The therapeutic potential of TRAIL receptor signalling in cancer cells

In tumour cells, activation of the apoptotic machinery by death receptor ligands of the tumour necrosis factor (TNF) receptor superfamily of cytokines represents a novel therapeutic strategy. However, systemic treatment of tumours with TNF-α and CD95 ligand may produce severe toxic effects. The tumour necrosis-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family capable of inducing apoptosis in a wide variety of cancer cells upon binding to pro-apoptotic receptors, while having no effect on the majority of normal human cells tested. Interestingly, preclinical studies in mice and nonhuman primates showed no systemic cytotoxicity upon injection of either recombinant TRAIL or agonistic TRAIL-receptor antibodies. Furthermore, these treatments have been shown to effectively suppress the growth of a range of tumour xenografts. Although unwanted effects of some TRAIL preparations have been reported in normal cells, the use of TRAIL receptor agonists could represent a suitable approach in cancer therapy. Here, we shall review our current understanding of apoptotic and non-apoptotic TRAIL signalling, the therapeutic potential of TRAIL-based approaches in cancer treatment, and the results of phase 1 and 2 clinical trials with recombinant TRAIL or agonistic TRAIL receptor antibodies, either as monotherapy or in combination with other chemotherapeutic agents.     

TRAIL and apoptosis induction by TNF-family death receptors

Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family of ligands capable of initiating apoptosis through engagement of its death receptors. TRAIL selectively induces apoptosis of a variety of tumor cells and transformed cells, but not most normal cells, and therefore has garnered intense interest as a promising agent for cancer therapy. TRAIL is expressed on different cells of the immune system and plays a role in both T-cell- and natural killer cell-mediated tumor surveillance and suppression of suppressing tumor metastasis. Some mismatch-repair-deficient tumors evade TRAIL-induced apoptosis and acquire TRAIL resistance through different mechanisms. Death receptors, members of the TNF receptor family, signal apoptosis independently of the p53 tumor-suppressor gene. TRAIL treatment in combination with chemo- or radiotherapy enhances TRAIL sensitivity or reverses TRAIL resistance by regulating the downstream effectors. Efforts to identify agents that activate death receptors or block specific effectors may improve therapeutic design. In this review, we summarize recent insights into the apoptosis-signaling pathways stimulated by TRAIL, present our current understanding of the physiological role of this ligand and the potential of its application for cancer therapy and prevention.     

TRAIL receptor-targeted therapy

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines. Based on its ability to induce apoptosis selectively in a wide variety of cancer cell lines and human tumor xenografts, TRAIL has been in drug development as a potential biological agent for cancer therapy. A variety of chemotherapy agents have been shown to enhance the cytotoxic effects of TRAIL. The potential benefits of TRAIL as an anticancer therapy have been further indicated by its ability to enhance the efficacy of radiotherapy. Preclinical studies have shown the potential use of agonistic monoclonal antibodies that selectively bind TRAIL death receptors for cancer therapy. This review provides an overview of TRAIL receptor-mediated apoptosis of tumor cells, with TRAIL or agonistic monoclonal antibodies only or with chemotherapy drugs. Treatment of tumor xenografts with these ligands, alone or in combination with chemotherapy or radiation, are discussed along with preliminary information about early clinical trials. Additional clinical trials with TRAIL receptor ligands in combination treatment regimens are required to determine their potential for targeted therapy of cancer.     

