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BACKGROUND: Dysregulated apoptosis is a hallmark of cancer development and progression. TRAIL and its receptors (R1 and R2) are key players in the extrinsic apoptotic pathway. Genetic alteration or blockade of TRAIL-R1 may alter its apoptotic function, and subsequently provide growth advantage to neoplastic cells. OBJECTIVE: to investigate the possible association between -C626G, -A683C and -A1322G single nucleotide polymorphisms (SNPs) of TRAIL-R1 gene and the susceptibility to B-NHL in a cohort of Egyptians. METHODS: Genotypic analysis was performed for 100 newly diagnosed B-NHL patients and 150 age and gender matched healthy controls. RESULTS: The polymorphic alleles of -C626G and -A1322G conferred almost twofold increased risk of B-NHL (OR = 1.76; 95%CI = 1.01–3.22 and OR = 1.89; 95%CI = 1.01–3.75 respectively). There was no statistical difference in the distribution of TRAIL-R1-A683C alleles/genotypes between B-NHL patients and controls. B-NHL risk increased when -C626G and -A1322G polymorphic genotypes were co-inherited (OR = 3.57; 95%CI = 1.29–9.84). The risk conferred by -C626G SNP increased for DLBCL (OR = 3.39, 95% CI: 1.61–7.16). CONCLUSION: TRAIL-R1–C626G and -A1322G polymorphisms could be considered as molecular risk factors for B-NHL especially DLBCL. The data provided by the current study constitute an initial millstone towards developing a large-scale dataset for genetic variations that could contribute to lymphomagenesis in Egyptian population. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (TRAIL-R1) has limited expression in normal tissues but was highly expressed in various types of tumors, making it an attractive target for cancer immunotherapy. Here, we utilized the single-chain variable fragment (scFv) from our previously identified TRAIL-R1–targeting monoclonal antibody (TR1419) with antitumor efficacy and produced the TR1419 chimeric antigen receptor (CAR) T cells. We characterized the phenotypes and functions of these CAR-T cells and found that the third-generation TR1419-28BBζ CAR-T cells exhibited greater target sensitivity and proliferative capability, with slightly higher PD-1 expression after antigen stimulation. Importantly, we found that the TR1419 CAR-T cells could induce TRAIL-R1–positive tumor cell death via a dual mechanism of the death receptor–dependent apoptosis as well as the T-cell–mediated cytotoxicity. Altogether, the TR1419 CAR-T cells could serve as a promising strategy for targeting the TRAIL-R1–positive tumors.

Abstract Background The death receptors TRAIL-R1 and TRAIL-R2 are frequently overexpressed in cancer and there is an emerging evidence for their important role in malignant progression, also in the case of pancreatic ductal adenocarcinoma (PDAC). In their canonical localization at the plasma membrane, TRAIL-R1/−R2 may induce cell death and/or pro-inflammatory signaling leading to cell migration, invasion and metastasis. Although, they have repeatedly been found intracellular, in the cytoplasm and in the nucleus, their functions in intracellular locations are still not well understood. Likewise, studies dealing with the prognostic relevance of TRAIL-Rs located in particular cellular compartments are very rare. For PDAC, the correlation of nuclear TRAIL-R2 with worse patients’ prognosis has been shown recently. Corresponding data on TRAIL-R1 are not available so far. Methods In the present study we analyzed the expression of TRAIL-R1 in 106 PDACs and 28 adjacent, peritumoral non-malignant pancreatic ducts with special emphasis on its cytoplasmic and nuclear localization and correlated the immunohistochemical findings with clinico-pathological patient characteristics. Results TRAIL-R1 was found in 93.4% of all PDAC samples. Cytoplasmic staining was present with very similar intensity in tumor and normal tissue. In contrast, nuclear TRAIL-R1 staining was significantly stronger in tumor compared to normal tissue (p = 0.006). Interestingly, we found that the number of cells with cytoplasmic TRAIL-R1 staining negatively correlates with tumor grading (p = 0.043). No such correlation could be detected for nuclear TRAIL-R1. Neither, cytoplasmic nor nuclear TRAIL-R1 staining showed a correlation with other clinico-pathological parameter such as pTNM categories. However, Kaplan-Meier analyses revealed significantly prolonged median survival of patients with positive cytoplasmic TRAIL-R1 expression in more than 80% of tumor cells compared to patients with tumors containing a smaller quantity of cells positively stained for cytoplasmic TRAIL-R1 (20 vs. 8 months; p = 0.004). Conclusion Cytoplasmic TRAIL-R1 is a positive prognostic marker for patients with PDAC. Our findings indicate that loss of cytoplasmic TRAIL-R1 results in recurrent disease with more malignant phenotype thus suggesting anti-tumor activities of cytoplasmic TRAIL-R1 in PDAC.

