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Insulin and insulin-like growth factor signalling in neoplasia

Nature Reviews Cancer volume 8, pages 915–928 (2008)Cite this article

An Erratum to this article was published on 30 January 2009

Key Points

  • Insulin and insulin-like growth factor (IGF) signalling systems are ancient and involve regulation of physiology in ways beyond their well-known medically recognized roles concerning regulation of carbohydrate metabolism and growth.

  • There is substantial experimental and clinical evidence that cancer cells express insulin and IGF1 receptors, and that these receptors are important activators of the Akt and mitogen-activated protein kinase signalling networks in neoplastic tissue.

  • Population studies provide substantial direct and circumstantial evidence that cancer risk and cancer prognosis are influenced by IGF1 and insulin levels.

  • Preclinical evaluation of drug candidates that target IGF1 and/or insulin signalling has revealed antineoplastic activity.

  • At least 10 different drug candidates are being evaluated in clinical trials; early results have justified expansion of clinical trial programmes.

  • Energy metabolism is an important topic in cancer research. IGF1 and insulin might have roles, along with other regulators, in mediating effects of perturbations of whole organism energy balance (for example, dietary excess, caloric restriction and exercise) on cellular energy physiology.

Abstract

Insulin and insulin-like growth factors (IGFs) are well known as key regulators of energy metabolism and growth. There is now considerable evidence that these hormones and the signal transduction networks they regulate have important roles in neoplasia. Epidermiological, clinical and laboratory research methods are being used to investigate novel cancer prevention and treatment strategies related to insulin and IGF signalling. Pharmacological strategies under study include the use of novel receptor-specific antibodies, receptor kinase inhibitors and AMP-activated protein kinase activators such as metformin. There is evidence that insulin and IGF signalling may also be relevant to dietary and lifestyle factors that influence cancer risk and cancer prognosis. Recent results are encouraging and have justified the expansion of many translational research programmes.

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Figure 1: Timeline of key findings related to the roles of insulin and insulin-like growth factors (IGFs) in neoplasia.
Figure 2: Key elements of insulin-like growth factor (IGF) signalling at the cellular and whole organism levels.
Figure 3: Anti-ligand, anti-receptor and receptor tyrosine kinase inhibition approaches to targeting.
Figure 4: An example of an objective response to monotherapy with an insulin-like growth factor 1 receptor (IGF1R)-specific antibody.
Figure 5: Endocrine response to IGF1R blockade.
Figure 6: Metformin actions that are relevant to neoplasia.

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Acknowledgements

I thank L. Lui for valuable assistance in manuscript preparation, and students and colleagues for useful discussions. I apologize to those whose work could not be cited due to space constraints. The author has received research support from the National Cancer Institute of Canada, the Canadian Breast Cancer Research Alliance, the Prostate Cancer Foundation (Santa Monica, California, USA), the Prostate Cancer Foundation of Canada, and the National Cancer Institute (Washington, DC, USA).

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Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8, 915–928 (2008). https://doi.org/10.1038/nrc2536

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