1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  8. Acknowledgements

Tumor necrosis factor (TNF) is a cytokine that mediates tumor necrosis. To date, 20 different members of the TNF super-family and 21 different receptors have been identified. All ligands of the TNF super-family have been found to activate transcription factor NF-κB and c-Jun kinase. Members of this family have diverse biological effects, including induction of apoptosis, promotion of cell survival, and regulation of the immune system and hematopoiesis. The current review focuses on the biological effects of TNF-related apoptosis-inducing ligand (TRAIL), a TNF super-family member which, a few years ago, generated considerable enthusiasm for its anticancer activity, not accompanied by general toxicity in most normal tissues and organs. © 2004 Wiley-Liss, Inc.

Molecular structure and receptors

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  8. Acknowledgements

The story of TNF-related apoptosis-inducing ligand (TRAIL) begins when a new member of the super-family of tumor necrosis factor (TNF) capable of inducing apoptosis was identified and characterized (Wiley et al., 1995) by virtue of its sequence homology to CD95/Fas/Apo1 Ligand (FasL) and TNF. This protein was independently discovered by another group of investigators and named Apo2L (Pitti et al., 1996). TRAIL/Apo2L consists of 281–291 aa in the human and murine forms, respectively, which share 65% aa identity. TRAIL has the characteristics of a type II membrane protein, i.e., no leader sequence and an internal trans-membrane domain, and its extra-cellular region forms a soluble molecule upon proteolytic cleavage (Mariani and Krammer, 1998). To determine where the TRAIL gene resides in the human genome, in an initial study Wiley et al. (1995) analyzed metaphase chromosomes from two normal males by fluorescent in situ hybridization, observing that it is located on chromosome 3 at position 3q26 most likely in the region q26.1-q26.2. Later on, the human TRAIL/Apo2L gene was better characterized concerning both its structure and regulation as reported in Gong and Almasan (2000). Like other TNF family ligands (TNFα and β, lymphotoxin α and β, CD95/Fas/Apo1, etc.), TRAIL has an N-terminal (cytoplasmic) domain, which is not conserved across family members, while the C-terminal (extracellular) domain shows significant conservation and is sufficient for biological activity (Smith et al., 1994). Among the structurally related proteins belonging to the TNF family of cytokines (Gruss and Dower, 1995; Baker and Reddy, 1996), TRAIL shares the highest amino acid identity with CD95L (Wiley et al., 1995; Mariani and Krammer, 1998). What immediately distinguished TRAIL from CD95L and TNFα was its ability to induce apoptosis on various continuous cell lines and primary tumor cells (Walczak and Krammer, 2000), displaying minimal or no toxicity on most normal cells and tissues (reviewed in Ashkenazi and Dixit, 1999).

To facilitate biological studies, an epitope-tagged soluble form of TRAIL was constructed and identified by SDS–PAGE with an apparent molecular weight of 28 kDa (Wiley et al., 1995). Gel filtration analysis of the purified soluble TRAIL disclosed that the native molecule was multimeric in solution with a size of ∼80 kDa. Since then, a lot of recombinant TRAIL preparations have been obtained (Marsters et al., 1996; Pitti et al., 1996; Ashkenazi et al., 1999; Walczak et al., 1999) and commercialized so that the variety of techniques of construction/purification employed may justify some data inconsistencies (for details see LeBlanc and Ashkenazi, 2003). However, both full-length cell surface expressed TRAIL and picomolar concentrations of the soluble form rapidly induce apoptosis in a wide variety of transformed cell lines of diverse origin (Table 1).

Table 1. List of cell lines and primary cells sorted according to their different TRAIL sensitivity
  1. Immortalized non transformed breast epithelial cell lines.