Caspase-mediated p65 cleavage promotes TRAIL-induced apoptosis

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is cytotoxic to a wide variety of transformed cells, but not to most normal cells, implying potential therapeutic value against advanced cancer. However, signal transduction in TRAIL-mediated apoptosis is not clearly understood compared with other TNF family members. Specifically, it is not yet understood how TRAIL controls nuclear factor kappaB (NF-kappaB) activation and overcomes its anti-apoptotic effect. We explored the regulation of NF-kappaB activity by TRAIL and its role in apoptosis. TRAIL combined with IkappaBalpha-"superrepressor" induced potent apoptosis of SK-Hep1 hepatoma cells at low concentrations of TRAIL that do not independently induce apoptosis. Apoptosis by high concentrations of TRAIL was not affected by IkappaBalpha-superrepressor. Although TRAIL alone did not induce NF-kappaB activity, TRAIL combined with z-VAD significantly increased NF-kappaB activation. Analysis of the NF-kappaB activation pathway indicated that TRAIL unexpectedly induced cleavage of p65 at Asp97, which was blocked by z-VAD, accounting for all of these findings. p65 expression abrogated apoptosis and increased NF-kappaB activity in TRAIL-treated cells. Cleavage-resistant p65D97A further increased NF-kappaB activity in TRAIL-treated cells, whereas the COOH-terminal p65 fragment acted as a dominant-negative inhibitor. XIAP levels were increased by TRAIL in combination with z-VAD, whereas XIAP levels were decreased by TRAIL alone. Cleavage of p65 was also detected after FRO thyroid cancer cells were treated with TRAIL. These results suggest that TRAIL induces NF-kappaB activation, but simultaneously abrogates NF-kappaB activation by cleaving p65, and thereby inhibits the induction of anti-apoptotic proteins such as XIAP, which contributes to the strong apoptotic activity of TRAIL compared with other TNF family members.     

Effects and expression of TRAIL and its apoptosis-promoting receptors in human pancreatic cancer

Pancreatic cancer cells are usually resistant to apoptosis mediated by tumor necrosis factor (TNF)-alpha or FasL, and their toxicity towards normal cells hampers their application for therapeutic use. TNF-related apoptosis-inducing ligand (TRAIL), a novel member of the TNF family, triggers apoptosis in a variety of malignant cells, but exhibits less cytotoxicity in normal cells. To investigate the therapeutic potential of TRAIL, we analyzed the expression of TRAIL and its apoptosis-inducing receptors (DR4 and DR5) in the normal and cancerous human pancreas, and the sensitivity of pancreatic cancer cells to TRAIL cytotoxicity. TRAIL, DR4 and DR5 mRNA levels were concomitantly increased in pancreatic cancers compared with normal controls (P<0.01), and there were positive correlations between the expression levels of TRAIL and DR4, TRAIL and DR5 and between DR4 and DR5 mRNA (r=0.85, r=0.87, r=0.91; P<0.01). Immunostaining revealed the presence of the corresponding proteins frequently within the same cancer cells. In five pancreatic cancer cell lines, TRAIL, DR4 and DR5 mRNA expression was detectable at various levels. However, independent of the presence of DR4 and DR5, TRAIL cytotoxicity assays revealed that pancreatic cancer cells showed a significantly lower sensitivity (LD(50)>85 ng/ml) to TRAIL treatment than Jurkat T lymphoma cells (LD(50)=7.2 ng/ml). These findings show that pancreatic cancers are insensitive towards TRAIL-mediated apoptosis despite expression of TRAIL and its receptors, suggesting the presence of mediators which inhibit the TRAIL cell-death-inducing pathway in pancreatic cancer cells.     

TRAIL and its receptors as targets for cancer therapy

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging the death receptors DR4 and DR5, while sparing most normal cells. Preclinical studies in mice and non-human primates have shown the potential utility of recombinant soluble TRAIL and agonistic anti-DR5 or DR4 antibodies for cancer therapy. Moreover, we have recently revealed a vital role for endogenously expressed TRAIL in immunosurveillance of developing and metastatic tumors. In this review, we summarize recent knowledge about TRAIL and its receptors as promising targets for cancer therapy.     

