CD95 promotes tumour growth

Abstract

CD95 (also called Fas and APO-1) is a prototypical death receptor that regulates tissue homeostasis mainly in the immune system through induction of apoptosis 1-3. During cancer progression CD95 is frequently downregulated or cells are rendered apoptosis resistant 4,5 raising the possibility that loss of CD95 is part of a mechanism for tumour evasion. However, complete loss of CD95 is rarely seen in human cancers 4 and many cancer cells express large quantities of CD95 and are highly sensitive to CD95 mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for CD95, CD95L 6. These data raise the intriguing possibility that CD95 could actually promote the growth of tumours through its nonapoptotic activities 7. Here we show that cancer cells in general, regardless of their CD95 apoptosis sensitivity, depend on constitutive activity of CD95, stimulated by cancer-produced CD95L, for optimal growth. Consistently, loss of CD95 in mouse models of ovarian cancer and liver cancer reduces cancer incidence as well as the size of the tumours. The tumorigenic activity of CD95 is mediated by a pathway involving JNK and c-Jun. These results demonstrate that CD95 plays a growth promoting role during tumorigenesis and suggest that efforts to inhibit its activity rather than to enhance its activation should be considered during cancer therapy.

Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

“…Fas) or other proteins in the death receptor pathways (e.g. caspase-8 and Fas-associated death domain) promotes tumor formation, growth, invasion, and even metastasis (45)(46)(47)(48)(49)(50)(51)(52). Thus, it is also possible that Ras-induced DR5 expression is involved in promoting Ras-mediated oncogenesis and/or metastasis, particularly under apoptosis-compromised conditions.…”

Dice

“…Consistent with this assumption are data demonstrating roles for CD95 in promoting cancer cell migration, growth, epithelial-to-mesenchymal transition (EMT), and development, as shown in lung cancer, 19,20 colon cancer, [21][22][23][24] gastrointestinal cancers, 25,26 pancreatic cancer, 27,28 glioblastoma multiforme (GBM), 29 and in 22 cell lines representing various cancers. 30 Our most recent finding is that cancer fails to develop in mouse models of low-grade or endometrioid ovarian cancer or liver cancer unless CD95 is expressed, 14,31 suggesting that the reason cancer cells usually express CD95 goes beyond a function of CD95 as a tumor promoter.…”

“…When either CD95 or CD95L were downregulated by siRNAs or shRNAs, growth of all tested tumors cells slowed down, 14 and if the knockdown was sustained for a sufficient length of time, the tumor cells died. 31 We reported that a substantial fraction of all tested cancer cells underwent death induced by CD95/ CD95L elimination (DICE).…”

“…The few normal cells that seem to be affected in their growth/viability after elimination of CD95 are proliferating T cells 66 and hepatocytes in the regenerating liver, 14 both tissues prone to neoplastic transformation.…”

“…[11][12][13] In fact, CD95 acts in some tissues as a survival factor. For example, CD95 is required for efficient liver regeneration following partial hepatectomy; 14,15 CD95 is important for neurite outgrowth, 16,17 and CD95 is a potent activator of neurogenesis in both healthy and injured brains, where it activates neuronal stem cells. 18 The expression of CD95 on cancer cells suggests that cancer cells maintain CD95 expression for activities other than apoptosis induction.…”