Harnessing Tumor Necrosis Factor Receptors to Enhance Antitumor

Jul 8, 2011 - 1. Introduction. 1610. 2. Tumor Necrosis Factor Receptor Superfamily. 1610 ... factor receptor (TNF-R) superfamily that have been evalua...
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Harnessing Tumor Necrosis Factor Receptors to Enhance Antitumor Activities of Drugs Jordi Muntane* Liver Research Unit, IMIBIC (Instituto Maimonides para la Investigacion Biomedica de Cordoba), “Reina Sofia” University Hospital, Cordoba, Spain, and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd) ABSTRACT: Cancer is the second-leading cause of death in the U.S. behind heart disease and over stroke. The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The inhibition of cell death pathways is one of these tumor characteristics which also include sustained proliferative signaling, evading growth suppressor signaling, replicative immortality, angiogenesis, and promotion of invasion and metastasis. Cell death is mediated through death receptor (DR) stimulation initiated by specific ligands that transmit signaling to the cell death machinery or through the participation of mitochondria. Cell death involving DR is mediated by the superfamily of tumor necrosis factor receptor (TNF-R) which includes TNF-R type I, CD95, DR3, TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 (TRAIL-R1) and -2 (TRAIL-R2), DR6, ectodysplasin A (EDA) receptor (EDAR), and the nerve growth factor (NGF) receptor (NGFR). The expression of these receptors in healthy and tumor cells induces treatment side effects that limit the systemic administration of cell death-inducing therapies. The present review is focused on the different therapeutic strategies such as targeted antibodies or small molecules addressed to selective stimulated DR-mediated apoptosis or reduce cell proliferation in cancer cells.

’ CONTENTS 1. Introduction 2. Tumor Necrosis Factor Receptor Superfamily 2.1. TNF-R1 2.2. CD95 2.3. DR3 2.4. TRAIL-R 2.5. DR6, EDAR, and NGFR 3. Concluding Remarks and Future Directions Author Information Acknowledgment Abbreviations References

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1. INTRODUCTION Hundreds of relatively specific drugs are in development, but few have been approved for common malignancies. The administration of drugs targeting widely expressed kinases in broad patient populations have resulted in modest response rates, marginal changes in natural history, and toxicities that may impact patient quality of life.1 Different clinical trials have described marginal benefits in a population which also includes a harmed fraction of patients.2 In fact, the presence of mutations and/or alterations in downstream molecules may confer adverse impact on overall survival in a precise subset of the treated r 2011 American Chemical Society

patients. Biological characterization must describe areas of tumor biology relevant to therapeutic effectiveness: the underlying patient-specific abnormality and the integrity of cell death and survival pathways, as well as drug transport mechanisms relevant to potential therapeutic agents. The present review is addressed to the current biologic characterization affecting cell proliferation and death pathways involving the tumor necrosis factor receptor (TNF-R) superfamily that have been evaluated as potential antitumoral target strategies.

2. TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY Apoptotic cell death is a regulated genetic process which plays an important role in the remodeling of tissue, as well as in the maintenance of physiologic growth control and homeostasis. The resistance to apoptosis is a key event in the development of tumors.3 The induction of apoptosis is carried out through cell death receptor (DR) stimulation initiated by specific ligands that transmit signaling to the cell death machinery (type I cells, extrinsic way) or through the participation of the mitochondria (type II cells, intrinsic way). In this sense, the selective triggering of DR-mediated apoptosis in cancer is a novel approach in cancer therapy. The superfamily of TNF-R includes 8 cell DRs: TNF-R type I, CD95, DR3, TNF-related apoptosis inducing ligand (TRAIL) receptor-1 (TRAIL-R1) and -2 (TRAIL-2), DR6, Received: June 6, 2011 Published: July 08, 2011 1610

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Chemical Research in Toxicology

