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Insulin-like growth factors and neoplasia

Key Points

  • Insulin-like growth factor 1 (IGF1) has characteristics of both a circulating hormone and a tissue growth factor.

  • Circulating IGF1 levels vary considerably between normal individuals and there is evidence from epidemiological studies that individuals with levels at the higher end of the normal range have increased cancer risk. As this risk could apply to 25% of the population, the attributable disease burden might be substantial, even though the relative risk associated with higher IGF1 levels is modest.

  • Laboratory carcinogenesis models have provided data consistent with the population studies.

  • Higher IGF1 levels might be associated with higher risk of a cancer diagnosis because of subtle influences on renewal dynamics of epithelial-cell populations: somatic cells of individuals with higher levels of IGF1 might show slightly higher proliferation rates and have a slightly increased chance of survival in the presence of genetic damage, because of the anti-apoptotic effects of IGF1. This would facilitate stepwise carcinogenesis. Higher IGF1 levels might also reduce the time interval between emergence of a transformed clone of cells and a clinically significant cancer.

  • The syndrome of insulin resistance, characterized by increased insulin levels and obesity, is also associated with increased cancer risk and might involve similar mechanisms.

  • In experimental models, the growth of many established cancers can be inhibited by pharmacological strategies that reduce IGF1-receptor (IGF1R) signalling; this observation will lead to clinical trials of new drug candidates, such as anti-IGF1R antibodies and IGF1R tyrosine kinase inhibitors.

  • Dietary restriction confers protection against carcinogens and extends life expectancy in experimental models; there is evidence that both of these actions involve IGF signalling. Whereas higher levels of IGF signalling are associated with a shorter lifespan in model organisms, at the cellular level IGF1R activation activates anti-apoptotic pathways. A 'rate of living' model reconciles these observations.

Abstract

The insulin-like growth factor 1 (IGF1) signalling pathway has important roles in regulating cellular proliferation and apoptosis. Converging results from epidemiological research and in vivo carcinogenesis models indicate that high levels of circulating IGF1 are associated with increased risk of several common cancers. Ongoing research seeks to clarify the mechanisms underlying these observations and to determine the extent to which IGF physiology influences patterns of cancer incidence. Various therapeutic strategies that target the IGF1 receptor have demonstrated impressive antineoplastic activity in laboratory models, and clinical trials of several novel drug candidates are planned.

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Figure 1: Regulation of circulating and tissue levels of insulin-like growth factors.
Figure 2: Overview of insulin-like growth factor 1 receptor activation and downstream signalling.
Figure 3: Model of the influence of insulin-like growth factor 1 signalling on the stepwise accumulation of somatic-cell genetic damage in carcinogenesis.
Figure 4: Insulin-like growth factor 1 receptor targeting: therapeutic strategies.
Figure 5: Why is life expectancy increased when insulin-like growth factor 1 levels are reduced?

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Acknowledgements

The authors are grateful for helpful comments from the anonymous reviewers and the editors. We apologize to colleagues whose contributions could not be cited due to space constraints.

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Correspondence to Michael N. Pollak.

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Michael Pollak has consulted for pharmaceutical firms developing therapies that target IGF1R.

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DATABASES

Cancer.gov

breast cancer

colon cancer

endometrial cancer

lung cancer

multiple myeloma

prostate cancer

Entrez Gene

AKT

EGFR

ERBB2

GH

GHRH

IGF1

IGF1R

IGF2

IGF2R

IGFBP1

IGFBP2

IGFBP3

IRS

PSA

PTEN

somatostatin

TOR

Glossary

AUTOCRINE

A form of bioregulation in which a secreted factor affects only the cell from which it was secreted.

GROWTH HORMONE

A polypeptide that is produced by the anterior pituitary gland that, among other functions, stimulates the liver to produce IGF1.

ENDOCRINE

A form of signalling whereby hormones are secreted into the circulation by specialized cells that affect the metabolism or behaviour of target cells that are distant from the site of hormone secretion.

PARACRINE

A form of bioregulation in which a secretion produced by one cell type in a tissue diffuses through the tissue and affects another cell type in the same tissue.

GENOMIC IMPRINTING

The epigenetic marking of a gene on the basis of parental origin, which results in monoallelic expression.

ACROMEGALY

A condition that results from the excess production of growth hormone in the anterior lobe of the pituitary gland.

POLYMORPHIC VARIATION

Occurrence, at a single genetic locus, of two or more alleles that differ in nucleotide sequence.

HAPLOTYPE

A fixed pattern of several linked genetic polymorphisms.

TAMOXIFEN

An anti-oestrogen drug that can be given to women with oestrogen-receptive tumours to reduce oestrogen-receptor activation.

PRE-ECLAMPSIA

A toxaemia of late pregnancy that is characterized by hypertension, oedema and proteinuria.

NESTED CASE–CONTROL STUDY

A population study where individuals with (cases) or without (controls) a disease are identified from within a larger cohort of individuals being followed for research purposes.

CACHEXIA

Astate of ill health, weight loss and negative nitrogen balance that is often associated with advanced cancer.

TRAMP CARCINOGENESIS MODEL

A mouse model of prostate cancer that is characterized by spontaneous development of prostate tumours.

SMALL INTERFERING RNAS

Small RNAs, typically 21–23 nucleotides in length, that can interfere with expression of specific genes.

ANGIOGENESIS

Development of new blood vessels to supply blood to a cancer, a process stimulated by vascular endothelial growth factor and that is necessary for micrometastases to grow to a clinically detectable size.

ADJUVANT TREATMENT

Following resection of a primary cancer, adjuvant treatment of an apparently well patient who might have micrometastases is given to prevent the later development of microscopic metastatic disease.

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Pollak, M., Schernhammer, E. & Hankinson, S. Insulin-like growth factors and neoplasia. Nat Rev Cancer 4, 505–518 (2004). https://doi.org/10.1038/nrc1387

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