Tumor necrosis factor-a in the pathogenesis and treatment
`of cancer
`G Mark Anderson , Marian T Nakada and Mark DeWitte
`
`The critical pathogenic role of tumor necrosis factor (TNF)a
`in inflammatory disorders such as rheumatoid arthritis and
`inflammatory bowel disease is well established. The role
`played by TNFa in both the treatment and pathogenesis of
`cancer remains less understood. Recent advances help to
`create a framework for understanding seemingly paradoxical
`effects of TNFa as both an anti-tumour agent and a mediator
`of tumour growth. High pharmacological doses of TNFa
`combined with chemotherapy can regress otherwise
`intractable tumours, and efforts continue to optimize delivery
`to avoid severe toxicities. Mounting evidence demonstrates
`that pathophysiological concentrations of endogenous TNFa
`act to promote tumour genesis and growth. The cellular and
`molecular pathways mediating these phenomena are starting
`to be clarified. Current data support the continued
`development of both TNFa and anti-TNFa therapy for
`clinical treatment of cancers in distinct settings.
`
`Addresses
`Centocor, 200 Great Valley Parkway, Malvern, PA 19355, USA
` e-mail: MAnders4@cntus.jnj.com
`
`Current Opinion in Pharmacology 2004, 4:314–320
`
`This review comes from a themed issue on
`Cancer
`Edited by Aristides Eliopoulos and Lawrence Young
`
`Available online 17th June 2004
`
`1471-4892/$ – see front matter
`ß 2004 Elsevier Ltd. All rights reserved.
`
`DOI 10.1016/j.coph.2004.04.004
`
`Abbreviations
`CLL
`chronic lymphocytic leukemia
`GVHD graft versus host disease
`IL
`interleukin
`MDS
`myelodysplastic syndrome
`MMP
`matrix metalloproteinase
`NF-jB nuclear factor-kB
`TNF
`tumor necrosis factor
`TNFR
`TNF receptor
`
`has previously been reviewed [1,2,3]. TNFa mediates
`tumour regression, and recombinant TNFa is approved in
`Europe to be administered locoregionally at supra-
`physiological levels as a therapy for sarcoma [4]. The
`concept that the major effects of endogenous TNFa in
`cancer are opposite to the effects observed with high dose
`TNFa therapy has gained momentum recently [5].
`Instead of causing tumour regression, cancer-derived
`TNFa can mediate tumour progression by causing the
`proliferation, invasion and metastasis of tumour cells (see
`also Update). The paradox that this cytokine is both a
`‘tumour necrosis factor’ and a ‘tumour-promoting factor’
`is lucidly explored by Balkwill [6]. This paradox can be
`explained partly by the differences in levels of TNFa in
`distinct settings. When TNFa is administered therapeu-
`tically in extremely high doses, it acts as a vasculotoxic
`tumour-regressing agent. However, when TNFa is pro-
`duced by tumours and tumour-associated macrophages or
`stromal cells at physiological levels, it promotes tumour
`growth and additional macrophage recruitment, stimulat-
`ing the elaboration of angiogenic and growth factors from
`infiltrating cells.
`
`TNFa-mediated cellular signaling
`The signaling pathways that determine whether a cell
`will respond to endogenous TNF by proliferating or by
`undergoing apoptosis continue to be elucidated. Micheau
`and Tschopp [7] reported a new model with evidence
`for the production of two distinct intracellular complexes
`after TNFa binds to TNFR1 in HT1080 fibrosarcoma
`cells. The first complex promotes cell survival by induc-
`tion of nuclear factor-kB (NF-kB). The second complex,
`formed substantially later after receptor ligation, is cyto-
`plasmic and spatially removed from the initial receptor
`complex. The second complex is pro-apoptotic but can be
`inhibited by anti-apoptotic gene products previously
`induced via the NF-kB pathway. This system represents
`a switch that can determine the fate of a given cell
`receiving a TNFa signal. That fate clearly will vary
`depending upon the presence or absence of key signaling
`factors resulting from cell-specific gene expression or the
`mutational status of the cell.
`
`Introduction
`Tumor necrosis factor (TNF)a is a potent pleiotropic
`proinflammatory cytokine produced by macrophages,
`neutrophils, fibroblasts, keratinocytes, NK cells, T and
`B cells, and tumour cells. TNFa mediates host responses
`in acute and chronic inflammatory conditions, and is a
`mediator of protection from infection and malignancy.