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Table 1. DR Belonging to the Superfamily of Tumor Necrosis Factor Receptors death receptors

alternative names

ligands

TNF-R1

p55, CD120a, DR1

TNF-R

CD95 TRAMP

Fas, Apo1, DR2 Apo3, TRAMP, WSL-1, LARD, DR3

CD95L VEGI, TL1A

TRAIL-R1

DR4, TNFRSF10A

TRAIL

TRAIL-R2

KILLER, TRICK2, DR5, APO-2,

TRAIL

TNFRSF10B DR-6

TR-7, TNFRSF21

EDAR

Anhidrotic receptor, DL, ED1R, ED3,

EDA

ED5, EDA-A1R, EDA3 NGFR

CD271, TNFRSF16

NGF

Figure 1. Therapeutic strategies involving DR. Scheme of cell death receptor signaling. Antibody-dependent cell-mediated cytotoxicity, ADCC; B-cell lymphoma 2, Bcl-2; cellular FLICE inhibitory protein, cFLIP; complement-dependent cytotoxicity, CDC; death domain, DD; death inducing signaling complex, DISC; death receptors, DR; ectodisplasin A, Fas-associated DD, FADD; nuclear factor kappa-light-chainenhancer of activated B cells, NF-kB; receptor-interacting protein, RIP; TNF-R-receptor associated factor 2, TRAF2; TNF-R-associated DD, TRADD.

ectodisplasin A (EDA) receptor (EDAR), and the nervous growth factor (NGF) receptor (NGFR) (Table 1).4 DRs are diverse in primary structure, but all of them contain not only the typical amino-terminal cysteine-rich domain, which define their ligand specificity,5,6 but also a cytoplasmatic death domain (DD) of around 80 amino acids, which plays a central role in the activation of the caspase-dependent pathway and induction of apoptosis.7,8 The secretion of DR ligands by immune cells stimulates tumor cell apoptosis (Table 1). Adaptor molecules like Fas-associated death domain (FADD), TNFR-associated death domain (TRADD), or DD-associated protein (DAXX) themselves contain DD so that they can interact with DRs. Two different intracellular signaling complexes coupled to DR exist, one is the complex type I that drive to cell survival,9 and the other is the death inducing signaling complex (DISC) in CD95, TRAIL-R1, TRAIL-R2, or complex II in TNF-R1, DR3, DR6, and EDAR10 (Figure 1). The constituents of complexes I and II, and DISC may vary among receptors according to the assembling of different adaptor molecules.