TRAIL as a target in anti-cancer therapy

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can initiate apoptosis through the activation of their death receptors. The ability of TRAIL to selectively induce apoptosis of transformed or tumor cells but not normal cells promotes the development of TRAIL-based cancer therapy. Accumulating preclinical studies demonstrate that the TRAIL ligand can effectively induce cancer cell apoptosis. Completed and ongoing Phases I and II clinical trials using TRAIL are showing clinically promising outcomes without significant toxicity. Importantly, TRAIL, DR4 and DR5 can all be induced by chemotherapeutics and/or radiation, which can sensitize cancer cells to TRAIL. Thus, understanding the regulation of the TRAIL apoptosis pathway can help develop more selective TRAIL-based agents for the treatment of human cancer.     

The promise of cancer therapeutics targeting the TNF-related apoptosis-inducing ligand and TRAIL receptor pathway

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and has been shown to induce apoptosis in cancer cells but not normal cells. TRAIL triggers apoptosis through binding to its receptors DR4 and KILLER/DR5. Chemo or radiotherapy induces apoptosis through activation of p53 in response to cellular damage, whereas TRAIL induces apoptosis independent of p53. Mutations or deletions of p53 occurred in more than half of human tumors confer resistance to chemo-radiotherapy. Treatment of TRAIL-resistant tumors with agents targeting death receptors, intrinsic Bcl-2 family members, inhibitor of apoptosis proteins or PI3K/Akt pathway restores the sensitivity to TRAIL-induced apoptosis. Combination of rhTRAIL or the agonist antibody for TRAIL receptor with conventional chemotherapeutic agents results in enhanced efficacy in preventing tumor progression and metastasis. Therefore, the rational design of TRAIL-based therapy combining with other modality that either synergizes to apoptosis induction or overcomes the resistance represents a challenging strategy to achieve the systemic tumor targeting and augment the antitumor activity of cancer therapeutics.     

Repression of NF‐κB and activation of AP‐1 enhance apoptosis in prostate cancer cells

TNFα and TRAIL, 2 members of the tumor necrosis factor family, share many common signaling pathways to induce apoptosis. Although many cancer cells are sensitive to these proapoptotic agents, some develop resistance. Recently, we have demonstrated that upregulation of c‐Fos/AP‐1 is necessary, but insufficient for cancer cells to undergo TRAIL‐induced apoptosis. Here we present a prostate cancer model with differential sensitivity to TNFα and TRAIL. We show that inhibition of NF‐κB or activation of AP‐1 can only partially sensitize resistant prostate cancer cells to proapoptotic effects of TNFα or TRAIL. Inhibition of NF‐κB by silencing TRAF2, by silencing RIP or by ectopic expression of IκB partially sensitized resistant prostate cancer. Similarly, activation of c‐Fos/AP‐1 only partially sensitized resistant cancer cells to proapoptotic effects of TNFα or TRAIL. However, concomitant repression of NF‐κB and activation of c‐Fos/AP‐1 significantly enhanced the proapoptotic effects of TNFα and TRAIL in resistant prostate cancer cells. Therefore, multiple molecular pathways may need to be modified, to overcome cancers that are resistant to proapoptotic therapies. © 2008 Wiley‐Liss, Inc.     

Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to the TNF family known to transduce their death signals via cell membrane receptors. Because it has been shown that Apo2L/TRAIL induces apoptosis in tumor cells without or little toxicity to normal cells, this cytokine became of special interest for cancer research. Unfortunately, cancer cells are often resistant to Apo2L/TRAIL-induced apoptosis; however, this can be at least partially negotiated by parallel treatment with other substances, such as chemotherapeutic agents. Here, we report that cardiac glycosides, which have been used for the treatment of cardiac failure for many years, sensitize lung cancer cells but not normal human peripheral blood mononuclear cells to Apo2L/TRAIL-induced apoptosis. Sensitization to Apo2L/TRAIL mediated by cardiac glycosides was accompanied by up-regulation of death receptors 4 (DR4) and 5 (DR5) on both RNA and protein levels. The use of small interfering RNA revealed that up-regulation of death receptors is essential for the demonstrated augmentation of apoptosis. Blocking of up-regulation of DR4 and DR5 alone significantly reduced cell death after combined treatment with cardiac glycosides and Apo2L/TRAIL. Combined silencing of DR4 and DR5 abrogated the ability of cardiac glycosides and Apo2L/TRAIL to induce apoptosis in an additive manner. To our knowledge, this is the first demonstration that glycosides up-regulate DR4 and DR5, thereby reverting the resistance of lung cancer cells to Apo2/TRAIL-induced apoptosis. Our data suggest that the combination of Apo2L/TRAIL and cardiac glycosides may be a new interesting anticancer treatment strategy.     