`The biology of the TNF/TNF receptor (TNFR) system
`
`TNFa as a therapy for cancer
`Systemically administered TNF-a was evaluated in the
`clinic in the 1980s as a therapy for solid tumours, and was
`found to have severe toxicities, most notably hypotension
`and organ failure [8]. Studies revealed that the maximally
`tolerated dose of TNFa was significantly lower than that
`required to cause anti-tumour effects. The delivery of
`locally high levels of TNFa, without systemic exposure,
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`TNF-a in the pathogenesis and treatment of cancer Anderson, Nakada and DeWitte 315
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`is now accomplished by isolated limb perfusion in which
`the circulation of the limb is connected surgically to a
`bypass circuit into which drugs are administered [9].
`Isolated limb perfusion with TNFa in combination with
`chemotherapy is approved in Europe for the treatment of
`locally advanced unresectable soft-tissue sarcomas (for a
`summary of the clinical studies of isolated limb perfusion
`with TNFa, see [9]). Positive clinical data have been
`reported with this TNFa therapy for in-transit melanoma
`and drug-resistant bony sarcomas [9]. Although effective,
`this procedure is highly specialized and not widely used.
`The mechanism of action is believed to involve direct
`toxic effects on the tumour, without affecting normal
`vasculature. TNFa causes vessel regression, as well as
`hemorrhagic necrosis, because it induces endothelial cell
`apoptosis,
`resulting in a procoagulant endothelium.
`TNFa enhances vascular permeability, facilitating the
`uptake and accumulation of chemotherapeutic drugs
`such as melphalan and doxorubicin [9], as well as anti-
`bodies [10]. TNFa alone is not effective when adminis-
`tered via isolated limb perfusion,
`suggesting that
`chemotherapy accumulation is a major mechanism of
`action. The specific effect of TNFa on angiogenic,
`but not normal, vasculature might be attributable to
`the deactivation of the angiogenesis-associated integrin
`avb3. TNFa in combination with interferon-g leads to
`endothelial apoptosis [11].
`
`Many approaches are being used to target therapeutic
`TNFa directly to tumours, without causing systemic
`toxicity. These include gene therapy (TNFerade) [12]
`and TNFa conjugated to targeting peptides or single
`chain antibody fragments (see also Update) [13–15].
`
`Role of TNFa in the pathogenesis of cancer
`In contrast to the use of pharmacologic doses of TNFa as
`an anti-cancer therapeutic, mounting evidence suggests
`that TNFa acts to promote tumour growth and progres-
`sion at physiologically relevant concentrations [16]. Some
`of the most detailed work regarding the role of TNFa as a
`tumour promoter was published in a series of papers from
`the laboratory of Fran Balkwill [16,17,18]. The authors
`used the induction of skin tumours in mice as a model
`system to understand the growth-promoting actions of
`TNFa and its
`signaling pathway.
`In this
`system,
`9,10-dimethyl-1,2-benzanthracene (DMBA) is used as a
`topical DNA-damaging tumour inducer; 12-O-tetrade-
`canoylphorbol-13-acetate (TPA) is then applied as a
`tumour promoter. TNFa was first implicated in tumour
`growth in this model by the observation that TNFa
`knockout mice are highly resistant to the generation of
`skin tumours by this method. The presence of functional
`TNFa has no effect on DNA mutation rates or tumour
`initiation, but
`instead profoundly influences tumour
`promotion. TPA was shown to induce TNFa in skin
`keratinocytes of wild-type mice. The production of
`gene products induced by the activating protein-1 tran-
`
`such as granulocyte-macrophage
`scription pathway,
`factor, matrix metalloproteinase
`colony-stimulating
`(MMP)-3 and MMP-9, is important for the tumour-pro-
`moting effect. Anti-tumour effects were also observed
`following pharmacologic intervention with a neutralizing
`anti-mouse TNFa antibody. The potential role of TNFa
`in the growth of human skin cancers, initiated largely by
`UV radiation, is an important area for future investigation.