Background: The death receptors TRAIL-R1 and TRAIL-R2 are frequently overexpressed in cancer and there is an emerging evidence for their important role in malignant progression, also in the case of pancreatic ductal adenocarcinoma (PDAC). In their canonical localization at the plasma membrane, TRAIL-R1/-R2 may induce cell death and/or pro-inflammatory signaling leading to cell migration, invasion and metastasis. Although, they have repeatedly been found intracellular, in the cytoplasm and in the nucleus, their functions in intracellular locations are still not well understood. Likewise, studies dealing with the prognostic relevance of TRAIL-Rs located in particular cellular compartments are very rare. For PDAC, the correlation of nuclear TRAIL-R2 with worse patients' prognosis has been shown recently. Corresponding data on TRAIL-R1 are not available so far.Methods: In the present study we analyzed the expression of TRAIL-R1 in 106 PDACs and 28 adjacent, peritumoral non-malignant pancreatic ducts with special emphasis on its cytoplasmic and nuclear localization and correlated the immunohistochemical findings with clinico-pathological patient characteristics.Results: TRAIL-R1 was found in 93.4% of all PDAC samples. Cytoplasmic staining was present with very similar intensity in tumor and normal tissue. In contrast, nuclear TRAIL-R1 staining was significantly stronger in tumor compared to normal tissue (p = 0.006). Interestingly, we found that the number of cells with cytoplasmic TRAIL-R1 staining negatively correlates with tumor grading (p = 0.043). No such correlation could be detected for nuclear TRAIL-R1. Neither, cytoplasmic nor nuclear TRAIL-R1 staining showed a correlation with other clinico-pathological parameter such as pTNM categories. However, Kaplan-Meier analyses revealed significantly prolonged median survival of patients with positive cytoplasmic TRAIL-R1 expression in more than 80% of tumor cells compared to patients with tumors containing a smaller quantity of cells positively stained for cytoplasmic TRAIL-R1 (20 vs. 8 months; p = 0.004).Conclusion: Cytoplasmic TRAIL-R1 is a positive prognostic marker for patients with PDAC. Our findings indicate that loss of cytoplasmic TRAIL-R1 results in recurrent disease with more malignant phenotype thus suggesting anti-tumor activities of cytoplasmic TRAIL-R1 in PDAC. [ABSTRACT FROM AUTHOR]

Tumor necrosis-factor related apoptosis-inducing ligand, also known as TRAIL or APO2L (Apo-2 ligand), is a cytokine of the TNF superfamily acknowledged for its ability to trigger selective apoptosis in tumor cells while being relatively safe towards normal cells. Its binding to its cognate agonist receptors, namely death receptor 4 (DR4) and/or DR5, can induce the formation of a membrane-bound macromolecular complex, coined DISC (death-signaling inducing complex), necessary and sufficient to engage the apoptotic machinery. At the very proximal level, TRAIL DISC formation and activation of apoptosis is regulated both by antagonist receptors and by glycosylation. Remarkably, though, despite the fact that all membrane-bound TRAIL receptors harbor putative glycosylation sites, only pro-apoptotic signaling through DR4 and DR5 has, so far, been found to be regulated by N- and O-glycosylation, respectively. Because putative N-glycosylation sequons and O-glycosylation sites are also found and conserved in all these receptors throughout all animal species (in which these receptors have been identified), glycosylation is likely to play a more prominent role than anticipated in regulating receptor/receptor interactions or trafficking, ultimately defining cell fate through TRAIL stimulation. This review aims to present and discuss these emerging concepts, the comprehension of which is likely to lead to innovative anticancer therapies. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by both, overexpression of transforming growth factor (TGF)β and resistance of the tumor cells to many apoptosis-inducing stimuli. The latter negatively impacts the outcome of therapeutic efforts and represents one important mechanism which tumor cells utilize to escape the immune surveillance. Since TGFβ acts as a tumor promoter in advanced tumor stages and suppression of apoptosis is a known driver of tumor progression, it is possible that TGFβ functions as a crucial determinant of tumor cell sensitivity to apoptosis in PDAC. Here, we have studied the impact of TGFβ on TNF-related apoptosis inducing ligand (TRAIL)-induced signaling in PDAC cells. In TGFβ-responsive Panc1 and Colo357 cells, TGFβ1 reduced total and plasma membrane-associated levels of TRAIL-R1 but not those of TRAIL-R2. Consistent with the known predominant role of TRAIL-R1 in TRAIL-mediated signaling in PDAC, TGFβ1 inhibited TRAIL-induced DISC formation and apoptosis as well as phosphorylation of MAPKs and IκBα. Similarly, it also reduced signaling of TRAIL-R1 following its specific activation with an agonistic antibody. In contrast, specific