IGF and cancer risk

Epidemiological observations have linked circulating concentrations of insulin-like growth factor 1 (IGF1) and its main binding protein, IGFBP3, to cancer risk. Andrew Renehan et al. have published a systematic review and meta-regression analysis of case–control studies, which explores this association further.

IGFs and their binding proteins regulate cell proliferation, differentiation and apoptosis — the biology of the IGF1 axis is complex. IGF1 is mitogenic and anti-apoptotic, and IGFBP3 inhibits growth by sequestering IGF1. IGFBP3 is also possibly antiproliferative and pro-apoptotic independent of IGF1. There are high concentrations of IGFs and IGFBPs in the circulation, and they are dependent on growth-hormone concentrations, age, sex and nutritional status. Their concentrations also vary greatly between individuals. Epidemiological studies have linked high circulating levels of IGF1 with prostate, breast, colorectal and lung cancer, while high IGFBP levels have been associated with decreased risk of cancer. However, findings have been inconsistent.

Renehan et al. identified 139 published epidemiological studies that were potentially relevant to IGF assessment and cancer risk. Of these, 21 fulfilled the authors' inclusion criteria — the studies were published as full articles, the findings were expressed as odds ratios (ORs) with 95% confidence intervals and detailed associations of peptide concentrations were reported. Combined, these studies included 3,609 cases and 7,137 controls.

High concentrations of IGF1 were associated with an increased risk of prostate cancer (OR comparing 75th with 25th percentile of circulating peptide concentrations, 1.49) and pre-menopausal breast cancer (OR 1.65). Why IGF1 concentrations, which decrease with increasing age, are associated with prostate cancer, which has peak incidence in older age, is unknown. Also, why IGF1 is associated with pre-menopausal breast cancer risk, but not with post-menopausal breast cancer, requires further investigation.

High concentrations of IGFBP3 were associated with an increased risk of pre-menopausal breast cancer (OR 1.51), but not with any other cancer. However, there was great heterogeneity between studies for associations with IGFBP3 concentrations, in particular for lung cancer. The authors' analysis included the CARET study, which recruited only male heavy smokers and asbestos workers — when this study was excluded, high concentrations of IGFBP3 were associated with a decreased risk of lung cancer (OR 0.53). The link between IGFBP3 and cancer risk is therefore still unclear, but the protective effects of higher concentrations of IGFBP3 for all cancers were not shown.

Although the authors used stringent inclusion criteria, meta-analyses of this type do have some limitations, as they are vulnerable to biases and confounding in the original studies. IGF1 and IGFBP3 concentrations can be measured easily in blood and might therefore be a useful assessment of risk for specific cancer types. ORIGINAL REFERENCE Renehan, A. G. et al. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363, 1346–1353 (2004)