ReviewSystematic review of the association between circulating interleukin-6 (IL-6) and cancer
Introduction
Interleukin-6. (IL-6) is a pleiotropic inflammatory cytokine. First discovered as a B-cell growth factor, it is synthesised by many cell types, including T-cells, macrophages and stromal cells, in response to stimulation from tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1).1, 2 The activation of the IL-6 complex activates Janus kinases (JAK), signal transducers and activators of transcription (STATs), which regulate cell proliferation and apoptosis.3, 4 In healthy adults, IL-6 concentrations over 10 pg/ml are considered abnormally elevated.5 Blood IL-6 concentrations in humans follow a biphasic variation in any 24 h period, with peaks at about 19.00 and 05.00 h.6
High circulating IL-6 concentrations are associated with many diseases, including cardiovascular disease7, 8 and type 2 diabetes.9 IL-6 may also have a role in cancer. IL-6 regulates chronic inflammation, which can create a cellular microenvironment beneficial to cancer growth.10, 11 It is also a growth factor for lymphatic, renal, bladder and colorectal cancer cells12 and involved in the control of cell proliferation and apoptosis.13 Despite the large number of publications the epidemiologic evidence for the role of IL-6 in cancer remains unclear and to our knowledge no one has previously systematically reviewed this literature. Therefore, in order to better understand the role of IL-6 in cancer and to suggest directions for future research, we conducted a systematic review to summarise the epidemiologic evidence for the association between circulating IL-6 and any type of prevalent or incident cancer.
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Materials and methods
Electronic databases Medline and Embase were searched systematically in December 2006. The Web of Science database was searched for publications citing the articles identified from previous searches, and papers cited in the reviewed articles were included where relevant. The search terms are detailed in Table 1. If the title or abstract of an article seemed relevant, the abstract or the complete article were reviewed. Two reviewers (K.H. and D.A.L.) independently extracted data from a sample of
Studies
Our Medline search found 2026 and the Embase search found 2487 potentially relevant publications. These abstracts were reviewed and 279 potentially relevant studies identified (Fig. 1). Eighty-one studies did not fulfil the inclusion criteria and were excluded; 198 studies contained relevant data and were reviewed. The main characteristics and findings of the studies of circulating IL-6 and cancer identified in our systematic review are described in detail in Web Tables W1-W21. There were nine
Discussion
The role of inflammation in cancer in general and certain forms of cancer in particular has been the focus of extensive research.60 Determining whether an association between inflammatory markers, such as IL-6, and cancer exists, and understanding the nature (causal or otherwise) of any association are important because such knowledge could inform preventative strategies or help in the development of methods for early diagnosis of cancer.
IL-6, first identified as a B-cell growth factor, is an
Conflict of interest statement
None declared.
Acknowledgements
D.A.L is funded by a (UK) Department of Health career scientist award and when this work was conducted, K.H. was funded by the (UK) Medical Research Council PhD Studentship. We thank Guobing Lu and Leona Gabrysova for their assistance in translating foreign language papers for this review.
References (74)
- et al.
The role of IL-6 and STAT3 in inflammation and cancer
Eur J Cancer
(2005) - et al.
The role of IL-6 and STAT3 in inflammation and cancer
Eur J Cancer
(2005) - et al.
The role of IL-6 and STAT3 in inflammation and cancer
Eur J Cancer
(2005) - et al.
Inflammation and cancer: how hot is the link?
Biochem Pharmacol
(2006) - et al.
Preoperative plasma levels of interleukin-6 and its soluble receptor predict disease recurrence and survival of patients with bladder cancer
J Urol
(2002) - et al.
Adiponectin and the systemic inflammatory response in weight-losing patients with non-small cell lung cancer
Cytokine
(2004) - et al.
Increased aberrance of cytokine expression in plasma of patients with more advanced squamous cell carcinoma of the head and neck
Cytokine
(2004) - et al.
Alterations of routine blood tests in adult patients with soft tissue sarcomas: relationships to cytokine serum levels and prognostic significance
Ann Oncol
(2001) - et al.
Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma
J Urol
(1999) - et al.
Correlation between tumor necrosis factor-alpha and D-dimer levels in non-small cell lung cancer patients
Lung Cancer
(2004)
Reduction in serum IL-6 after vacination of breast cancer patients with tumour-associated antigens is related to estrogen receptor status
Cytokine
Preoperative plasma levels of interleukin-6 and its soluble receptor predict disease recurrence and survival of patients with bladder cancer
J Urol
Relation between insulin resistance and serum concentrations of IL-6 and TNF-alpha in overweight or obese women with early stage breast cancer
Cytokine
Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis
Urology
C-reactive protein and cardiovascular disease: a review of risk prediction and interventions
Clin Chim Acta
Inflammation and cancer: how hot is the link?
Biochem Pharmacol
Inflammation and the development of pancreatic cancer
Surg Oncol
Inflammation as a tumor promoter in cancer induction
Semin Cancer Biol
Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma
Blood
Interleukin-6 polymorphisms, Helicobacter pylori infection in adult Brazilian patients with chronic gastritis and gastric adenocarcinoma
Arch Med Res
Interleukin-6
Crit Care Med Cellular Mol Biol Intensivists: A Primer
Interleukin-6
Crit Care Med Cellular Mol Biol Intensivists: A Primer
Interleukin-6
Crit Care Med Cellular Mol Biol Intensivists: A Primer
IL-6 and its circadian secretion in humans
Neuroimmunomodulation
Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men
Circulation
C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women
New Eng J Med
C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus
J Am Med Assoc
Inflammation, a key event in cancer development
Mol Cancer Res
STAT proteins: from normal control of cellular events to tumorigenesis
J Cell Physiol
Relationship of serum levels of interleukin-6, soluble interleukin-6 receptor and tumour necrosis factor receptors to the acute-phase protein response in advanced pancreatic cancer
Clin Sci (Lond)
The clinical and prognostic significance of erythrocyte sedimentation rate (ESR), serum interleukin-6 (IL-6) and acute phase protein levels in multiple myeloma
Clin Lab Haematol
Expression of proliferating cell nuclear antigen (PCNA) in multiple myeloma: its relationship to bone marrow microvessel density and other factors of disease activity
Int J Immunopathol Pharmacol
Significance of inflammatory cytokines in the progression of colorectal cancer
Hepatogastroenterology
Necessity of biotherapeutic treatments inducing TH1 cell functions in colorectal cancer
Cancer Biother Radiopharm
Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer
Br J Cancer
Disregulation in TH1 and TH2 subsets of CD4+ T cells in peripheral blood of colorectal cancer patients and involvement in cancer establishment and progression
Cancer Immunol Immunother
Interleukin-6 and its relationships to acute phase proteins in serous effusion differentiation
Oncol Rep
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