TRAIL-R2 signaling remained unchanged. The TGFβ1 effect on TRAIL-R1 expression was mimicked by ectopic expression of a kinase-active version of the TGFβ type I receptor ALK5 (ALK5-T204D) but not by ALK5 double mutant lacking the ability to phosphorylate Smad proteins (RImL45-T204D). Moreover, TGFβ regulation of TRAIL-R1 was absent in two PDAC cell lines lacking the Smad4 gene DPC4 and siRNA-mediated silencing of Smad4 in Smad4-positive Panc1 cells abolished the TGFβ-mediated decrease in TRAIL-R1 expression, together showing that ALK5/Smad4 signaling is crucial for TGFβ regulation of TRAIL-R1 expression. Our results suggest a novel tumor-promoting function of TGFβ1. By downregulating TRAIL-R1, TGFβ1 may not only promote tumor escape from immune surveillance but also negatively impact on TRAIL- or TRAIL-R1-based therapy regimens for treatment of PDAC. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic antibodies targeting TRAIL-receptors (TRAIL-Rs) can selectively induce apoptosis in cancer cells. However, they have limited antitumor efficacy in clinical trials. We previously generated ten fully human monoclonal Abs to TRAIL-receptor type 1 (TR1-mAbs) using immunospot array assay on a chip (ISAAC technology). We found that the TR1-mAbs exhibited different effects on TRAIL-induced apoptosis (enhanced or blocked apoptosis). Here, we further demonstrated that some mAbs competed with TRAIL for binding to TRAIL-R1 expressed on tumor cells that blocked TRAIL-induced apoptosis (B-TR1-Ab), whereas others did not compete with TRAIL that enhanced TRAIL-induced apoptosis (E-TR1-Ab). Combination of E-TR1-Ab (TR1-419) with TRAIL leads to enhanced antitumor activity in various tumor cells in vitro . E-TR1-419 and TRAIL could cooperate to upregulate the mRNA expression and protein levels of TRAIL-R1 and to promote caspase-8 cleavage and increased JNK phosphorylation. Our results suggest that combining E-TR1 Ab with TRAIL could provide a new therapeutic strategy for tumor immunotherapies. [ABSTRACT FROM AUTHOR]

Abstract: Formation of the pro-apoptotic death-inducing signaling complex (DISC) can be initiated in cancer cells via binding of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to its two pro-apoptotic receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2. Primary components of the DISC are trimerized TRAIL-R1/-R2, FADD, caspase 8 and caspase 10. The anti-apoptotic protein FLIP can also be recruited to the DISC to replace caspase 8 and form an inactive complex. Caspase 8/10 processing at the DISC triggers the caspase cascade, which eventually leads to apoptotic cell death. Besides TRAIL, TRAIL-R1- or TRAIL-R2-selective variants of TRAIL and agonistic antibodies have been designed. These ligands are of interest as anti-cancer agents since they selectively kill tumor cells. To increase tumor sensitivity to TRAIL death receptor-mediated apoptosis and to overcome drug resistance, TRAIL receptor ligands have already been combined with various therapies in preclinical models. In this review, we discuss factors influencing the initial steps of the TRAIL apoptosis signaling pathway, focusing on mechanisms modulating DISC assembly and caspase activation at the DISC. These insights will direct rational design of drug combinations with TRAIL receptor ligands to maximize DISC signaling. [Copyright &y& Elsevier]

Background: Recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour-selective apoptosis in various pre-clinical models by binding its specific receptors expressed on cancer cells. Mapatumumab is a fully human monoclonal antibody that is agonistic to the TRAIL Receptor 1 (TRAIL-R1).Methods: This phase II multicentre study was designed to evaluate the efficacy and safety of mapatumumab in patients with colorectal cancer (CRC) who had failed to respond to, were intolerant to, or not candidates for fluoropyrimidine, oxaliplatin, and irinotecan-based regimens. All patients received two loading doses of mapatumumab (20 mg kg(-1) every 14 days), followed by maintenance therapy with 10 mg kg(-1) infused every 14 days.Results: A total of 38 patients, who had progressive disease after a median of three earlier chemotherapy lines, were enrolled. No response according to the Response Evaluation Criteria in Solid Tumors was observed. A total of 12 patients (32%) achieved stable disease for a median of 2.6 months. The median progression-free survival was 1.2 months. The most common adverse events reported, regardless of relationship, were fatigue, nausea, anorexia, and abdominal pain. Plasma mapatumumab concentrations were within the range of exposures predicted by the results of phase I studies of mapatumumab.Conclusion: No clinical activity of single-agent mapatumumab was observed in patients with advanced refractory CRC. However, on the basis of its favourable safety profile and pre-clinical evidence of potential synergy in combination with agents commonly used in the treatment of colorectal cancer, further evaluation of mapatumumab