2.1. TNF-R1. TNF-R, discovered over 30 years ago, is implicated in apoptosis and cell proliferation.11 TNF-R acts as a pro-inflammatory cytokine in a wide spectrum of human inflammatory-related diseases12 but also can induce tumor initiation, proliferation, invasion, angiogenesis, and metastasis.13 TNF-R1 signaling is initiated through the association of its DD to TRADD which may bind to three adaptor molecules: TNF-R-receptor associated factor 2 (TRAF2), receptor interacting protein (RIP), and FADD. The stimulation of cell survival through TNF-R1 requires protein synthesis with the generation of membrane-bound complex 1 in which TRAF2 and RIP engages major survival pathways such as the nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) and mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)/Activator protein 1 (AP-1)14,15 (Figure 1). The induction of cell death involves biochemical alteration of TRADD, TRAF2, and RIP1 with the generation of soluble complex II (traddosome), which lacks TNF-R1 but includes Fas-associated DD (FADD), pro-caspase-8, and variable cFLIPS/L content.15 The therapeutic strategies involve the regulation of TNF-R1 expression and stimulation of cell death. The administration of chemotherapy (doxorubicin, mitoxantrone, and bleomycin) increases the expression of TNF-R,16 18 which increases the susceptibility of tumor cells to cell death (Figure 1). The limited use of TNF-R in clinical oncology has been due to the powerful and toxic systemic side effects of this cytokine. The targeting of TNF-R increasing the local delivery into the cancer site is a useful strategy. The isolated limb perfusion approach coupled to the chemical conjugation of TNF-R to polyethylene glycol prolongs the plasma half-life and increases antitumoral effectiveness of the cytokine.19 Another approach is the locally delivered high doses of TNF-R fused to antibodies or natural ligands targeting surface proteins on cancer cells.20 However, the most promising approach in the TNF-based fusion protein therapy is probably represented by the TNF-R pro-drugs. Here, a homotrimeric molecule comprising an N-terminal single-chain antibody variable fragment targets the fibroblast activation protein (FAP) present in virtually all tumor cell membranes but not in normal cells, a trimerization domain (derived from tenascin), TNF-R, and a C-terminal TNF-R1 fragment which protects TNF-R from activation.21 TNFerade, employs a replication-deficient adenovector carrying the gene for human TNF-R, and is under evaluation in several advanced phase I, II, and III clinical trials for patients with sarcomas, melanomas, and cancers of the pancreas, esophagus, rectum, head and neck.22 The inhibition of survival pathways during TNF-R1 stimulation is an interesting approach for antitumoral properties of the pathway. TNF-R-induced apoptosis in tumor cells is increased by the inhibition of NF-kB activation by overexpression of its inhibitor IkB or administration of selective NF-kB inhibitors.23 25 Bortezomib (PS-341), a boronic acid dipeptide, is a proteasome inhibitor that has been shown in phase II clinical trials to be useful for the treatment of patients with myeloma resistant to conventional therapy.26 Several chimeric or humanized monoclonal antibodies against TNF-R such as Infliximab, Adalimumab, Golimumab, and CDP-571 lead to complement-dependent cytotoxicity (CDC), antibody dependent cell-mediated cytotoxicity (ADCC), and to interfering cell signaling (apoptosis/survival and cytokine production).27 This strategy has shown to induce cell cycle arrest and apoptosis in different experimental conditions.28,29 However, TNF-R antagonist has been demonstrated to be associated with opportunist infections, autoimmune diseases, lymphoproliferative disorders, and other malignancies that may be caused by 1611

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Chemical Research in Toxicology chronic inflammation.30 Thalidomide that increases degradation of TNF-R mRNA31 has demonstrated to increase peripheral CD8 T cells and reduce angiogenesis and the proliferation of tumor cells.32 2.2. CD95. The DISC configuration during CD95 activation requires trimerization of the receptor and recruitment of FADD, caspase-8 and -10, and cFLIPL/S.10,33,34 The binding of procaspase-8 to DISC induces its processing and the formation of an active tetramer which propagates the apoptotic signal.35 cFLIPL/S inhibits the activation of pro-caspase-8.36 The binding of TRAF2 or RIP to FADD will shift the signal to cell survival pathways such as NF-kB, Akt, JNK, and p3837 40 (Figure 1). Therapeutic properties of different antitumoral agents have been related to the regulation of the expression of the CD95/ CD95L system, as well as the use of defective adenoviralencoding recombinant CD95L or tissue-specific CD95 agonistic antibodies to induce apoptosis in tumor cells. The administration of doxorubicin, mitomycin, mitoxantrone, methotrexate, cisplatin, adriamycin, and bleomycin increases the expression of CD95 through the accumulation of p53, which may increase the susceptibility of tumoral cells to cell death.16,41 44 The expression of CD95L is regulated by dependent and independent p53 mechanisms.45 47 The expression of cFLIP has been shown to correlate with resistance to Fas-induced apoptosis in different tumor cell lines,36 as well as with tumor escape from T cell immunity and enhanced tumor progression in vivo.48 Different agents reduce cFLIP expression and consequently increase cell death, through mechanisms that could involve the stimulation of the ubiquitin proteasome pathway.49 Intense research in the field has identified a tissue-specific CD95-agonist antibody R-125224 which induces apoptosis in type I activated lymphocytes but not in type II cells.50 The increased expression of CD95L in tumor cells to promote cell death has also been developed using adenoviral vector51,52 and cell surface-targeted CD95L fusion protein such as sc40-FasL constituted by the extracellular domain of CD95L fused to a single-chain antibody that specifically recognizes the tumor stroma marker FAP.53,54 The use of CD95L recombinant protein increased adriamycin-induced cell death in a model of hepatocellular carcinoma.55 The use of another CD95L recombinant form (APO010) is under phase I clinical study.20 2.3. DR3. DR3 is preferentially expressed in peripheral blood leukocytes and in lymphocyte-rich tissues, including the thymus and spleen, and to a lesser extent in the small intestine, colon, fetal lung, and fetal kidney.56,57 DR3 contains four characteristic cysteine-rich motifs as well as a DD capable of inducing cellular apoptosis and proliferation.58 The ligand of DR3 is the vascular endothelial cell-growth inhibitor (VEGI or TL1A) produced by endothelial and dendritic cells.59,60 DR3 interacts with TRADD, TRAF2, FADD, and pro-caspase-8 to similar extent as TNF-R1 but at lower affinity than the CD95 receptor.61,62 The administration of anti-VEGI and -DR3 antibodies lead to increases of both cell proliferation and motility, and an induction of the formation of tube network.63 As observed in other DRs, the inhibition of protein synthesis by cycloheximide increases the apoptotic response associated with VEGI-stimulated cells.64 DR3-deficiency induces an impaired T cells immunopathology, local T cell accumulation, and cytokine production in autoimmune and inflammatory diseases.65 Therapy for cancer should aim to promote the antitumor activity of T cells, antigen presenting cells, NK, and NKT cells to induce cell death in tumor cells and to promote immunological memory that protects against tumor recurrence. In this sense, DR3 stimulation may promote cytokine

