    1. 8
    2. 2
    3. Pages: 151-160
  4. Type of Article: Article
  1. Abstract:

    Lewis lung carcinoma (3LL) cells were constitutively resistant to Fas-mediated apoptosis, but overexpression of Fas on 3LL cells allowed Fas-mediated apoptosis after crosslinking with agonist anti-Fas antibody (Jo2) in vitro. Surprisingly, Fas- overexpressing 3LL cells showed enhanced in vivo tumor progression, whereas no promotion of in vivo tumor growth was observed for dominant negative (DN) Fas-overexpressing 3LL transfectants in which the cytoplasmic death domain was deleted. In addition, the promotion of in vivo tumor growth by Fas-overexpression was reduced in gld (FasL-mutation) mice compared to normal mice. These data indicate that intact Fas/FasLcell signaling is required for the promotion of in vivo tumor growth by Fas overexpression in 3LL cells. In contrast to the efficient Fas-mediated killing induced in vitro by crosslinking with anti-Fas antibody, Fas-overexpressing 3LL cells were resistant in vitro to Fas-mediated apoptosis by activated T cells or transient FasL transfection. These data suggest that agonist anti-Fas antibody and natural FasL can transmit qualitatively different signals, and crosslinking of Fas with natural FasL on 3LL cells does not deliver the expected death signal. Thus, our results demonstrate that in some cases overexpression of Fas can result in a survival advantage for tumor cells in vivo.

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