in combination with chemotherapy is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Published data on the association between tumour necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1 or DR4) polymorphisms rs20575 (C626G), rs2230229 (A1322G) and rs20576 (A683C) and cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of nine studies, among which eight articles including 2941 cases and 3358 controls described C626G genotypes, three articles including 736 cases and 668 controls described A1322G genotypes and three studies totalling 1550 cases and 2257 controls described A683C genotypes were involved in this meta-analysis. Overall, all three polymorphisms were associated with cancer susceptibility. For C626G polymorphism, there was no association between C626G polymorphism and the risk of cancer in all genetic models when all the eligible studies were pooled into the meta-analysis. In the subgroup analysis by source of controls, statistically significantly reduced cancer risks were found among groups with population-based controls for CG versus CC (OR=0.77, 95% CI:0.65–0.91, P heterogeneity =0.007) and dominant model (OR=0.84, 95% CI:0.72–0.99, P heterogeneity =0.409). For A1322G polymorphism, we found it was associated with a significantly elevated cancer risk of all cancer types in different genetic models (homozygote comparison: OR=2.80, 95% CI:1.16–6.76, P heterogeneity =0.905; dominant model comparison: OR=1.57, 95% CI:1.02–2.41, P heterogeneity =0.167; and recessive model comparison: OR=1.22, 95% CI:0.94–1.60, P heterogeneity =0.535). Similar results were obtained from A683C polymorphism (homozygote comparison: OR=3.21, 95% CI:1.26–8.20, P heterogeneity =0.012; dominant model comparison: OR=1.61, 95% CI: 1.09–2.36, P heterogeneity =0.000; and recessive model comparison: OR=2.79, 95% CI: 1.17–6.68, P heterogeneity =0.025). In summary, this meta-analysis suggests that TRAIL-R1 C626G polymorphism is marginally associated with cancer susceptibility, and both TRAIL-R1 A1322G G allele and A683C C allele are associated with increased risk for cancer. [Copyright &y& Elsevier]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a member of TNF superfamily able to induce programmed death in cancer cells with no toxicity against normal tissues. TRAIL mediate apoptosis follows binding to the two death receptors, TRAIL-R1 (DR4) and/or TRAIL-R2 (DR5). In this study we investigated the cytotoxic and apoptotic effect of TRAIL on bladder cancer cells and the expression of death receptor TRAIL-R1 and TRAIL-R2 on the surface of these cancer cells. Three human bladder transitional cancer cell (TCC) lines - SW780, 647V and T24 were tested for TRAIL sensitivity. The bladder cancer cells were incubated with human soluble recombinant TRAIL. Cytotoxicity was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-dimethyltetrazolium bromide) and LDH (lactate dyhydrogenase) assays. Apoptosis was detected by flow cytometry with annexin V-FITC/propidium iodide and by fluorescence microscopy with Hoechst 33342/annexin V-FITC/Ethidium Homodimer. The cell surface expression of TRAIL death receptors on bladder cancer were determined using flow cytometry with phycoerythrin-conjugated monoclonal anti-human TRAIL-R1 and TRAIL-R2. Our investigations confirmed that SW780 cells were sensitive to TRAIL, and two other bladder cancer cell lines, 647V and T24, were resistant to TRAIL induced apoptosis. We therefore examined the expression of TRAIL death receptors on bladder cancer cell surfaces. We showed decreased expression of TRAIL-R2 receptor in TRAIL-resistant bladder cancer cells and increased expression of this death receptor in TRAIL-sensitive SW780 cells. The expression of TRAILR1 receptor was similar in all bladder cancer cell lines. TRAIL is one of the promising candidates for cancer therapeutics. However, some cancer cells are resistant to TRAIL-mediated apoptosis. It is therefore important to overcome this resistance for the clinical use of TRAIL in cancer therapy. TRAIL death receptors are attractive therapeutic targets in cancer treatment. The cytotoxic agents capable of up-regulating the expression of TRAIL-R1 and TRAIL-R2 can sensitize cancer cells to TRAIL induced apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Drug resistance is believed to cause treatment failure in patients with metastatic colorectal carcinoma (CRC). Resistance to chemotherapy can involve different processes, including apoptosis, whose extrinsic pathway is regulated by expression of death-inducing TRAIL-R1 and -R2 and inhibitory TRAIL-R3 and -R4 cell surface receptors. Therefore, we investigated whether variations in their expression could influence the response to 5-Fluorouracil (5-FU) in metastatic CRC. We analysed TRAIL-R 1, -2, -3 and -4 expression by immuno-histochemistry in CRC, using tissue micro arrays, and found that concomitant low/medium TRAIL-R1 and high TRAIL-R3 expression in primary CRC is significantly associated with a poor response to 5-FU-based first-line chemotherapy and with shorter progression-free survival. Specifically, the median progression-free survival was 3.1 months (poor prognostic group) versus 10.1 in the good prognostic group. Thus, the combination of TRAIL-R1 and TRAIL-R3 expression might represent a predictive and prognostic factor of the response to 5-FU-based first-line chemotherapy in patients with metastatic CRC. [Copyright &y& Elsevier]