`
`Clinical observations supporting a role for
`TNFa in tumor growth
`TNFa plasma levels in cancer patients
`Several reports have associated detection of abnormally
`high levels of TNFa protein in the blood of cancer
`patients with a wide range of tumour types [19], including
`pancreatic [20], kidney [21], breast [22], asbestosis
`induced lung [23] and prostate cancer [24]. Within groups
`of patients with the same tumour type, higher levels of
`TNFa have been correlated with advanced tumour
`stage, greater paraneoplastic complications and shorter
`survival time. However, circulating TNFa is not always
`detectable in cancer patients and can vary within indi-
`vidual patients over time and course of disease [25].
`Regulation of TNFRs is critical to tumour cell respon-
`siveness to TNFa, and tumour tissue levels of TNFa
`might be more relevant than blood levels in explaining
`pro-tumourigenic associations.
`
`Endometriosis and ovarian cancer develop along a con-
`tinuum of malignant
`transformation and promotion.
`Serum TNFa has been associated significantly with
`endometriomas and malignant, cystic and ovarian cancers,
`but not with benign tumours [26]. Inflammatory condi-
`tions associated with endometriosis and ovarian cancer
`include exposure to exogenous irritants and ovulation,
`accompanied by cell proliferation, oxidative stress, vas-
`cular permeability, and overproduction of prostaglandins,
`leukotrienes, TNFa, interleukin (IL)-6 and IL-1 [27].
`mRNA for these cytokines is found in epithelial ovarian
`tumours and in related ascites. TNFa is prevalent in
`peritoneal fluid around endometrial foci. Attracted plate-
`lets and macrophages secrete vascular endothelial growth
`factor, MMP-9 and transforming growth factor-b, and
`promote infiltration of ectopic endometrium and/or inva-
`sion and metastasis. The invasive tissue of endometriosis
`is surrounded by an ineffective immune response, just as
`ovarian tumours are surrounded by inflammatory cells
`impotent against the neoplasia. Chronic inflammation
`might
`invoke a switch from Th1-dominant
`to a
`Th2-dominant microenvironment linked to mutagenesis.
`Progression can be modified by immunosuppression, sug-
`gesting a therapeutic role for anti-inflammatory agents.
`
`in the
`Esophageal metaplasia (Barrett’s oesophagus),
`setting of chronic inflammation can progress to adeno-
`carcinoma (Barrett’s adenocarcinoma). Tselepsis et al.
`[28] showed that epithelial TNFa expression was
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`316 Cancer
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`absent in normal gastric and esophageal squamous muco-
`sae, but increased in sections from metaplasia through
`dysplasia to carcinoma. Elevated TNFa immunoreactiv-
`ity in non-dysplastic Barrett’s oesophagus is localized to
`mucosal regions of prominent lymphoid infiltrate where
`metaplastic stem cells are located. Within individual
`glands, the most dysplastic cells express TNFa, and
`TNFR1 levels are increased during disease progression,
`potentially amplifying the TNFa signal. This study
`demonstrated a novel signaling pathway for oncogene
`activation by an inflammatory cytokine.
`
`In chronic lymphocytic leukemia (CLL), neoplastic lym-
`phocytes release TNFa spontaneously in vitro, and leu-
`kaemic lymphocytes are more proliferative and viable
`when exposed to TNFa. TNFa in CLL patients corre-
`lated with extent of disease, serum b2-microglobulin, low
`hemoglobin and low platelets, as well as with karyotype.
`TNFa levels were predictive of survival, independent of
`staging, b2-microglobulin, hemoglobin, and white blood
`cell and platelet counts [29].
`
`Anti-TNFa therapy in cancer
`Tsimberidou and Giles [30] review potential clinical
`indications for agents that block or inactivate TNFa
`(Figure 1), specifically the soluble TNFa receptor fusion
`protein etanercept and the anti-TNFa antibody inflix-
`imab, in multiple myeloma, myelodysplastic syndrome
`
`Figure 1
`
`Multiple anti-TNF agents are currently marketed or in clinical
`development. Several anti-TNF biologics are illustrated above,
`including antibodies (infliximab and adalimumab), the modified
`antibody fragment CDP870, and the soluble receptor etanercept.
`The various domains present in the structures are illustrated for
`each agent. Reproduced with permission from [63].
`
`(MDS), acute myelogenous leukemia and myelofibrosis
`[30]. The limited efficacy of monotherapy points to
`the need to optimize dose and schedule, to combine
`anti-TNFa agents with active biological or cytotoxic
`agents, and to understand individual patient proteomic
`patterns of disease and gene polymorphisms that could
`predict response.
