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.
ReviewTumour necrosis factor α: a potential target for the therapy of solid tumours
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
References (75)
- et al.
The TNF and TNF receptor superfamilies: integrating mammalian biology
Cell
(2001) - et al.
Clinical applications of TNF-alpha in cancer
Curr Opin Immunol
(1998) - et al.
Radiation-induced tumour necrosis factor-α expression: clinical application of transcriptional and physical targeting of gene therapy
Lancet Oncol
(2002) Tumor necrosis factor or tumor promoting factor?
Cytokine Growth Factor Rev
(2002)- et al.
The hallmarks of cancer
Cell
(2000) - et al.
Inflammation and cancer: back to Virchow?
Lancet
(2001) TNF receptor subtype signalling: differences and cellular consequences
Cell Signal
(2002)- et al.
Cells secreting tumour necrosis factor show enhanced metastasis in nude mice
Eur J Cancer
(1990) - et al.
Tumors secreting human TNF/cachectin induce cachexia in mice
Cell
(1987) - et al.
Tumor necrosis factor-alpha represses androgen sensitivity in the LNCaP prostate cancer cell line
J Urol
(2000)
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
Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor
Cell
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
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
Synthesis and release of platelet-activating factor by human vascular endothelial cells treated with tumor necrosis factor or interleukin 1 alpha
J Biol Chem
Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome
Blood
Tumor necrosis factor-alpha gene mutations and genotype changes in renal cell carcinoma
J Urol
Frequent genotype changes at -308, and 488 regions of the tumor necrosis factor-alpha (TNF-alpha) gene in patients with prostate cancer
J Urol
Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition
Chest
An endotoxin-induced serum factor that causes necrosis of tumors
Proc Natl Acad Sci USA
A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man
Acta Medica Scandinavia
Identity of tumour necrosis factor and the macrophage-secreted factor cachectin
Nature
Identity of differentiation inducing factor and tumour necrosis factor
Nature
TNF-alpha targeted therapeutic approaches in patients with hematologic malignancies
Expert Rev Anticancer Ther
Chapters on TNFα and TNF receptors
TNF-R1 signaling: a beautiful pathway
Science
Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB
J Clin Invest
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
Compromised anti-tumor responses in tumor necrosis factor-alpha knockout mice
Eur J Immunol
Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis
Nat Med
Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice
Cancer Res
Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha- and AP-1-dependent pathway
Oncogene
Cytokines in non-genotoxic hepatocarcinogenesis
Carcinogenesis
Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice
J Exp Med
Essential roles of tumor necrosis factor receptor p55 in liver metastasis of intrasplenic administration of colon 26 cells
Cancer Res
Tumor necrosis factor sustains the generalized lymphoproliferative disorder (gld) phenotype
J Exp Med
Enhancement of experimental metastasis by tumor necrosis factor
J Exp Med
Cited by (351)
Impact of selenium nanoparticles in the regulation of inflammation
2022, Archives of Biochemistry and BiophysicsNanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways
2022, Seminars in Cancer BiologyPolyester nanomedicines targeting inflammatory signaling pathways for cancer therapy
2022, Biomedicine and PharmacotherapyLocal and global sensitivity analysis of spheroid and xenograft models of the acid-mediated development of tumor malignancy
2022, Applied Mathematical ModellingTumor Necrosis Factor Receptors: A Brief Digestion
2022, Encyclopedia of Cell Biology: Volume 1-6, Second Edition