Summary: Background: Preclinical pharmacological properties of mapatumumab (agonistic human monoclonal antibody to TRAIL-R1) suggest that this antibody reduces cell viability, induces cell death in many types of cancer cell lines in vitro, inhibits or reduces tumor growth in xenograft models of solid tumors, and can induce significant tumor regression in some models. The receptor for mapatumumab, TRAIL-R1, is expressed on NSCLC cell lines. This pharmacologic profile suggests that mapatumumab may have therapeutic benefit in the treatment of NSCLC. Methods: This Phase 2 multi-center study was designed to evaluate the efficacy, safety, and tolerability of mapatumumab in patients with advanced non-small cell lung cancer (NSCLC) previously treated with at least 1 platinum-based regimen. Each patient was to receive mapatumumab at a dose of 10mg/kg administered intravenously (IV) every 21 days in absence of disease progression. Results: A total of 32 patients with relapsed or refractory Stage IIIB or IV or recurrent NSCLC were enrolled. Patients had received a median of 3 previous therapeutic regimens (range 1–7). Mapatumumab was well tolerated by the patients in this study with no discontinuations due to adverse events. The most common adverse events reported, regardless of relationship, were fatigue, cough, nausea, dyspnea, constipation, and vomiting. Laboratory analyses revealed no appreciable evidence of hepatic or renal toxicity among the study patients. No patients developed anti-mapatumumab antibodies. The plasma mapatumumab concentrations observed in this study were consistent with the predicted exposures, based on Phase 1 pharmacokinetic results. None of the 32 treated patients showed a response according to the RECIST criteria. Nine patients (29%) had stable disease (SD). Conclusion: In a group of heavily pretreated NSCLC patients, no objective single agent activity of mapatumumab was demonstrated, but the drug was safe and well tolerated. Based on this favorable safety profile, and preclinical evidence of potential synergy in combination with agents commonly used to treat NSCLC, future evaluation of mapatumumab in combination with chemotherapy is warranted. [Copyright &y& Elsevier]

Death ligands such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and certain forms of CD95L are attractive therapeutic options for metastatic melanoma. Since knowledge about the regulation of death receptor sensitivity in melanoma is sparse, we have analysed these signaling pathways in detail. The loss of CD95 or TRAIL-R1, but not of TRAIL-R2, surface expression correlated with apoptosis sensitivity in a panel of melanoma cell lines. In contrast, the expression of proteins of the apical apoptosis signaling cascade (FADD, initiator caspases-8 and cFLIP) did not predict apoptosis sensitivity. Since both TRAIL-R1 and -R2 transmit apoptotic signals, we asked whether cFLIP, highly expressed in several of the cell lines tested, is sufficient to maintain resistance to TRAIL-R2-mediated apoptosis. Downregulation of cFLIP in TRAIL-R2-positive, TRAIL-resistant IGR cells dramatically increased TRAIL sensitivity. Conversely ectopic expression of cFLIP in TRAIL-sensitive, TRAIL-R2-expressing RPM-EP melanoma cells inhibited TRAIL- and CD95L-mediated cell death. Thus, modulation of cFLIP is sufficient to sensitize TRAIL-R2-expressing cells for TRAIL. Taken together, albeit expressing all proteins necessary for death receptor-mediated apoptosis, TRAIL-R1 negative melanoma cells cannot undergo TRAIL- or CD95L-induced apoptosis due to expression of cFLIP. Hence, cFLIP represents an attractive therapeutic target for melanoma treatment, especially in combination with TRAIL receptor agonists.Oncogene (2008) 27, 3211–3220; doi:10.1038/sj.onc.1210985; published online 17 December 2007 [ABSTRACT FROM AUTHOR]

Apoptosis resistance is crucially involved in cancer development and progression, represents the leading cause for failure of anticancer therapy and is caused, for example, by downregulation of proapoptotic intracellular signaling molecules such as caspase-8. We found that the cytotoxic drugs methotrexate (MTX) and 5-fluorouracil (5-FU) were both able to sensitize resistant tumor cells for induction of apoptosis by p53-mediated upregulation of caspase-8. Increase in caspase-8 messenger RNA and protein expression disabled tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced proliferation and restored sensitivity toward TRAIL-induced apoptosis which was inhibited by transfection of p53 decoy oligonucleotides, p53 shRNA and caspase-8 shRNA. Upregulation of caspase-8 and sensitization toward TRAIL-induced apoptosis was found both in a broad panel of tumor cell lines with downregulated caspase-8 and in TRAIL-resistant primary tumor cells of children with acute leukemia. Taken together, we have identified caspase-8 as an important p53 target gene regulated by cytotoxic drugs. These findings highlight a new drug-induced modulation of physiological apoptosis pathways, which may be involved in successful anticancer therapy using MTX and 5-FU in leukemia and solid tumors over decades.Oncogene (2008) 27, 783–793; doi:10.1038/sj.onc.1210666; published online 16 July 2007 [ABSTRACT FROM AUTHOR]