Adriamycin sensitizes the adriamycin-resistant 8226/Dox40 human multiple myeloma cells to Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-mediated (TRAIL) apoptosis.

The newly discovered member of the tumor necrosis factor superfamily, Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), has been identified as an apoptosis-inducing agent in sensitive tumor cells but not in the majority of normal cells, and hence it is of potential therapeutic application. However, many tumor cells are resistant to Apo2L/TRAIL-mediated apoptosis. Various chemotherapeutic drugs have been shown to sensitize tumor cells to members of the tumor necrosis factor family. However, it is not clear whether sensitization by drugs and sensitivity to drugs are related or distinct events. This study examined whether an Adriamycin-resistant multiple myeloma (MM) cell line (8226/Dox40) can be sensitized by Adriamycin (ADR) to Apo2L/TRAIL-mediated apoptosis. Treatment with the combination of Apo2L/TRAIL and subtoxic concentrations of ADR resulted in synergistic cytotoxicity and apoptosis for both the parental 8226/S and the 8226/Dox40 tumor cells. Adriamycin treatment modestly up-regulated Apo2L/TRAIL-R2 (DR5) and had no effect on the expression of Fas-associated death domain, c-FLIP, Bcl-2, Bcl(xL), Bax, and IAP family members (cIAP-1, cIAP-2, XIAP, and survivin). The protein levels of pro-caspase-8 and pro-caspase-3 were not affected by ADR, whereas pro-caspase-9 and Apaf-1 were up-regulated. Combination treatment with Apo2L/TRAIL and ADR resulted in significant mitochondrial membrane depolarization and activation of caspase-9 and caspase-3 and apoptosis. Because ADR is shown to sensitize ADR-resistant tumor cells to Apo2L/TRAIL, these findings reveal that ADR can still signal ADR-resistant tumor cells, resulting in the modification of the Apo2L/TRAIL-mediated signaling pathway and apoptosis. These in vitro findings suggest the potential application of combination therapy of Apo2L/TRAIL and subtoxic concentrations of sensitizing chemotherapeutic drugs in the clinical treatment of drug-resistant/Apo2L/TRAIL-resistant multiple myeloma.     

TRAIL resistance results in cancer progression: a TRAIL to perdition?

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL, APO-2L) is a mediator of cell death that preferentially targets cancer cells. The potential of TRAIL as a chemotherapeutic agent is limited, however, because of the emergence of TRAIL resistance. Furthermore, recent studies have demonstrated that alternative TRAIL signaling is unmasked in TRAIL resistant cells. In these cells, the predominant effect of TRAIL receptor activation is the activation of nuclear factor-kappaB (NF-kappaB), which promotes tumor metastases and invasion. TRAIL resistance can occur at the level of the death inducing signaling complex via upregulation of cFLIP or via an increase in antiapoptotic proteins of the Bcl-2 family. A paradigm emerges from this information, that chemotherapy, targeting NF-kappaB, cFLIP, or antiapoptotic proteins of the Bcl-2 family, in combination with TRAIL maybe more rational than TRAIL therapy alone.     

