Elsevier

The Lancet

Volume 363, Issue 9418, 24 April 2004, Pages 1346-1353
The Lancet

Articles
Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis

https://doi.org/10.1016/S0140-6736(04)16044-3Get rights and content

Summary

Background

Insulin-like growth factor (IGF)-I and its main binding protein, IGFBP-3, modulate cell growth and survival, and are thought to be important in tumour development. Circulating concentrations of IGF-I might be associated with an increased risk of cancer, whereas IGFBP-3 concentrations could be associated with a decreased cancer risk.

Methods

We did a systematic review and meta-regression analysis of case-control studies, including studies nested in cohorts, of the association between concentrations of IGF-I and IGFBP-3 and prostate, colorectal, premenopausal and postmenopausal breast, and lung cancer. Study-specific dose-response slopes were obtained by relating the natural log of odds ratios for different exposure levels to blood concentrations normalised to a percentile scale.

Findings

We identified 21 eligible studies (26 datasets), which included 3609 cases and 7137 controls. High concentrations of IGF-I were associated with an increased risk of prostate cancer (odds ratio comparing 75th with 25th percentile 1·49, 95% CI 1·14–1·95) and premenopausal breast cancer (1·65, 1·26–2·08) and high concentrations of IGFBP-3 were associated with increased risk of pre-menopausal breast cancer (1·51, 1·01–2·27). Associations were larger in assessments of plasma samples than in serum samples, and in standard case-control studies compared with nested studies.

Interpretation

Circulating concentrations of IGF-I and IGFBP-3 are associated with an increased risk of common cancers, but associations are modest and vary between sites. Although laboratory methods need to be standardised, these epidemiological observations could have major implications for assessment of risk and prevention of cancer.

Introduction

Insulin-like growth factors (IGFs) are multifunctional peptides that regulate cell proliferation, differentiation, and apoptosis1—attributes important in tumorigenesis. Unlike most other growth factors, IGF peptides occur in large concentrations in the circulation and have systemic, hormonal, and local paracrine effects on cell behaviour.2 In the circulation, IGF-I binds mainly to the main IGF binding protein, IGFBP-3.2 Both peptides are dependent on growth hormone, but are also affected by age (concentrations decline with age after puberty), sex, and nutritional status.3 IGF-I and IGFBP-3 concentrations vary greatly between individuals, which might affect the distribution of cancer risk in a population.4

Results of early studies on risk of prostate,5 breast,6 colorectal,7 and lung8 cancer suggested that high circulating IGF-I concentrations are associated with an increased risk of cancer, whereas high IGFBP-3 concentrations are associated with a decreased risk.9, 10 This hypothesis is supported by laboratory evidence: IGF-I is mitogenic and antiapoptotic,1 whereas IGFBP-3, conventionally thought to inhibit growth through ligand sequestration, might also be antiproliferative and proapoptotic11 through actions independent of the IGF-I receptor—properties that affect tumour development.

IGF-I and IGFBP-3 concentrations can be measured easily in blood and might be useful in assessment of cancer risk. Since the associated cancers are common (half of all malignant diseases in developed countries),12 the epidemiological observations could have major implications for public health. However, the results from studies have been inconsistent,10 and the reasons underlying heterogeneous results, including differences between cancer sites, study populations, and designs, and assay characteristics need to be investigated further. We have investigated these questions in a systematic review and meta-regression analysis.

Section snippets

Identification of studies

We searched MEDLINE and EMBASE from January, 1996, to December, 2002, to identify epidemiological studies. The search combined key words: plasma IGF* and serum IGF* with prostate cancer, breast cancer, colorectal cancer, and lung cancer. We searched specialist journals and conference proceedings by hand and searched reference lists from relevant articles, general reviews,4, 9, 10, 13 and a previously published meta-analysis in prostate cancer.14 No language restrictions were imposed.

We included

Results

From an initial 139 potentially relevant articles, we included 21 (26 datasets since breast cancer was analysed by menopausal status) in our analysis (figure 1). Six studies investigated prostate cancer,5, 22, 23, 24, 25, 26 five colorectal cancer,7, 27, 28, 29, 30 six breast cancer,6, 31, 32, 33, 34, 35 and four lung cancer.8, 36, 37, 38 Combined, these studies included 3609 cases and 7137 controls. Two additional studies39, 40 were eligible for subgroup analyses. Further details of the search

Discussion

We have systematically reviewed published epidemiological reports on the association between circulating total IGF-I and total IGFBP-3 concentrations and the risk of cancer. Higher concentrations of IGF-I were associated with prostate, colorectal, and premenopausal breast cancer, whereas higher concentrations of IGFBP-3 were associated with premenopausal breast cancer only. When modelling the dose-response relation between blood concentrations and cancer risk, associations were confirmed for

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