Clinical trials have been initiated with Apo2L/TRAIL (Genentech) and agonistic mAbs to TRAIL receptors, -R1 and -R2 (Human Genome Sciences). The apoptosis-inducing ability of these mAbs and different TRAIL preparations, in the presence or absence of histone deacetylase inhibitors (HDACi), varied markedly against primary chronic lymphocytic leukaemia (CLL) cells and various tumor cell lines, demonstrating an unanticipated preferential apoptotic signaling via either TRAIL-R1 or -R2. Contrary to literature reports that TRAIL-induced apoptosis occurs primarily via signaling through TRAIL-R2, CLL cells, in the presence of HDACi, undergo predominantly TRAIL-R1-mediated apoptosis. Consequently, Apo2L/TRAIL, which signals primarily through TRAIL-R2, is virtually devoid of activity against CLL cells. To maximize therapeutic benefit, it is essential to ascertain whether a primary tumor signals via TRAIL-R1/-R2, prior to initiating therapy. Thus combination of an agonistic TRAIL-R1 Ab and an HDACi, such as the anticonvulsant sodium valproate, could be of value in treating CLL.Cell Death and Differentiation (2005) 12, 773–782. doi:10.1038/sj.cdd.4401649 Published online 29 April 2005 [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in tumor cells without toxicity to normal cells, but some recombinant versions of TRAIL caused hepatocyte death. We generated fully human monoclonal antibodies (mAbs) that bind specifically to TRAIL receptor 1 (TRAIL-R1) and TRAIL receptor 2 (TRAIL-R2), which mediate apoptosis signal when they ligate with TRAIL, to investigate the contribution of each receptor to induce tumor cell apoptosis and hepatocyte toxicity. All of mAbs to TRAIL-R1 and TRAIL-R2 induced cell death in several cancer cell lines susceptible to TRAIL but not in human umbilical vein endothelial cells in vitro. Both anti-TRAIL-R1 mAbs and anti-TRAIL-R2mAbs also caused cell death in hepatocytes. However, a subset of mAbs to TRAIL-R2, which was characterized by the TRAIL blocking activity, did not show strong hepatocyte toxicity. These results indicate that human normal hepatocytes are susceptible to both TRAIL-R1- and TRAIL-R2-mediated apoptosis signal.Cell Death and Differentiation (2004) 11, 203-207. doi:10.1038/sj.cdd.4401331 Published online 24 October 2003 [ABSTRACT FROM AUTHOR]

Apoptosis of testicular germ cells is critical for the maintenance of functional spermatogenesis. Previously, we have demonstrated that the Fas (Apo-1, CD95) receptor participates in the regulation of germ cell apoptosis, particularly after toxicant-induced Sertoli cell injury. In this study, we show that germ cells from B6.SMNC3H-Fasgld,gld (gld) mice that express a dysfunctional form of FasL still undergo significant apoptosis, albeit at a lower incidence than seen in B6 mice, following mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell injury. In addition, we show the presence of Fas, TRAIL-R1 (Death Receptor-4, DR4), and TRAIL-R2 (DR5) in the testis of C57BL/6 (B6) and gld mice (4 weeks old), and Sprague–Dawley rats (5 weeks old) and their responsiveness after MEHP treatment. More importantly, Western blot analysis of cellular fractions showed an increase in death receptor localization on the membrane fractions taken from Sprague–Dawley rats. Immunohistochemical analysis indicated localization of Fas and DR5 primarily to the spermatocyte subpopulation of germ cells. Examination of downstream receptor-mediated signals (i.e., cleavage of procaspase-8 and NFκB activation) revealed an early increase in NFκB–DNA binding and an increase in procaspase-8 processing in mutant gld mice. In summary, germ cell-associated death receptors, as well as downstream signaling elements, appear to be responsive to MEHP-induced Sertoli cell injury. Whether this is directly responsible for the increases in germ cell apoptosis after MEHP exposure is yet to be determined. The observed robust and early increase in Fas in wild-type testis and diminished rates of germ cell apoptosis in mutant testis (gld and lprcg) reiterates the importance of the Fas signaling pathway. [Copyright &y& Elsevier]

TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) is a typical member of the TNF ligand family that induces apoptosis by activating the death receptors TRAIL-R1 and TRAIL-R2. TRAIL has attracted great attention in recent years as a promising anti cancer reagent because recombinant soluble TRAIL derivatives induce apoptosis in a broad range of tumor cells but not or only rarely in non-transformed cells. In this review we will address the putative role of TRAIL in cancer treatment in the light of the emerging importance of TRAIL in tumor surveillance and discuss the molecular basis of the cooperation of TRAIL and chemotherapeutic drugs. In particular, we debate controversial data in the literature concerning the cytotoxicity of different TRAIL derivatives on primary human cells. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) has limited expression in normal tissues but was highly expressed in various types of tumors, making it an attractive target for cancer immunotherapy. Here, we utilized the single-chain variable fragment (scFv) from our previously identified TRAIL-R1-targeting monoclonal antibody (TR1 419 ) with antitumor efficacy and produced the TR1 419 chimeric antigen receptor (CAR) T cells. We characterized the phenotypes and functions of these CAR-T cells and found that the third-generation TR1 419 -28BBζ CAR-T cells exhibited greater target sensitivity and proliferative capability, with slightly higher PD-1 expression after antigen stimulation. Importantly, we found that the TR1 419 CAR-T cells could induce TRAIL-R1-positive tumor cell death via a dual mechanism of the death receptor-dependent apoptosis as well as the T-cell-mediated cytotoxicity. Altogether, the TR1 419 CAR-T cells could serve as a promising strategy for targeting the TRAIL-R1-positive tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nai, Du, Shen, Li, Huang, Han, Luo, Wang, Pang and Jin.)

Background: Dysregulated apoptosis is a hallmark of cancer development and progression. TRAIL and its receptors (R1 and R2) are key players in the extrinsic apoptotic pathway. Genetic alteration or blockade of TRAIL-R1 may alter its apoptotic function, and subsequently provide growth advantage to neoplastic cells., Objective: to investigate the possible association between -C626G, -A683C and -A1322G single nucleotide polymorphisms (SNPs) of TRAIL-R1 gene and the susceptibility to B-NHL in a cohort of Egyptians., Methods: Genotypic analysis was performed for 100 newly diagnosed B-NHL patients and 150 age and gender matched healthy controls., Results: The polymorphic alleles of -C626G and -A1322G conferred almost twofold increased risk of B-NHL (OR = 1.76; 95%CI = 1.01-3.22 and OR = 1.89; 95%CI = 1.01-3.75 respectively). There was no statistical difference in the distribution of TRAIL-R1-A683C alleles/genotypes between B-NHL patients and controls. B-NHL risk increased when -C626G and -A1322G polymorphic genotypes were co-inherited (OR = 3.57; 95%CI = 1.29-9.84). The risk conferred by -C626G SNP increased for DLBCL (OR = 3.39, 95% CI: 1.61-7.16)., Conclusion: TRAIL-R1-C626G and -A1322G polymorphisms could be considered as molecular risk factors for B-NHL especially DLBCL. The data provided by the current study constitute an initial millstone towards developing a large-scale dataset for genetic variations that could contribute to lymphomagenesis in Egyptian population.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1/2 (TRAIL-R1/R2), also known as death receptors, are expressed in a wide variety of tumor cells. Although TRAIL can induce cell apoptosis by engaging its cognate TRAIL-R1/R2, some tumor cells are or become resistant to TRAIL treatment. Monoclonal antibodies (mAbs) against TRAIL-R1/R2 have been developed to use as potential antitumor therapeutic agents instead of TRAIL. However, TRAIL-R1/R2-based tumor therapy has not yet been realized. We previously generated a series of fully human monoclonal antibodies against TRAIL-R1 (TR1-mAbs) that induced tumor cell apoptosis. In this study, we identified the antigenic binding sites of these TR1-mAbs and proposed two major epitopes on the extracellular domain of TRAIL-R1. The analysis revealed that the epitopes of some TR1-mAbs partially overlaps with the beginning of TRAIL-binding sites, and other epitopes are located within the TRAIL-binding region. Among these mAbs, TR1-422 and TR1-419 mAbs have two antigenic binding sites that bound to the same binding region, but they have different essential amino acid residues and binding site sizes. Furthermore, we investigated the apoptosis activity of TR1-419 and TR1-422 mAbs in the form of IgG and IgM. In contrast to the IgG-type TR1-419 and TR1-422 mAbs, which enhanced and inhibited TRAIL-induced apoptosis, respectively, both IgM-type TR1-419 and TR1-422 mAb strongly induced cell apoptosis with or without soluble TRAIL (sTRAIL). Moreover, the results showed that IgM-type TR1-419 and TR1-422 mAbs alone can sufficiently activate the extrinsic and intrinsic apoptosis signaling pathways and suppress tumor growth in vivo . Consequently, we identified two antigenic binding sites with agonistic activity, and their specific IgM-type mAbs exhibited strong cytotoxic