Cell lines   
 Neuroblastoma SK-N-MC* Milani et al. (2003)
 Non-small cell lung cancer NSCLC* Spierings et al. (2003)
 Human oral squamous cell carcinomas  Fukuda et al. (2003)
 Human hepatocellular carcinoma HCC  Evi-Cheol et al. (2002)
  Hep G2 * 
  Hep G 2.2.15 * 
  Hep 3B * 
  SNU-182 * 
  SNU-354 * 
  SNU-398 * 
  SNU-449 * 
  MCF 7*  
 Human B-cells pancreatic CM* Ou et al. (2002)
 Human colon carcinomas  Tillman et al. (2003)
  GC (3)/cl**  
  HCT 116**  
  HT 29*  
  RKO * 
  HCT 8 * 
 Human colon cancer cell SW480* Xu et al. (2003)
 Colon carcinoma cell lines  Van Geelen et al. (2003)
  CaCo-2 * 
  Colo 320 * 
 Prostate cancer lines  Nesterov et al. (2001)
  DU 145**  
  LNCaP * 
 Human Adenocarcinoma Cervix HeLa *Bernard et al. (2001)
 HCT 116* Wen et al. (2000)
 Breast normal °  Keane et al. (1999)
  MCF 10A*  
  184B5 * 
 Breast cancer   
  ZR 75-1 * 
  MCF-7 * 
  MDA-MB-453 * 
  MDA-MB-468 * 
  MDA-MB-157 * 
  ShBr-3 * 
 Osteogenic sarcoma  Evdokion et al. (2002)
  HOS * 
  MG-63 * 
  SSSA-1 * 
  G-292 * 
  SAOS 2 * 
 Sarcoma RPMI-8826* Suzuki et al. (2003)
 Mieloma MG-63 * 
 Melanoma cell lines   
  Me 4405* Zhang et al. (1999)
  Me 1007*  
  Me 10538*  
  MM 200*  
  Mel-LT* Zhang et al. (2000)
 Human melanoma A375* Steven et al., 1995
 Murine fibroblast L929* Steven et al., 1995
 Burkitt lymphoma*  
 Monocytic THP-1 * 
 Large cell aneuplastic lymphoma K229 * 
 Spontaneous B cell MP-1 * 
 Lymphoid cells  Martin et al. (2000)
 BL-60 (human B cell line)*  
 BSAB (human B cell line)*  
 CEM (human T cell line)*  
 CEM *Scaffidi et al. (1998)
 Histiocytic lymphoma U937* Steven et al., 1995
  Molt-4 *Lee et al. (2003)
  Jurkat* Lee et al. (2003)
   Martin et al. (2000)
   Scaffidi et al. (1998)
 Human HL-60* Secchiero et al. (2002)
 Erithroleukemia  Di Pietro et al. (2001)
  K562* Secchiero et al. (2002)
Primary cultures   
 Endothelial cells HUVEC *Zauli et al. (2003)
   Zhang et al. (2000)
 * Li et al. (2003)
 Endothelial cells from dermal microvessels*  
 Human bone cells NHB *Evdokion et al. (2002)
 CD34+ cells *Secchiero et al. (2002)
   Di Pietro et al. (2001)
 Foetal pancreas* Chen et al. (2003)
 Human pancreatic islet cells *Ou et al. (2002)
 Colonic epithelium *Strater et al. (2002)
 Human prostate ephitelium cells PrEC* Nesterow et al. (2002)
 Aorta smooth muscle cells * 
 Human articular chondrocytes* Pettersen et al. (2002)
 Human primary hepatocytes NHPHs *Lin et al. (2000)
 Thyroid tissues *Mitstedes et al. (2001)
 Human thymus organ culture HTOC* Simonet et al. (1997)
 Cervical epithelium *Ryu et al. (2000)
 Human oral squamous cell carcinomas HOSSCCs* Fukuda et al. (2003)
 Neoplastic thyroid tissues* Mitstedes et al. (2001)
 Tumor cervical cells* Ryu et al. (2000)

