Systematic review of the association between circulating interleukin-6 (IL-6) and cancer

doi:10.1016/j.ejca.2008.02.047

European Journal of Cancer

Volume 44, Issue 7, May 2008, Pages 937-945

https://doi.org/10.1016/j.ejca.2008.02.047 Get rights and content

Abstract

Our aim was to systematically review the epidemiologic evidence for an association of circulating interleukin-6 (IL-6), an inflammatory cytokine and cancer. We systematically searched electronic databases Embase, Medline and Web of Science for the studies of circulating IL-6 and any form of cancer. We identified and reviewed 189 discrete studies, consisting of 177 prevalent studies and three prospective studies. Cancer patients’ IL-6 concentrations were higher than healthy controls’ in most studies, but the results of investigations comparing IL-6 in cancer patients and individuals with benign diseases were less consistent. Due to the small number of prospective studies it is impossible to determine whether IL-6 is causally related to cancer. Large prospective studies of circulating IL-6 or studies using the functional variants of the IL-6 gene as instruments for circulating IL-6 concentrations would provide information on possible aetiological links between IL-6 and malignancy.

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.

Section snippets

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.

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ReviewSystematic review of the association between circulating interleukin-6 (IL-6) and cancer

Abstract

Introduction

Section snippets

Materials and methods

Studies

Discussion

Conflict of interest statement

Acknowledgements

Eur J Cancer

Eur J Cancer

Eur J Cancer

Biochem Pharmacol

J Urol

Cytokine

Cytokine

Ann Oncol

J Urol

Lung Cancer

Cytokine

J Urol

Cytokine

Urology

Clin Chim Acta

Biochem Pharmacol

Surg Oncol

Semin Cancer Biol

Blood

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

Review
Systematic review of the association between circulating interleukin-6 (IL-6) and cancer