`
`Investigative and clinical uses of TNFa blockade in graft
`versus host disease (GVHD) are founded on the estab-
`lished role of upregulated TNFa as a consequence of
`conditioning regimens and as an effector molecule in
`multi-organ reactivity to allogeneic graft cells [31,32].
`Infliximab has shown activity in refractory acute and
`chronic GVHD [33]. With added immunosuppression
`and risk of serious infections, vigilance is required when
`using anti-TNF agents in patients with GVHD [34]. No
`studies yet have elucidated the kinetics, optimal dose and
`schedule of anti-TNF agents in GVHD [35].
`
`Anti-TNFa agents can inhibit the excessive apoptosis
`in haematopoietic cells, which is suspected as the cause
`of cytopenias in MDS. The hyperproliferative marrow of
`MDS, with excessive apoptosis and overexpression of
`TNFa, compels intervention to modulate the dysregu-
`lated cytokine milieu in haematopoietic tissues. Thera-
`peutic
`activity
`of
`infliximab suggests
`that
`the
`microenvironment of the marrow is more directly affected
`than are the dysplastic haematopoietic cells [36,37]. A
`logical next step would be to use a specific anti-TNF
`agent to modulate cell–cell signaling and stromal inter-
`actions in the marrow, combined with a cytotoxic agent
`known to be active against the myelodysplastic clone.
`Etanercept was tested in a Phase I clinical study in
`combination with IL-2 to determine if it could modulate
`the biological effects, and reduce toxicity, of high-dose
`IL-2 administration. TNFa bioactivity was inhibited, and
`the polymorphonuclear leukocyte chemotactic defect
`normally seen with IL-2 was not observed. Increases in
`levels of C-reactive protein, IL-6, IL-8 and IL-1 receptor
`antagonist were partially suppressed relative to historical
`controls [38].
`
`A pilot study of etanercept in patients with refractory
`multiple myeloma reported tolerability but no objective
`responses, and some evidence of acceleration of disease
`soon after starting therapy [39]. TNFa was increased
`during treatment compared with pretreatment values;
`this is probable evidence of accumulation of the bound
`cytokine. More research on mRNA expression in the
`myeloma and stromal cells might determine if the bioac-
`tivity of increased TNFa was attenuated fully. Infliximab
`and etanercept differ in function: etanercept binds and
`blocks both TNFa and lymphotoxin (TNFb), whereas
`infliximab binds only to TNFa. Infliximab, but not eta-
`nercept, binds to soluble TNFa bound to cell-surface
`receptors. Soluble TNFa forms stable complexes with
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`TNF-a in the pathogenesis and treatment of cancer Anderson, Nakada and DeWitte 317
`
`infliximab; TNFa dissociates more rapidly from etaner-
`cept, releasing bioactive TNFa [40]. Given these differ-
`ences and the expectation that blocking TNFa should
`show anti-myeloma activity [41], it could be worthwhile
`to investigate infliximab in this disease.
`
`Potential risks of anti-TNF-a therapy
`Because of the adaptive protective purpose of inflamma-
`tion, pharmacological inhibition of this proinflammatory
`cytokine could have adverse effects in the host, unre-
`lated to the target disease of the anti-TNFa therapy. The
`risk of reactivation of latent tuberculosis is addres-
`sed in the prescribing information for
`infliximab
`(REMICADE1; Centocor Inc, Malvern, PA). Pre-
`emptive systemic antifungal therapy is recommended
`for patients receiving infliximab for treatment of GVHD
`[34]. Smith and Skelton [42] reported cases of squamous
`cell carcinoma that became evident and grew rapidly
`during an initial period of etanercept therapy for rheu-
`matoid arthritis. The tumours might have been present,
`but occult before disruption of immunological control.
`Etanercept could disable innate anti-tumour surveil-
`lance by blockade of both lymphotoxin a and the cyto-
`toxic effects of TNFa. Additional proposed mechanisms
`include the inhibition of the Th1 cytokine pattern and
`impairment of cytotoxic T cells. All cases were in chron-
`ically UV-damaged actinic skin predisposed to tumour-
`igenesis by long-term, low-level production of TNFa.
