Fas receptor‐mediated apoptosis: a clinical application?

Abstract

Fas is a membrane protein belonging to the death receptor family. Cross-linking of Fas by its ligand, FasL, or agonistic anti-Fas antibodies, induces apoptosis of cells expressing Fas on the membrane by triggering a cascade of caspases. Since many different tumours express Fas on their membrane, targeting Fas-mediated apoptosis by anti-Fas antibodies may be a promising anticancer therapy. Unfortunately, not all Fas-expressing cells are sensitive to Fas-mediated apoptosis. This has resulted in the discovery of many different inhibition mechanisms of Fas-mediated apoptosis. In addition, mutations in the Fas or p53 gene can also influence the sensitivity for Fas-mediated apoptosis. However, the role of wild-type p53 in Fas expression is still controversial. Because several different cytotoxic drugs are able to induce Fas membrane expression, combination therapy of anticancer drugs with anti-Fas antibodies or FasL is conceivable as an anticancer strategy. The efficiency of the induction of Fas-mediated apoptosis by anti-Fas antibodies, FasL-expressing cells or recombinant FasL (rFasL) in tumours has been demonstrated in vivo in solid tumours implanted in mice. Unfortunately, systemic treatment with anti-Fas antibodies or rFasL causes severe damage to the liver, so most preclinical studies are now focusing on circumvention of this problem by local administration of FasL, or on the use of inducible FasL-expressing vectors as gene therapy.

Differential modulation of the TRAIL receptors and the CD95 receptor in colon carcinoma cell lines

“…The upregulation of CD95 can sensitise tumour cells to the CD95 death signal (Timmer et al, 2002). In the present study, we have found that cisplatin treatment increased the CD95 membrane expression.…”

“…However, almost no studies have looked into whether anticancer drugs can change TRAIL-receptor membrane expression, while this effect has been described for CD95 (Timmer et al, 2002). Furthermore, it is not known whether this change in receptor expression levels at the cell surface or expression levels of pro-and antiapoptotic proteins are the key determinants for sensitivity to TRAIL or CD95L.…”

Modulation of death receptors by cancer therapeutic agents

“…The Fas gene has been shown to be mutated in both hematopoietic malignancies (0-65%) and solid tumors (0-28%). 17 Among the hematopoietic malignancies, high frequencies of Fas mutations occur in thyroid lymphoma (65.4%), cutaneous T-cell lymphoma (59%), and nasal NK/T cell lymphoma (50%). Among solid tumors, Fas mutations occur frequently in bladder transitional cell carcinoma (28%) and burn scar-related squamous cell carcinoma (14.3%).…”

“…Among solid tumors, Fas mutations occur frequently in bladder transitional cell carcinoma (28%) and burn scar-related squamous cell carcinoma (14.3%). 17 Compared to Fas, the frequencies of DR4 and DR5 mutations detected in cancers including lung, head and neck, breast, bladder, gastric and hepatocellular carcinomas, non-Hodgkin's lymphoma and chronic myelogenous leukemia are very low (0-10.6%). [18][19][20] Downregulation of expression of death receptors has also been observed in cancer.…”

Abundant Fas expression by gastrointestinal stromal tumours may serve as a therapeutic target for MegaFasL

“…At the molecular level, binding of FasL to Fas induces receptor trimerisation, followed by the binding of Fas-associated death domain (FADD) with caspase 8 and/or 10 to the intracellular death domain of Fas. Caspase activation within this complex initiates cleavage and activation of an intracellular cascade of effector caspases (e.g., caspases 3, 6, and 7), eventuating in cleavage of specific death substrates and apoptosis (Timmer et al, 2002). Thus, in tumours expressing Fas, targeting of Fas-mediated apoptosis could be a promising therapy.…”