Significant levels of TRAIL transcripts have been detected in many human tissues and expressed constitutively in some cell lines (Wiley et al., 1995; Pitti et al., 1996). Such a widespread distribution of TRAIL transcripts differs from that of FasL and suggests that TRAIL must not be cytotoxic to most tissues in vivo. To justify the ability of TRAIL of inducing apoptosis in many different types of cultured cells, it was hypothesized either that the TRAIL receptors were restricted in their distribution or that they acted to induce apoptosis only under certain restricted circumstances. Like most other TNF family members, Apo2L/TRAIL forms a homotrimer (Hymowitz et al., 1999), which triggers apoptosis through interaction with the death receptors DR4 (TRAIL-R1) (Pan et al., 1997a) and DR5 (TRAIL-R2) (Chaudhary et al., 1997; Pan et al., 1997b; Schneider et al., 1997a; Screaton et al., 1997; Sheridan et al., 1997; Walczak et al., 1997; Wu et al., 1997). On the other hand, antagonistic decoy receptors, DcR1 (TRAIL-R3) (Degli-Esposti et al., 1997a; Pan et al., 1997b; Schneider et al., 1997a; Sheridan et al., 1997), DcR2 (TRAIL-R4) (Marsters et al., 1997; Degli-Esposti et al., 1997b; Pan et al., 1998), and osteoprotegerin (OPG; TRAIL-R5) (Simonet et al., 1997; Emery et al., 1998) can compete with DR4 and DR5 for ligand binding, thus protecting many normal cell types from induction of apoptosis. More recent evidences, based on the use of monoclonal anti-TRAIL receptor antibodies instead of over-expression models, have pointed at the primary role of intracellular mechanisms in controlling TRAIL resistance in a number of cell types (Griffith et al., 1998; Zhang et al., 1999; Leverkus et al., 2000), thus cutting down the importance of control at decoy receptors level, whose biochemical function is still to be clarified.

Signaling pathways and genes activated

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  8. Acknowledgements

Although much effort has been made to elucidate the molecular mechanisms of TRAIL signaling, the components of different TRAIL signaling routes are still largely undefined. Instead, signaling pathways involved in the generation of TRAIL-induced apoptosis have been extensively reviewed (Walczak and Krammer, 2000; Almasan and Ashkenazi, 2003; LeBlanc and Ashkenazi, 2003). Briefly, following engagement of death receptors by their ligand is the recruitment of proteins to the intracellular death domain of the receptor to form a structure known as the death-inducing signaling complex (DISC) (Kischkel et al., 1995). TRAIL DISC resembles that of Fas since the adaptor protein Fas-associated death domain (FADD) and the apoptosis initiator caspase-8 are recruited to DR4 and/or DR5 shortly after addition of the ligand (Bodmer et al., 2000; Kischkel et al., 2000; Sprick et al., 2000). Although initial studies (Kischkel et al., 2000; Sprick et al., 2000) have attributed a central role to caspase-8 in mediating the apoptotic signal of TRAIL, more recent study has demonstrated that apoptosis can be triggered independently through DR4 or DR5 and proteolytic activation of effector caspases by apical caspase-8 or -10 (Kischkel et al., 2001). Similarly to CD95L (Scaffidi et al., 1998), the response to TRAIL is cell type specific and might be characterized by two distinct cell death pathways (reviewed in LeBlanc and Ashkenazi, 2003): in the type I pathway, extrinsic signals lead to the activation of large amounts of caspase-8 and the rapid cleavage of caspase-3 prior to loss of mitochondria trans-membrane potential (ΔΨm); in the type II pathway of apoptosis, intrinsic signals, like DNA damage, lead to the Bcl-2 family member Bax translocation to the mitochondria followed by loss of ΔΨm. This, in turn, induces the release of cytochrome c and its association with Apaf-1 and procaspase-9, which leads to the activation of caspase-9 and the final recruitment of effector caspases (Susin et al., 1999; Green, 2000). Pro-apoptotic members of the Bcl-2 family, such as Bax or its homologue Bak, are counteracted by the anti-apoptotic family members Bcl-2 or Bcl-XL (Bouillet and Strasser, 2002). Other proteins belonging to the Bcl-2 family, such as Bim, Bid, PUMA, and NOXA, contain only one of the four Bcl-2 homology domains (BH3) common to the rest of the family and increase the activity of Bcl-2 family pro-apoptotic members. When low concentrations of caspase-8/-10, insufficient to allow an effective downstream activation of caspase-3, induce cleavage of Bid (tBid), this protein translocates to the mitochondria where it activates Bax and Bak, so that a mechanism for crosstalk between the death receptors and the intrinsic pathway is provided (Li et al., 1998; Bouillet and Strasser, 2002).