`No new squamous cell carcinomas developed in patients
`who continued treatment
`for more than one year,
`suggesting prolonged anti-TNFa therapy could be pre-
`ventive of cutaneous malignancies.
`
`Pharmacovigilance data on etanercept, infliximab and
`adalimumab were reviewed by the FDA in 2003, with
`a focus on lymphoproliferative disease in patients treated
`with these anti-TNFa agents,
`relative to the rate
`expected in populations with immune-mediated diseases
`[43]. The potential role of TNFa-blocking therapy in the
`development of malignancies is not known. A prospective
`study of 18 572 patients with rheumatoid arthritis treated
`with anti-TNFa therapy plus methotrexate reported
`an increased standard incidence ratio compared with
`patients not receiving methotrexate or biologics, but
`confidence intervals overlapped for all treatments [44].
`Patients with highly active disease and/or chronic expo-
`sure to immunosuppressant therapies could have several-
`fold higher risk for development of lymphoma, thus
`caution should be exercised when considering anti-TNFa
`agents in patients either with a history of malignancy or
`who develop malignancy during treatment.
`
`The FDA also reported on the risk of histoplasmosis [45],
`lymphoma [46] and/or listeriosis [47]. The Mayo clinic
`reviewed the safety of infliximab in 500 patients with
`Crohn’s disease treated with infliximab [48]. The biolo-
`gical basis of concern warrants heightened vigilance and
`
`consideration of the benefit to risk ratio when prescribing
`anti-TNF therapies.
`
`Anti-TNFa therapy in cancer supportive care
`In addition to direct anti-tumour effects, anti-TNFa
`therapies are being tested for supportive care indications.
`These include cancer-related cachexia, fatigue, depres-
`sion, amelioration of chemotherapy-induced toxicities
`and metastatic bone pain [49,50]. TNFa has long been
`associated with cachexia, and trials are underway testing
`anti-TNFa agents in this condition [51,52]. Ramesh and
`Reeves [53] recently demonstrated a role for TNFa in a
`mouse model of cisplatin-mediated renal injury. Treat-
`ment of animals with TNFa synthesis inhibitors or anti-
`TNFa antibodies prevented kidney damage in the
`model.
`
`TNFa appears to play a complex role in side effects of
`radiotherapy, and anti-TNFa treatments could be useful
`in their management [54,55]. TNFa is also a known
`activator of osteoclasts [56] and mediator of neuropathic
`pain [57]. An intriguing pair of clinical cases, in which
`etanercept was used to treat refractory metastatic bone
`pain, suggest that anti-TNFa agents may ultimately play
`a role in controlling cancer pain [58]. The potential value
`of anti-TNFa agents in these debilitating conditions
`presents broad opportunities to improve cancer care.
`
`Conclusions
`It is likely that there is no ‘right’ or ‘wrong’ answer to the
`question of whether TNFa is good or bad for the
`tumour. Research should continue to optimize the use
`of pharmacological TNFa to treat cancer, as well as the
`use of neutralizing therapies to inhibit the effects of
`pathophysiologically derived TNFa. As we increase our
`understanding of the complex biology of TNFa in
`differing contexts within oncology and hematology,
`these opposing approaches should prove more effective
`against cancer.
`
`Update
`Recent results further support the anti-tumor effective-
`ness of TNFa when delivered by gene therapy
`approaches. Hecht et al. [59] reported preliminary evi-
`dence for dose-dependent improvement in progression-
`free survival in a phase I/II trial of TNFerade in combi-
`nation with radiation and 5-flourouracil
`in pancreatic
`cancer patients. Zarovni et al. [60] demonstrated substan-
`tially improved anti-tumor efficacy in animal models with
`tumor vessel-targeted peptide–TNFa fusion proteins.
`The molecules were delivered by intramuscular injection
`of cDNA expression vectors.
`
`Additional evidence demonstrating the pro-metastatic
`effects of TNFa has been published recently. Mochizuki
`et al. [61] reported that TNFa promoted metastasis of
`xenografted human gastric cancer cells to the abdominal
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`318 Cancer
`
`wall in a mouse model. Hagemann et al. [62] showed that
`macrophage-induced invasion by human breast cancer
`cells was mediated by MMPs and was dependent upon
`TNFR activity.
`
`Acknowledgements
`The authors would like to thank Patti Sassoli for her able and patient
`assistance in creating this review.
`
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