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production and T cell activation which stimulates the immune response against cancer cells. In fact, regulation of DR3 activity has been suggested to be an attractive therapeutic target for T cellmediated autoimmune and allergic diseases.66 However, the down regulation of DR3 by natural compounds has reduced NF-kBdependent cell survival and promotes cell death in pancreatic67 and hepatic68 cancer cells. 2.4. TRAIL-R. TRAIL is the ligand of DR4 and DR5 which induces apoptosis in tumorigenic or transformed cells and at a lower extent in normal cells.69 TRAIL is expressed in a wide range of tissues, in contrast to other TNF family members whose expression is tightly regulated and often only transient.69 Not all tumors simultaneously display TRAIL-R1 and -R2 or have both functional receptors.70,71 TRAIL efficiently induces trimerization and activation of DR4 and DR5, leading to the generation of the active DISC complex and apoptotic signaling.72,73 The therapeutic strategies involve the regulation of TRAIL-R expression, as well as the administration of recombinant human TRAIL, defective adenovirus-encoding TRAIL, or agonistic antiTRAIL monoclonal antibodies, ionizing radiation, and inhibitors of NF-kB, kinases and histone deacetylase, and immune-based therapies to sensitize tumor cells. 74 The administration of chemotherapeutic agents (doxorubicin, mitoxantrone, and bleomycin) or radiotherapy increases the expression of TRAILR1 and TRAIL-R216 through p53 which increases the susceptibility to cell death of tumoral cells.16 18,75 The administration of recombinant human TRAIL (hrTRAIL) induces apoptosis in multiple malignant cell lines derived from both solid and hematologic malignancies, and either alone or in combination with various chemotherapy agents or radiation.76,77 The administration of nonreplicative recombinant adenoviral vector encoding the human TRAIL cDNA can also trigger apoptosis in tumor cells77,78 and in tumor-bearing in vivo studies.79 The administration of Bortezomib sensitizes the breast, colon, and kidney cancer cell lines to apoptosis induced by TRAIL-R1 agonistic monoclonal antibodies80 and hrTRAIL.81 Other treatments such as sorafenib,82 histone deacetylase,83 and B-cell lymphoma 2 (Bcl-2) inhibitors84 sensitize cancer cells to TRAILinduced apoptosis (Figure 1). Several phase I clinical trials have obtained positive results on the administration of rhTRAIL85 and TRAIL-R1 agonistic antibodies either alone86 or combined with paclitaxel/carboplatin87 in solid tumors and/or non-Hodgkin’s lymphoma. TRAIL-R2 agonistic antibodies have also been evaluated in clinical trials for the treatment of patients with advanced solid tumors.20,88,89 2.5. DR6, EDAR, and NGFR. DR6 is an orphan member of the TNF-R receptor superfamily in which the cytoplasmatic domain possesses 4 copies of DD. DR6 is expressed in lymphoid organs such as the thymus, spleen, and lymphoid cells90 but also in numerous tumor cell lines.91 Similar to TNFR1 and DR3, the primary adaptor for DR6 is TRADD, around which FADD, TRAF2, and RIP assemble.92 DR6 has been mostly involved in inflammatory responses and immune regulation. DR6-deficient mice display increased humoral immunity based on profound polarization toward a Th2 response and increased B cell proliferation by the alteration of JNK/NF-kB-associated cell survival signaling.93,94 Therapeutic strategies leading to the reduction of DR6 expression in cancer cells may be useful to increase the immune response. EDA is involved in various signaling pathways including the immune response, inflammation, and ectoderm-derived organs in humans.95 Two splice EDA isoforms, EDA-A1 and EDA-A2, 1612