Upon binding of TRAIL-R1, -R2, or -R4, TRAIL can also activate the transcriptional factor NF-κB and c-Jun N-terminal kinase (JNK) (Chaudhary et al., 1997; Degli-Esposti et al., 1997b; Schneider et al., 1997b; Muhlenbeck et al., 1998); the activation of NF-κB or Jun-kinase by TRAIL is mediated via TRADD (TNF-R1-associated death domain protein), TRAF2 (TNF receptor-associated factor 2), and RIP (receptor-interacting protein) and occurs independently of caspase-8/-10 activation (Muhlenbeck et al., 1998; Lin et al., 2000; MacFarlane, 2003) (Fig. 1). Importantly, the level of NF-κB activation has been related to resistance of leukemic (Ehrhardt et al., 2003) and neuroblastoma cell lines (Yang and Thiele, 2003) to TRAIL cytotoxicity. These findings are consistent with the pleiotropic activity of NF-κB transcription factors, which are implicated in the control of cell survival and tumorigenesis (Ghosh et al., 1998; Foo and Nolan, 1999; Rayet and Gelinas, 1999). Activation and regulation of Rel/NF-κB proteins are tightly controlled by IκB proteins, which mask the nuclear localization signal (NLS) of NF-κB family members, thereby preventing their nuclear translocation (Siebenlist et al., 1994; Verma et al., 1995; Baeuerle and Baltimore, 1996). In response to many stimuli, such as TNFα, lipopolysaccharide (LPS), or interleukin-1 (IL-1), IκB kinase (IKK) is activated and can phosphorylate IκBs, which, in turn, can be polyubiquitinated and rapidly degraded by the proteasome (Baeuerle and Baltimore, 1996), allowing the release of sequestered NF-κB. Once translocated into the nucleus, NF-κB is able to activate its target genes, which, depending on the physiological circumstances (Barkett and Gilmore, 1999), can mediate cell survival or apoptosis. Among the anti-apoptotic genes up-regulated by NF-κB are included cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1 and c-IAP2), TNFR associated factors 1 and 2 (TRAF1 and TRAF2), cellular FLICE-like inhibitory protein (c-FLIP), and Bcl-XL (Beg and Baltimore, 1996; Liu et al., 1996; Van Antwerp et al., 1996; Wang et al., 1996; Wang et al., 1998). It has been recently documented that the dual function of NF-κB, as an inhibitor or activator of apoptosis, depends on the relative levels of RelA and c-Rel subunits (Chen et al., 2003). Over-expression of RelA or a transcriptional-deficient mutant of c-Rel inhibits TRAIL-induced apoptosis in mouse embryonic fibroblasts, whereas depletion of RelA increases cytokine-induced apoptosis (Chen et al., 2003). NF-κB inactivation has been reported to play a critical role in the sensitization of hepatoma cells to TRAIL-induced apoptosis by interferon-α (Shigeno et al., 2003).

thumbnail image

Figure 1. Schematic representation of TNF-related apoptosis-inducing ligand (TRAIL)-mediated signaling pathways in a hypothetical cell model. Activation of TRAIL receptors can trigger both death and survival pathways, depending on the cell system and environmental conditions. TRAIL-R1 and -R2 can lead to apoptotic cell death by the recruitment of FADD and the following cleavage of caspase-8 and -10. Both death receptors together with the decoy TRAIL-R4 are also involved in the priming of survival genes through the activation of (a) NF-κB and JNK pathways triggered by the engagement of TRAF2 and RIP; (b) PI-3K/Akt and MAPK/ERK1-2 pathways, by means of still unknown mechanisms (highlighted with a question mark). Other mechanisms leading to TRAIL resistance include different caspase or PI-3K physiological inhibitors. The connection between PI-3K/Akt and NOS pathways is also shown.