Cisplatin sensitizes human hepatocellular carcinoma cells, but not hepatocytes and mesenchymal stem cells, to TRAIL within a therapeutic window partially depending on the upregulation of DR5

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines and has been shown to induce cell apoptosis in many types of tumors, but not in normal cells. This tumor-selective property has made TRAIL a promising approach for the development of cancer therapy. However, hepatocellular carcinoma (HCC) cells display a striking resistance to TRAIL. Although some chemotherapeutic agents can overcome this resistance, safety issues remain a concern because the combination of these agents and TRAIL has been reported to induce toxicity in normal hepatocytes. In this study, we examined whether cisplatin could reverse TRAIL resistance in HCC cells with different p53 status and evaluated the toxicity of combination TRAIL and cisplatin to normal hepatocytes and mesenchymal stem cells (MSCs). We observed that cisplatin could efficiently sensitize HCC cells, but not hepatocytes and MSCs to TRAIL-induced apoptosis within a wide therapeutic window. The apoptosis of HCC cells only partially depended on the upregulation of DR5 and the status of p53. In addition, we provide favorable evidence supporting the feasibility of the combination of chemotherapy and MSCs transduced with TRAIL.     

Regulation of TRAIL-induced apoptosis by XIAP in pancreatic carcinoma cells

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy because of its relative tumor selectivity. However, many cancers including pancreatic cancer remain resistant towards TRAIL. To develop TRAIL for cancer therapy of pancreatic carcinoma, it will therefore be pivotal to elucidate the molecular mechanisms of TRAIL resistance. Here, we identify X-linked inhibitor of apoptosis (XIAP) as a regulator of TRAIL sensitivity in pancreatic carcinoma cells. Full activation of effector caspases, loss of mitochondrial membrane potential and cytochrome c release following TRAIL treatment were markedly impaired in pancreatic carcinoma cell lines, which poorly responded to TRAIL (PaTuII, PancTu1, ASPC1, DanG), compared to TRAIL-sensitive Colo357 pancreatic carcinoma cells. Stable downregulation of XIAP by RNA interference significantly reduced survival and enhanced TRAIL-induced apoptosis in pancreatic carcinoma cells. Also, downregulation of XIAP significantly increased CD95-induced cell death. Importantly, knockdown of XIAP strongly inhibited clonogenicity of pancreatic cancer cells treated with TRAIL indicating that XIAP promotes clonogenic survival of pancreatic carcinoma cells. Thus, our findings for the first time indicate that targeting XIAP represents a promising strategy to enhance the antitumor activity of TRAIL in pancreatic cancer, which has important clinical implications.     

A human scFv antibody against TRAIL receptor 2 induces autophagic cell death in both TRAIL-sensitive and TRAIL-resistant cancer cells

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptotic cell death in a variety of tumor cells without significant cytotoxicity on normal cells. However, many cancer cells with apoptotic defects are resistant to treatment with TRAIL alone, limiting its potential as an anticancer therapeutic. Here, we report on the tumoricidal activity of a human single-chain fragment variable, HW1, which specifically binds to TRAIL receptor 2 (TR2) without competing with TRAIL for the binding. HW1 treatment as a single agent induces autophagic cell death in a variety of both TRAIL-sensitive and TRAIL-resistant cancer cells, but exhibits much less cytotoxicity on normal cells. The HW1-induced autophagic cell death was inhibited by an autophagy inhibitor, 3-methyladenine, or by RNA interference knockdown of Beclin-1 and Atg7. We also show that the HW1-mediated autophagic cell death occurs predominantly via the c-Jun NH(2)-terminal kinase pathway in a caspase-independent manner. Analysis of the death-inducing signaling complex induced by HW1 binding to TR2 exhibits the recruitment of TNF receptor-associated death domain and TNF receptor-associated factor 2, but not Fas-associated death domain, caspase-8, or receptor-interacting protein, which is distinct from that induced by TRAIL. Our results reveal a novel TR2-mediated signaling pathway triggering autophagic cell death and provides a new strategy for the elimination of cancer cells, including TRAIL-resistant tumors, through nonapoptotic cell death.     

TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells.

