© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 421-427, Copyright © 1997 by Oxford University Press
K Xie, S Huang, Z Dong, SH Juang, Y Wang and IJ Fidler
BACKGROUND: The activation of an enzyme, inducible nitric oxide synthase
(iNOS), catalyzes the production of endogenous nitric oxide (NO). NO, in
turn, is associated with cell death, suppression of tumor development, and
inhibition of metastasis of murine melanoma cells. Moreover, the in vivo
induction of iNOS is associated with regression of established hepatic
metastases. Whether this regression required the activation of the iNOS
gene in every tumor cell or whether NO-producing tumor cells can also kill
bystander (neighboring) cells has been previously unknown. PURPOSE: The
goal of this study was to determine whether cells producing NO and then
undergoing autolysis can also kill bystander cells in vitro and in vivo.
METHODS: Murine K-1735 C4.parental (C4.P) melanoma cells were transfected
with the functional iNOS gene (transfectant denoted as C4.L8) or with a
control truncated- nonfunctional iNOS gene (transfectant denoted as C4.S2).
NO-mediated cytolysis and bystander cell killing were determined in vitro
and in vivo. RESULTS: Only the functional iNOS-transfected C4.L8 cells
produced NO and underwent autolysis. C4.L8 cells also produced
statistically significant lysis of iNOS-negative C4.P cells. This lysis was
suppressed by the specific iNOS inhibitor N(G)-methyl-L-arginine.
NO-producing C4.L8 cells and control C4.P or C4.S2 cells were injected
subcutaneously into syngeneic C3H/HeN mice. Control C4.P and C4.S2 cells
produced rapidly growing subcutaneous tumors, whereas C4.L8 cells did not.
The mixture of C4.P and C4.S2 cells (1:5 ratio) produced rapidly growing
subcutaneous tumors, whereas the mixture of C4.P and C4.L8.5 cells (1:5
ratio) produced slow-growing tumors. The subcutaneous growth of C4.P cells
was not affected by C4.L8.5 cells injected subcutaneously at a distant
site. Mixtures of C4.P cells labeled with [(125)I]iododeoxyuridine and
C4.L8 cells (NO producing) or C4.S2 cells (control) were injected
subcutaneously. The survival rate of the radiolabeled cells indicated that
the NO-producing C4.L8.5 cells lysed the bystander C4.P cells. CONCLUSION:
The production of high- level endogenous NO causes autolysis in tumor cells
and lysis of bystander cells under in vitro and in vivo conditions.
IMPLICATIONS: NO- mediated cell killing does not require transfection of
genes into every cell in a neoplasm.
ARTICLES
Destruction of bystander cells by tumor cells transfected with inducible nitric oxide (NO) synthase gene
Department of Cell Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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