activity in tumor cells in vitro and in vivo . Thus, these agonistic antigenic binding sites may be useful for the development of effective Ab-based drugs or Ab-based cell immunotherapy for various human solid tumors., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Giant cell tumor of bone (GCT), which frequently occurs in the patients' spine, is relatively prevalent in Chinese population. A group of GCT invades into vessels and appears to be circulating tumor cells (CTCs) responsible for the distal metastasis of the primary tumor. So far the cell surface markers of GCT have not been determined. In the current study, we aimed to identify a novel CTC marker with higher specificity in GCT. TRAIL-R1+ cells were purified from GCT cell lines. The TRAIL-R1+ cells were compared with total GCT cells for tumor sphere formation, chemo-resistance, tumor formation in nude mice, and frequency of developing distal metastases. We found that TRAIL-R1+ GCT cells appeared to be highly enriched for CTCs in GCT. Compared to total GCT cells, TRAIL-R1+ GCT cells generated significantly more tumor spheres in culture, were higher chemo-resistant, and had a higher frequency of being detected in the circulation after subcutaneous transplantation as well as development of distal metastases. Thus, we conclude that TRAIL-R1+ may be a novel CTC marker in GCT. Selective elimination of TRAIL-R1+ GCT cells may improve the current GCT therapy., Competing Interests: CONFLICTS OF INTEREST The authors declared no competing interests.

Background: The genome of multiple myeloma (MM) clonal plasma cells is characterized by genetic changes of prognostic importance. Disease progression is accompanied by a number of secondary chromosomal aberrations including chromosome 8. We focused on the detection of chromosome 8 aberrations in patients with MM who were examined at 2 different phases: diagnosis and progression/relapse., Patients and Methods: A total of 62 patients with MM were examined at the time of diagnosis and at relapse/progression. The median age was 64 years (range, 39-78 years); the study included 29 males and 33 females. We analyzed bone marrow samples for detecting aberrations on chromosome 8 by the fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms (FICTION) and fluorescence in situ hybridization methods with specific probes., Results: Chromosome 8 aberrations were detected in 24 (38.7%) patients at diagnosis and in 29 (46.8%) patients at progression/relapse. Only 5 (8%) patients developed additional chromosome 8 changes at progression/relapse. The aberrations were heterogeneous, involving numerical and structural changes of the MYC gene. Aberrations of the short arm of chromosome 8, involving the genes TRAIL-R1/-R2, were less frequent (4 of 62 patients, 6.4%). All aberrations of chromosome 8 were accompanied with additional changes and with an advanced clinical phase of the disease. This finding significantly influenced the overall survival of patients., Conclusion: In the current study, chromosome 8 aberrations were highly heterogeneous, were presented at diagnosis in patients with advanced clinical stage, and were associated with worse overall survival. We have not confirmed the increase of frequency aberration of chromosome 8 in disease progression. The findings demonstrate the importance of fluorescence in situ hybridization examination of chromosome 8 in newly diagnosed patients with MM., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aims: Treatment with pegylated interferon-alpha (PEG-IFN) and ribavirin is the backbone of standard therapy of HCV by mechanisms that are not completely understood. Besides a direct antiviral effect, different immunomodulatory and apoptotic effects have been discussed. Tumor necrosis factor-related apoptosis inducing-ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family with immunomodulatory as well as pro- and antiapoptotic effects and is putatively involved in control of HCV infection. Thus, we analyzed the expression of the TRAIL/TRAIL-receptor system, caspase-8 and cFLIP and examined their prognostic and predictive value for HCV infection and antiviral therapy, respectively., Methods: We immunohistochemically analyzed liver biopsies of 116 therapy-naive HCV patients before treatment with PEG-IFNα and ribavirin in comparison to healthy liver tissue. Expression levels of TRAIL, TRAIL-R1 to TRAIL-R4, caspase-8 and cFLIP were correlated with sustained virologic response (SVR), genotype and staging of chronic hepatitis., Results: Caspase-8, cFLIP, TRAIL-R2 and TRAIL-R4 were strongly upregulated in HCV patients, whereas TRAIL-R3 was downregulated. SVR correlated with high expression of TRAIL and pro-apoptotic TRAIL-R2 on HCV infected hepatocytes., Conclusions: Our results suggest a pathophysiological role of TRAIL in both, HCV infection and therapy. Further studies need to elaborate possible TRAIL-related targets for clinical applications., (Copyright © 2013 Elsevier GmbH. All rights reserved.)