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A number of other reports investigated the intracellular molecules and mechanisms of TRAIL resistance although the complete comprehension of this matter is far from being obtained (Fig. 1). Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer (Chen et al., 2001) and protects HL60 leukemia cells from TRAIL-induced apoptosis by activating NF-κB and up-regulating c-FLIP (Bortul et al., 2003). Akt, also known as protein kinase B (PKB), is a serine/threonine kinase which acts as a transducer of many functions initiated by the growth factor receptors that activate phosphatidylinositol 3-kinase (PI 3-kinase). Experiments performed with a pharmacological inhibitor of the PI 3-kinase/Akt pathway (LY294002) or a dominant-negative Akt (K179M) demonstrated that TRAIL significantly protected primary human endothelial cells (HUVEC) from apoptosis induced by trophic withdrawal via Akt and that inhibition of Akt sensitized HUVEC to TRAIL-induced caspase-dependent apoptosis (Secchiero et al., 2003a). TRAIL also stimulated the ERK1/2, members of the mitogen-activated protein (MAP) kinase family, but not the p38 or the JNK pathways and induced a significant increase in endothelial cell proliferation in an ERK-dependent manner (Secchiero et al., 2003a). Moreover, our group has shown that TRAIL sequentially activates anti-apoptotic (Akt, ERK, and NF-κB) and pro-apoptotic (caspases) pathways in the SK-N-MC neuroblastoma cell model (Milani et al., 2003). A possible interplay between the Akt and caspase pathways has been already described in several cell systems (Cardone et al., 1998; Gibson et al., 2002; Jones et al., 2002; Rokhlin et al., 2002). The picture emerging from these studies is that, when survival signals dominate, Akt impairs the activation of the apical caspases, by directly phosphorylating caspase-9 (Cardone et al., 1998) or by inhibiting the recruitment of procaspase-8/-10 to the death-inducing signaling complex (Jones et al., 2002). On the other hand, when pro-apoptotic signals prevail, apical caspases-8/-10 activate downstream caspases, which cleave and inactivate Akt (Milani et al., 2003) as well as other anti-apoptotic pathways.

Additional cell survival promoting pathways are likely to influence sensitivity to TRAIL-induced apoptosis. The tumor suppressor p53 acts by up-regulating TRAIL-R2 and sensitizing cells to the cytotoxic action of TRAIL (Wu et al., 1997), while protein kinase C (PKC), once activated, is able to inhibit the recruitment of key obligatory death domain-containing adaptor proteins to their respective membrane-associated signaling complexes, thereby modulating TRAIL-induced apoptosis and NF-κB activation (Harper et al., 2003). The involvement of NO (nitric oxide)/NOS (nitric oxide synthase) and COX (cyclooxygenase) pathways has been evidenced in different cell models exposed to TRAIL: primary human endothelial cells (Zauli et al., 2003), HL60 cells, normal human CD34+ cells and freshly isolated peripheral blood (PB) CD14+ monocytes (Secchiero et al., 2002). Interestingly, whereas no cytotoxic effects were observed in primary normal cells, in myeloid leukemia cell lines TRAIL-mediated cytotoxicity was significantly enhanced by the association with NO donors, such as sodium nitroprusside (SNP), which, when used alone, displayed only minimal cytotoxicity on leukemic cells (Richardson et al., 1995; Shami et al., 1995; Secchiero et al., 2002).

Finally, beside the molecules activated by TRAIL inside the cell, it is worth outlining that TRAIL can itself transduce a reverse signal outside the cell (Chou et al., 2001) or can be induced itself at gene level by a number of molecules. Among these molecules, the most important are IFNs, which play an essential role in host defense through their anti-viral and anti-tumor effects, but which can also lead to apoptotic death in various cancer cell lines (reviewed in Chawla-Sarkar et al., 2003). The latter effect would be mediated by transcriptional induction of TRAIL gene following recruitment at receptor level of the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway (Stark et al., 1998).

Biological effects and physiological roles

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  8. Acknowledgements

Since a few years ago, the known biological activity of TRAIL was far limited to induce apoptosis in various cell lines, including some of hematopoietic origin (Snell et al., 1997; Clodi et al., 2000). In more recent years, new regulatory, pro-survival and proliferation effects are being attributed to this cytokine (Chu et al., 1997; Secchiero et al., 2002, 2003a; Zauli et al., 2003) and, what was more unexpected, this was not restricted to normal primary cells, but extended to neoplastic cell lines of leukemic and non-leukemic origin (Ehrhardt et al., 2003).