TRAIL, the ligand for the newly discovered DR-4 and DR-5 receptor, is a member of the TNF family of death signal transduction proteins with a mechanism of cell death similar to that of Fas and Fas ligand (Fas-L) system. We provide first time evidence that TRAIL is a potent inducer of apoptosis in multiple myeloma (MM) cell lines. TRAIL effectively induced extensive apoptosis in 8226 and ARP-1 MM cells in a time- and dose-dependent manner. Apoptosis with TRAIL reached about 80% within 48 h of treatment with a dose of 160 ng/ml. Furthermore, we provide first time evidence that similar to Fas, TRAIL-induced apoptosis is not blocked by bcl-2 in MM cell lines. Most importantly, TRAIL induced substantial apoptosis in freshly isolated, flow-sorted myeloma cells obtained from different MM patients expressing variable levels of bcl-2. Finally, we demonstrate for the first time that TRAIL is not cytotoxic to purified CD34+/CD45dim hematopoietic stem cells and does not inhibit CFU-GM or BFU-E colony formation in methylcellulose.     

Targeting p53 as a therapeutic strategy in sensitizing TRAIL-induced apoptosis in cancer cells

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been intensively studied as a cancer therapeutic agent due to its unique ability to induce apoptosis in malignant cells but not in normal cells. However, as more human cancer cells are reported to be resistant to TRAIL treatment, it is important to develop new therapeutic strategies to overcome this resistance. p53 is an important tumor suppressor that is widely involved in cellular responses to various stresses. In this mini-review, we aim to provide an overview of the intricate relationship between p53 and the TRAIL-mediated apoptosis pathway, and to summarize the current approaches of targeting p53 as a therapeutic strategy to sensitize TRAIL-induced apoptosis in human cancer cells. Although in some cases TRAIL kills cancer cells in a p53-independent manner, it is believed that in cancers with wild-type and functional p53, targeting p53 may be an important strategy for overcoming TRAIL-resistance in cancer therapy.     

Chetomin induces degradation of XIAP and enhances TRAIL sensitivity in urogenital cancer cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising anti-cancer agents, but some tumor types develop resistance to TRAIL. Here, we report that chetomin, an inhibitor of hypoxia-inducible factors, is a potent enhancer of TRAIL-induced apoptosis. TRAIL or chetomin alone weakly induced apoptosis, but the combination of chetomin and TRAIL synergistically induced apoptosis in prostate cancer PC-3 cells. The combination of chetomin and TRAIL induces the activation of caspase-3, -8, -9 and -10. Among the apoptotic factors related to the TRAIL pathway, chetomin markedly decreased the X-linked inhibitor of apoptosis (XIAP) protein levels in a dose-dependent manner, but other IAP family members, TRAIL receptors and Bcl-2 family members were not altered by chetomin. Using XIAP siRNA instead of chetomin, down-regulation of XIAP sensitized PC-3 cells to TRAIL-induced apoptosis. Conversely, transient transfection of XIAP reduced the apoptotic response to combined treatment with chetomin and TRAIL. Treatment with chetomin induced a rapid decrease in XIAP protein levels but had no effect on XIAP mRNA levels. Since chetomin-mediated XIAP down-regulation was completely prevented by proteasome inhibitors, it was suggested that chetomin induces the degradation of the XIAP protein in a proteasome-dependent manner. Additionally, chetomin also sensitized renal cancer Caki-1 cells and bladder cancer UM-UC-3 cells to TRAIL-induced apoptosis via down-regulation of XIAP. Co-treatment of chetomin and TRAIL did not enhance apoptosis in normal peripheral blood mononuclear cells (PBMC). Taken together, these findings suggest that TRAIL and chetomin synergistically induce apoptosis in human urogenital cancer cells through a mechanism that involves XIAP down-regulation by chetomin.     

TRAIL抗癌作用的研究进展

肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤坏死因子（TNF）超家族中的一员，能与死亡受体特异性结合后选择性诱导癌细胞发生凋亡。TRAIL作为靶向癌细胞的选择性杀伤配体，可在癌细胞中高度表达，在癌症的发生、发展和治疗方面扮演着重要的角色，被认为是一种非常具有开发潜力的抗肿瘤细胞因子。本文将对TRAIL的抗癌作用进行综述。