Up-regulation of Fas (CD95) expression in tumour cells in vivo.
Both the function and regulation of Fas expression in tumours is poorly understood. Our laboratory has reported that cultured, low Fas-expressing tumours undergo massive, yet reversible, up-regulation of cell surface Fas expression when injected into mice. The present study was aimed at determining what causes this enhanced Fas expression and whether the newly expressed Fas functions as a death receptor. Newly expressed Fas is indeed capable of inducing apoptosis. Based on our observation that Fas induction is reduced when tumour cells are injected into immune-deficient mice, we propose that Fas up-regulation in vivo involves the host's immune system. Accordingly, Fas up-regulation occurs in vitro when low Fas-expressing tumour cells are cocultured with lymphoid cells. Furthermore ascitic fluid extracted from tumour-bearing mice trigger Fas up-regulation in low Fas expressing tumours. This last finding suggests that a soluble factor(s) mediates induction of Fas expression. The best candidate for this soluble factor is nitric oxide (NO) based on the following observations: the factor in the ascites is unstable; Fas expression is induced to a lesser degree after injection into inducible NO synthase (NOS)-deficient (iNOS(-/-)) mice when compared to control mice; similarly, coculture with iNOS(-/-) splenocytes induces Fas less effectively than coculture with control splenocytes; and finally, the NO donor SNAP induces considerable Fas up-regulation in tumours in vitro. Our model is that host lymphoid cells in response to a tumour increase NO synthesis, which in turn causes enhanced Fas expression in the tumour.
Peshes-Yaloz
Naama
N
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Rosen
Dalia
D
Sondel
Paul M
PM
Krammer
Peter H
PH
Berke
Gideon
G
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D017209:Apoptosis; D003602:Cytotoxicity, Immunologic; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics
D000951:Antigens, Neoplasm; D019014:fas Receptor; D009569:Nitric Oxide