TRAIL has been shown to induce apoptosis in a number of tumor cell lines as well as in some primary tumors whereas cells from most normal tissues are highly resistant to TRAIL-induced apoptosis (Table 1). A number of drugs have been used in combination with TRAIL to increase the induction of apoptosis both in cell lines (Liu et al., 2003; Siervo-Sassi et al., 2003) and in cells freshly isolated from myeloma patients (Liu et al., 2003). Although a role for TRAIL in physiologic conditions has not been clearly envisioned yet, TRAIL shows inhibitory effects on normal immature erythroblasts (De Maria et al., 1999; Zamai et al., 2000; Secchiero et al., 2004), T lymphocytes (Marsters et al., 1996; Song et al., 2000), and hepatocytes (Jo et al., 2000). To explore whether TRAIL might play a role in the homeostatic control of hematopoiesis, freshly isolated adult PB CD34+ hematopoietic progenitors as well as erythroid (glycophorin A+), megakaryocytic (CD61+), granulocytic (CD15+), and monocytic (CD14+) precursor cells generated in vitro in liquid suspensions and semisolid cultures were employed (Zamai et al., 2000). Pre-exposure to TRAIL significantly decreased the number and size of erythroid colonies in semisolid assays without influencing the survival of cells differentiating along the megakaryocytic, granulocytic, or monocytic lineages. In spite of this negative regulation of erythropoiesis, TRAIL acts as a positive regulator of myeloid differentiation, since it is able to increase the number of mature monocytes and macrophages when added to liquid cultures of primary normal CD34+ cells induced with SCF and GM-CSF in the absence of cytotoxic effects (Secchiero et al., 2002). Instead, this maturation effect is paralleled by a rapid cytotoxicity in malignant HL60 cell line (Secchiero et al., 2002, 2003b), disclosing therapeutic implications for the treatment of acute myeloid leukemia.

TRAIL/Apo2L is expressed on different cells of the immune system including CD4+ T cells, NK cells, macrophages and dendritic cells and plays a role in NK cell-mediated tumor surveillance (Kayagaki et al., 1999a,b; Kaplan et al., 2000; Wallin et al., 2003) and in preventing autoimmunity, as recently displayed in mouse models (Song et al., 2000). On the other hand, the up-regulation of TRAIL expression was related to an enhanced lymphocyte proliferation and IFN-γ production in mouse models following TCR activation (Chou et al., 2001). This finding represents another example of reverse signal transduction already described in the activation of the immune system by other members of the TNF super-family (Wiley et al., 1996; Lens et al., 1999; Suzuki and Fink, 2000). Interestingly, in virus-induced diseases, including AIDS, an increased expression of TRAIL in infected cells is one of the mechanisms responsible for virus-induced apoptosis (Sedger et al., 1999; Clarke et al., 2000; Miura et al., 2001).

Finally, a novel role of this cytokine is emerging in endothelial cell physiology regulation (Secchiero et al., 2003a; Zauli et al., 2003). In fact, in primary human endothelial cells TRAIL is able to promote either survival or proliferation as well as cell migration and cytoskeleton reorganization, without inducing NF-κB activation and inflammatory markers.