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Chemical Research in Toxicology are generated that bind to EDAR and X-linked ectodermal dysplasia receptor (XEDAR). EDA receptors recruit the adaptor molecules TRAF1, TRAF3, and TRAF6, being the last one responsible for NF-kB activation. XEDAR expression is decreased in colon and breast cancer cells96 and appears to induce cell death after EDA-A2 binding.97,98 Chemotherapy increased susceptibility to EDA2R-induced cell death by p53-dependent transactivation (Figure 1).99 The neurotrophin family of growth factors (NGF, BDNF, NT-3, and NT-4/5) bind to the tyrosine kinase neutrophin (Trks A, B, C) and the intrinsic serine threonine kinase p75NGFR receptors. The signal has been implicated in the regulation of neuronal proliferation and death. All neutrotrophins bind to p75NGFR with low affinity but in concert with the appropriate Trk with high affinity.100 The extracellular domain has four pseudorepeats of cysteine-rich regions which include the neurotrophin-binding domain, and the cytoplasmatic domain shows a DD. p75NGFR is expressed in the nervous system, limb bud fibroblasts, kidneys, lungs, testes, inner ear, and hair follicles101 but also in different human cancer tissues such as breast cancer, acute leukemia, papillary thyroid carcinoma, human pancreatic cancer, and prostate carcinoma.102,103 Several signaling pathways have been linked to the Trk receptors, including PI-3 kinase/Akt, phospholipase C, MAP kinase, and the Ras GTPase activating protein,104 whereas p75NGFR signaling may lead to cell death or survival depending on the absence or presence of the ligand.100 The dysregulation of the NGF-mediated control of prostate cell growth is associated with malignant progression,105 which can be blocked by NTRK1 kinase inhibitors.106,107 The upregulation of p75NGFR led to the downregulation of different regulatory proteins of cell cycle progression which suggest a role of this receptor as a tumor suppressor in gastric cancer cells.108 However, anti-BDNF, anti-NT-4/5, anti-p75(NTR), or anti-TrkB-T1 treatments resulted in tumor growth inhibition in a breast cancer xenograft mouse model.109 In this sense, the successful therapeutic strategy will depend upon the presence of NGF ligands and differential NGFR expression in tumors.

