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-Dependent Delay of In Vivo Tumor Progression by Fas Overexpression on Murine Renal Cancer Cells1 ,2
*
Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD; and
Intramural Research Support Program, Science Applications International Corp.- Frederick,
Pediatric Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD
The role of Fas in the regulation of solid tumor growth was
investigated. Murine renal carcinoma (Renca) cells were constitutively
resistant to Fas-mediated killing in vitro, but exhibited increased
expression of Fas and sensitivity to Fas-mediated killing after
exposure to IFN-
and TNF. Transfected Renca cells overexpressing Fas
were efficiently killed in vitro upon exposure to anti-Fas Ab
(Jo2). When Fas-overexpressing Renca cells were injected into syngenic
BALB/c mice, there was a consistent and significant delay in tumor
progression, reduced metastasis, and prolonged survival that was not
observed for Renca cells that overexpressed a truncated nonfunctional
Fas receptor. The delay of in vivo tumor growth induced by Fas
overexpression was not observed in IFN--/- mice,
indicating that IFN- is required for the delay of in vivo tumor
growth. However, there was a significant increase of infiltrated T
cells and in vivo apoptosis in Fas-overexpressing Renca tumors, and
Fas-overexpressing Renca cells were also efficiently killed in vitro by
T cells. In addition, a strong therapeutic effect was observed on
Fas-overexpressing tumor cells by in vivo administration of
anti-Fas Ab, confirming that overexpressed Fas provides a
functional target in vivo for Fas-specific ligands. Therefore, our
findings demonstrate that Fas overexpression on solid tumor cells can
delay tumor growth and provides a rationale for therapeutic
manipulation of Fas expression as a means of inducing tumor regression
in vivo.
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