Clinical perspectives and therapeutic use

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  8. Acknowledgements

It has been shown that TRAIL induces growth arrest and apoptosis in cancer cells independently of p53 wild-type function (Levine, 1997), Bcl-2 and Bcl-XL (Walczak and Krammer, 2000) and MDR gene expression (Snell et al., 1997). Thus, TRAIL may offer an alternative or complementary approach to conventional anticancer therapy. Unlike other members of the TNF super-family, such as CD95L and TNFα, that are precluded from use in systemic anticancer therapy due to their severe toxic side effects (Tartaglia and Goeddel, 1992; Nagata, 1997), TRAIL is effective in selectively killing both in vitro and in vivo a vast array of tumor cells from lung, breast, kidney, colon, prostate, thyroid, and skin cancers (Sheikh et al., 1998; Gliniak and Le, 1999; Keane et al., 1999; Sedger et al., 1999; Walczak et al., 1999; Ahmad and Shi, 2000; Yu et al., 2000), without causing significant organ toxicity and inflammation in vivo. Although it is not established whether TRAIL causes liver toxicity in humans (Jo et al., 2000; Lawrence et al., 2001), pre-clinical studies are promising. Recombinant human TRAIL protein systematically injected in mice and non-human primates promotes potent apoptosis-inducing activity against tumor cells (Ashkenazi et al., 1999; Walczak et al., 1999). Moreover, newly developed anti-TRAIL-R2 antibodies exhibit strong anti-tumor activity both in vitro and in vivo without displaying hepatocyte cytotoxicity (Ichikawa et al., 2001). Therefore, TRAIL is a strong candidate for an effective but tolerable treatment of solid cancers, either used alone or in combination with radio/chemotherapy. In this respect, it has been proposed that TRAIL synergistically cooperates with: (i) chemotherapeutic drugs, such as etoposide, campthotecin-11, doxorubicin, 5-fluorouracil, taxol (Keane et al., 1999; Gliniak and Lee, 1999; Kim et al., 2000; Nagane et al., 2000; Gibson et al., 2002); and (ii) ionizing radiation (Chinnaiyan et al., 2000; Zhou et al., 2000), causing substantial regression or complete ablation of solid (colon and mammary) cancers in animal models. Besides acting as a tumor suppressor in vivo in primary tumors, TRAIL could play a substantial role in suppressing tumor metastasis. In fact, it has been observed that this cytokine may partially limit the formation of hepatic metastases of a variety of mouse tumors (Seki et al., 2003). It has also been shown that TRAIL exerts a variable cytotoxic activity on hematological malignancies (Snell et al., 1997), and we and other authors have demonstrated that TRAIL-mediated cytotoxicity is increased by ionizing radiation and chemotherapeutic drugs in both myeloid and erythroid leukemic cell lines as well as in T lymphoma cell lines (Gong and Almasan, 2000; Wen et al., 2000; Di Pietro et al., 2001). Day by day, an increasing number of drugs warrant further investigation as potential new strategies for the treatment of human glioma (Hermisson and Weller, 2003), lung cancer (Frese et al., 2003), myeloma (Liu et al., 2003), or acute myelogenous leukemia (AML) in combination with recombinant soluble TRAIL (Suh et al., 2003). In addition, TRAIL has been recently proposed to be used as an ex vivo purging agent for autologous transplantation in hematological malignancies (Lee et al., 2003).

The scenario emerging from all these studies is that the therapeutic use of TRAIL as an inducer of tumor specific cell death can be considered as an useful strategy to overcome resistance of cancer cells to conventional chemotherapeutic agents (Bhojani et al., 2003). But some concerns are inevitable in light of a very recent report showing that TRAIL, unlike other death inducing ligands, such as TNFα and CD95L, is able to induce cancer cell proliferation in a wide range of neoplastic diseases (Ehrhardt et al., 2003). Given the promising therapeutic potential of TRAIL as a novel anticancer drug, TRAIL-mediated survival or proliferation of target cells may restrict its use to apoptosis-sensitive tumors and may represent a potential risk for patients with TRAIL apoptosis-resistant tumor cells as it might increase tumor growth. Further studies based on in vivo animal models of TRAIL apoptosis-resistant tumors are necessary to elaborate the clinical relevance of TRAIL-mediated survival and proliferation of TRAIL apoptosis-resistant tumors.

Finally, a special mention deserves the new perspective to use TRAIL in association to immune therapy both in cancer therapy (Suh et al., 2003) and as a potential response marker for IFNβ treatment in multiple sclerosis (Wandinger et al., 2003).


  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  8. Acknowledgements

This review was focused to present new emerging anti-apoptotic roles of TRAIL in physiologic and patho-physiologic conditions. We are aware that few data are available up to now concerning normal cells and their different sensitivity to this ligand but we hope to have stimulated discussion and to have given a little contribution to the understanding of this intriguing ligand-receptor system in view of a possible use of TRAIL as a “protective” agent in particular body compartments and conditions.


  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  8. Acknowledgements

The authors thank Miss Luciana Caravatta for artwork and bibliographic research. This study was partially supported with 2001 MIUR COFIN funds “Studio dei meccanismi sottostanti la citotossicità di TRAIL in neoplasie ematologiche: basi per una terapia combinata.”


  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  8. Acknowledgements
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