Growth hormone, the insulin-like growth factor axis, insulin and cancer risk

Abstract

Growth hormone (GH), insulin-like growth factor (IGF)-I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of concern for several decades. The evidence that GH, IGF-I and insulin can promote and contribute to cancer progression comes from various sources, including transgenic and knockout mouse models and animal and human cell lines derived from cancers. Assessments of the GH–IGF axis in healthy individuals followed up to assess cancer incidence provide direct evidence of this risk; raised IGF-I levels in blood are associated with a slightly increased risk of some cancers. Studies of human diseases characterized by excess growth factor secretion or treated with growth factors have produced reassuring data, with no notable increases in de novo cancers in children treated with GH. Although follow-up for the vast majority of these children does not yet extend beyond young adulthood, a slight increase in cancers in those with long-standing excess GH secretion (as seen in patients with acromegaly) and no overall increase in cancer with insulin treatment, have been observed. Nevertheless, long-term surveillance for cancer incidence in all populations exposed to increased levels of GH is vitally important.

Key Points

  • Growth hormone (GH), insulin-like growth factor I (IGF-I) and insulin have the potential to promote tumor growth and progression

  • Cumulative evidence from epidemiological studies supports an association between raised circulating levels of IGF-I and a slightly increased risk of certain cancers

  • Acromegaly, a disorder characterized by long-standing excess GH secretion, is associated with a small increased risk of colorectal and thyroid cancers

  • In follow-up studies through childhood, cancer risk is not raised by therapeutic use of GH, with the exception of a small increase in second cancers in childhood cancer survivors

  • Conditions characterized by hyperinsulinemia, such as obesity and type 2 diabetes mellitus, are associated with increased risk of several cancer types

  • Overall, cancer risk is not increased by the therapeutic use of insulin and/or insulin analogs in patients with diabetes mellitus, but the evidence is complex

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Figure 1: Summary of meta-analyses linking circulating levels of IGF-I and IGFBP-3 with the incidence of prostate, breast, colorectal, and lung cancers.
Figure 2: Associations of acromegaly with colorectal and thyroid cancer in population-based studies.
Figure 3: Schematic diagram of insulin and IGF-I receptors, their main downstream pathways, and main biological end points.
Figure 4: Schematic representation of the inter-relationships between obesity, insulin resistance and pathways that might favor tumor development.
Figure 5: Summary of meta-analyses linking diabetes with cancer risk.
Figure 6: Illustration of the strength of evidence linking the GH–IGF axis to cancer.

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Acknowledgements

The authors are supported by the National Institute for Health Research Manchester Biomedical Research Center, UK. A. G. Renehan holds a senior lectureship award supported by the UK Clinical Research Collaboration.

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Correspondence to Peter E. Clayton.

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P. E. Clayton is a consultant and speaker for Ipsen and Merck Serono. He is a consultant for Pfizer. He is a speaker for, and has received grant/research support from, Novo Nordisk. A. G. Renehan is a consultant and speaker for, and has received grant/research support from, Novo Nordisk. The other authors declare no competing interests.

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Clayton, P., Banerjee, I., Murray, P. et al. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 7, 11–24 (2011). https://doi.org/10.1038/nrendo.2010.171

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