3. CONCLUDING REMARKS AND FUTURE DIRECTIONS The induction of cell death or prevention of cell proliferation through the regulation of DR signaling has been demonstrated to be useful strategies to treat cancer. The presence of mutations and/or alterations in downstream DR signaling may confer adverse impact on overall survival in a precise subset of patients. The careful selection of patients according to the specific DR-based biological characteristics will allow personalized therapy with increased overall survival of the patients. Although some of the DRs such as TRAIL-R induce apoptosis more efficiently in cancer than normal cells, the future strategies should evolve to targeted antitumoral strategies with local delivery of agents into tumors avoiding systemic administration and toxicity toward normal cells. The stimulation of DR expression and mitochondrial-associated cell death by chemotherapy administration may be useful for future combined targeted antitumoral therapies. This scenario opens a broad array of therapeutic interventions based on targeted antibodies or small molecules specifically addressed to DR-dependent cell signaling in synergism with chemotherapy, which can improve the clinical outcome of malignancies.

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’ AUTHOR INFORMATION Corresponding Author

*Unidad de Investigacion, Hospital Universitario Reina Sofía, Av. Menendez Pidal s/n, E-14004 Cordoba, Spain. Tel: (+34) (957) 011070. Fax: (+34) (957) 010452. E-mail: jordi.muntane.exts@ juntadeandalucia.es. Funding Sources

This study has been supported by Instituto de Salud Carlos III (FIS 09/00185) and Consejería de Salud (2008/169). I acknowledge a grant by Instituto de Salud Carlos III.

’ ACKNOWLEDGMENT CIBERehd was funded by Instituto de Salud Carlos III. ’ ABBREVIATIONS AP-1, activator protein 1; ADCC, antibody dependent cellmediated cytotoxicity; Bcl-2, B-cell lymphoma 2; CD95L, CD95 ligand; cFLIP, cellular FLICE inhibitory protein; JNK, c-Jun N-terminal kinase; CDC, complement-dependent cytotoxicity; DAXX, DD-associated protein; DD, death domain; DISC, death inducing signaling complex; DR, death receptors; EDA, ectodisplasin A; EDAR, EDA receptor; FADD, Fas-associated DD; FAP, fibroblast activation protein; MAPK, mitogen-activated protein kinase; NGF, nervous growth factor; NGFR, NGF receptor; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphatidylinositol 3-kinases; RIP, receptor interacting protein; TRAIL, TNF-related apoptosis inducing ligand; TRAF2, TNF-R-receptor associated factor 2; TRADD, TNF-R-associated DD; TNF-R, tumor necrosis factor receptors; VEGI, vascular endothelial cell-growth inhibitor; XEDAR, X-linked ectodermal displasia receptor. ’ REFERENCES (1) Ricciardi, S., Tomao, S., and de Marinis, F. (2009) Toxicity of targeted therapy in non-small-cell lung cancer management. Clin. Lung Cancer 10, 28–35. (2) Fojo, T., and Parkinson, D. R. (2010) Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much? Clin. Cancer Res. 16, 5972–5980. (3) Zhivotovsky, B., and Kroemer, G. (2004) Apoptosis and genomic instability. Nat. Rev. Mol. Cell Biol. 5, 752–762. (4) Bhardwaj, A., and Aggarwal, B. B. (2003) Receptor-mediated choreography of life and death. J. Clin. Immunol. 23, 317–332. (5) Naismith, J. H., and Sprang, S. R. (1998) Modularity in the TNFreceptor family. Trends Biochem. Sci. 23, 74–79. (6) Bodmer, J. L., Schneider, P., and Tschopp, J. (2002) The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26. (7) Fulda, S., and Debatin, K. M. (2004) Exploiting death receptor signaling pathways for tumor therapy. Biochim. Biophys. Acta 1705, 27–41. (8) Ashkenazi, A., and Dixit, V. M. (1998) Death receptors: signaling and modulation. Science 281, 1305–1308. (9) Lavrik, I., Golks, A., and Krammer, P. H. (2005) Death receptor signaling. J. Cell Sci. 118, 265–267. (10) Peter, M. E., and Krammer, P. H. (2003) The CD95(APO-1/ Fas) DISC and beyond. Cell Death Differ. 10, 26–35. (11) Locksley, R. M., Killeen, N., and Lenardo, M. J. (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501. 1613

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