Elsevier

The Lancet Oncology

Volume 4, Issue 9, September 2003, Pages 565-573
The Lancet Oncology

Review
Tumour necrosis factor α: a potential target for the therapy of solid tumours

https://doi.org/10.1016/S1470-2045(03)01196-3Get rights and content

Section snippets

TNFα and TNF receptor signalling

TNFα is a soluble 17 kDa molecule (157 aminoacids) that binds as a homotrimer to two distinct homotrimeric receptors on the cell surface: TNFRI (p55 receptor) and TNFRII (p75 receptor).12, 13 TNFα is synthesised as a 26 kDa (233 aminoacids) membrane-bound propeptide (pro-TNFα) and is secreted after cleavage by TNFα-converting enzyme (TACE). The 26 kDa form is also functional and binds to TNFRII via direct cell-to-cell contact. Although activated macrophages are a major source of TNFα, it can be

TNFα and experimental cancers

TNFα knockout mice (TNFα−/−) have provided evidence of a tumour immunosurveillance role for TNFα16, 17 and implicated the cytokine in tumour development and metastasis.18, 19 Moore and colleagues found that TNFα−/− mice had ten times fewer skin tumours than wild-type mice after initiation with a carcinogen and repeated application of 12-O-tetradecanoylphorbol-13-acetate (TPA). Although TNFα was important for de-novo carcinogenesis, the later stages of tumour progression were similar in TNFα−/−

TNFα as a tumour promoter

Evidence for a role of TNFα has come from several preclinical and clinical studies. Expression studies have confirmed abnormally high concentrations of TNFα in tumours, implicating the cytokine in specific preneoplastic lesions and in advanced malignant disease. Data from studies in vitro and in vivo suggests that TNFα, far from being an epiphenomenon, is an active player in tumorigenesis. Furthermore, several well-known paraneoplastic syndromes that commonly occur in patients with cancer seem

Treatment-related complications

Several proinflammatory cytokines, such as TNFα and interleukin 6, mediate cytokine release syndromes, which complicate antibody-based cancer therapy. For example, several studies have shown frequent first-dose infusion-related toxic effects with rituximab (a monoclonal antibody to the CD20 cell-surface antigen) in low-grade non-Hodgkin lymphoma—symptoms consist mainly of fever, rigors, and chills. Studies of rituximab in patients with haematological cancer have confirmed TNFα release as a

TNFα antagonists

Specific TNFα antagonists, such as infliximab and etanercept, are now accepted as successful treatments for various inflammatory and autoimmune conditions.69 In light of the evidence outlined in this review, and the similarities in inflammatory pathways in cancer and rheumatoid arthritis (figure 4), a case can be made for the use of TNFα antagonists in solid tumours. The behaviour of the inflammatory pannus of rheumatoid arthritis may be likened to the invasion and metastasis of cancer, with

Conclusion

TNFα has a paradoxical role in cancer, inducing destruction of blood vessels and cell-mediated killing of certain tumours, as well as acting as a tumour promoter. Chronic endogenous low production of TNFα favours the latter. TNFα may contribute to the development of tissue architecture necessary for tumour growth and metastasis, may induce other cytokines, angiogenic factors, and matrix metalloproteinases, contributing to DNA damage and increase growth and survival of tumour cells. Thus, TNFα

Search strategy and selection criteria

A search of PubMed was carried out using combinations of the terms “TNF-alpha”, “TNFRI”, “TNFRII”, “knockout”, “tumour”, “carcinogenesis”, “inflammation”, “cachexia”, and “cytokine release syndrome”. Additional information on infliximab, etanercept and rituximab was obtained from the Electronic Medicines Compendium (http://emc.vhn.net/) and from investigators involved in clinical trials of these agents.

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References (75)

  • R Foa et al.

    Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: a possible regulatory role of TNF in the progression of the disease

    Blood

    (1990)
  • GH Wong et al.

    Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor

    Cell

    (1989)
  • N Cheng et al.

    Tumor necrosis factor-alpha induction of endothelial ephrin A1 expression is mediated by a p38 MAPK- and SAPK/JNK-dependent but nuclear factor-kappa B-independent mechanism

    J Biol Chem

    (2001)
  • P De Cesaris et al.

    Activation of Jun N-terminal kinase/stress-activated protein kinase pathway by tumor necrosis factor alpha leads to intercellular adhesion molecule-1 expression

    J Biol Chem

    (1999)
  • F Bussolino et al.

    Synthesis and release of platelet-activating factor by human vascular endothelial cells treated with tumor necrosis factor or interleukin 1 alpha

    J Biol Chem

    (1988)
  • K Warzocha et al.

    Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome

    Blood

    (1998)
  • K Nakajima et al.

    Tumor necrosis factor-alpha gene mutations and genotype changes in renal cell carcinoma

    J Urol

    (2001)
  • BR Oh et al.

    Frequent genotype changes at -308, and 488 regions of the tumor necrosis factor-alpha (TNF-alpha) gene in patients with prostate cancer

    J Urol

    (2000)
  • R Vassallo et al.

    Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition

    Chest

    (2002)
  • EA Carswell et al.

    An endotoxin-induced serum factor that causes necrosis of tumors

    Proc Natl Acad Sci USA

    (1975)
  • HC Nauts et al.

    A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man

    Acta Medica Scandinavia

    (1953)
  • B Beutler et al.

    Identity of tumour necrosis factor and the macrophage-secreted factor cachectin

    Nature

    (1985)
  • K Takeda et al.

    Identity of differentiation inducing factor and tumour necrosis factor

    Nature

    (1986)
  • AM Tsimberidou et al.

    TNF-alpha targeted therapeutic approaches in patients with hematologic malignancies

    Expert Rev Anticancer Ther

    (2002)
  • BB Aggarwal et al.

    Chapters on TNFα and TNF receptors

  • G Chen et al.

    TNF-R1 signaling: a beautiful pathway

    Science

    (2002)
  • AS Baldwin

    Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB

    J Clin Invest

    (2001)
  • EA Havell et al.

    The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity

    J Exp Med

    (1988)
  • CN Baxevanis et al.

    Compromised anti-tumor responses in tumor necrosis factor-alpha knockout mice

    Eur J Immunol

    (2000)
  • RJ Moore et al.

    Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis

    Nat Med

    (1999)
  • M Suganuma et al.

    Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice

    Cancer Res

    (1999)
  • CH Arnott et al.

    Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha- and AP-1-dependent pathway

    Oncogene

    (2002)
  • RA Roberts et al.

    Cytokines in non-genotoxic hepatocarcinogenesis

    Carcinogenesis

    (1999)
  • B Knight et al.

    Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice

    J Exp Med

    (2000)
  • H Kitakata et al.

    Essential roles of tumor necrosis factor receptor p55 in liver metastasis of intrasplenic administration of colon 26 cells

    Cancer Res

    (2002)
  • H Korner et al.

    Tumor necrosis factor sustains the generalized lymphoproliferative disorder (gld) phenotype

    J Exp Med

    (2000)
  • P Orosz et al.

    Enhancement of experimental metastasis by tumor necrosis factor

    J Exp Med

    (1993)
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