Up‐regulation of Fas (CD95) expression in tumour cells in vivo

Abstract

SummaryBoth 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 upregulation 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.

Nitric Oxide Inhibits the Proliferation and Invasion of Pancreatic Cancer Cells through Degradation of Insulin Receptor Substrate-1 Protein

“…Recent articles reported that endogenous NO promotes oncogenesis and angiogenesis in various cancers (20,21). In contrast, other studies have shown that NO inhibits cell proliferation and induces apoptosis in various cells including cancer cells, in vitro and in vivo (22)(23)(24)(25)(26)(27)(28). These studies suggest that NO can act either as a tumor suppressor or as a tumor enhancer depending on cell type and the level of NO in the cells.…”

Nitric Oxide Regulates Growth Factor Signaling in Pancreatic Cancer Cells

“…Recent papers reported that endogenous NO promotes oncogenesis and angiogenesis in various cancers (Ambs et al, 1998;Camp et al, 2006). In contrast, other studies have shown that NO inhibits cell proliferation and induces apoptosis in various cells including cancer cells, in vitro and in vivo (Chawla-Sarkar et al, 2003;Jarry et al, 2004;Kalivendi et al, 2001;Kotamraju et al, 2007;Notas et al, 2006;Peshes-Yaloz et al, 2007;Wang et al, 2003). These studies suggest that NO can act either as a tumor suppressor or a tumor enhancer depending on cell type and the level of NO in the cells.…”

“…In contrast to the aforementioned effects of NO, other studies have shown that NO inhibits cell proliferation and induces apoptosis in various cells including cancer cells, in vitro and in vivo (Chawla-Sarkar et al, 2003;Jarry et al, 2004;Kalivendi et al, 2001;Kotamraju et al, 2007;Notas et al, 2006;Peshes-Yaloz et al, 2007;Wang et al, 2003). Nitrosylcobalamin (NO-Cbl), an analog of vitamin B12 that delivers nitric oxide (NO) and xhibits anti-tumor activity; NOCbl increases the expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors, resulting in apoptosis of human tumors.…”

NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

“…Recent papers reported that endogenous NO promotes oncogenesis and angiogenesis in various cancers (12,13). In contrast, other studies have shown that NO inhibits cell proliferation and induces apoptosis in various cells including cancer cells, in vitro and in vivo (14)(15)(16)(17)(18)(19)(20)(21). These studies suggest that NO can act either as a tumor suppressor or as a tumor enhancer depending on cell type and the level of NO in the cells.…”

“…In addition, Yasukawa et al reported that NO directly modifies Akt protein and inhibits its activity (11). Recent studies have shown that NO inhibits cell proliferation and induces apoptosis in various cells including cancer cells, in vitro and in vivo (14)(15)(16)(17)(18)(19)(20)(21).…”