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IGF binding proteins in cancer: mechanistic and clinical insights

Nature Reviews Cancer volume 14, pages 329–341 (2014)Cite this article

Subjects

Key Points

  • The insulin-like growth factor (IGF) binding proteins (IGFBPs) are a family of six proteins that function as transport proteins for IGF-I and IGF-II in the circulation and also regulate their access to the potentially oncogenic IGF-I receptor (IGF1R). 'Free' (unbound) IGFs have circulating half-lives of only a few minutes, whereas IGFBP-bound IGFs are much more stable.

  • IGFBPs modulate cell functions by both IGF-dependent mechanisms, which affect IGF1R signalling, and IGF-independent mechanisms, which do not involve changes in IGF1R signalling.

  • Many studies have examined the relationships between circulating IGFBP concentrations and cancer risk or prognosis, but few, if any, consistent associations have been found. By contrast, several studies suggest that tissue levels of IGFBPs or their mRNAs may be useful as prognostic markers.

  • No cancers have been attributed to IGFBP gene mutations, but some might be associated with epigenetic silencing of IGFBP gene expression (in particular, IGFBP3).

  • IGFBPs can function extracellularly but are also internalized into cells and can be transported into the nucleus. They inhibit tumour growth by promoting apoptosis and inhibiting cell proliferation, but in other circumstances they increase cell survival and stimulate proliferation.

  • Dichotomous effects on cell growth and survival are achieved by functional IGFBP interactions with many signalling systems, including both stimulatory and inhibitory cell-surface receptors (for example, the epidermal growth factor receptor and the transforming growth factor-β receptor, respectively), as well as nuclear receptors.

  • By regulating enzymes involved in sphingolipid metabolism, IGFBPs can affect the balance between growth-inhibitory lipids, such as ceramides, and growth-stimulatory lipids, such as sphingosine-1-phosphate. This could be a key mechanism by which IGFBP-3, IGFBP-5 and possibly other IGFBPs can regulate the balance between cell death and survival in response to certain cancer therapies.

  • These diverse properties of IGFBPs could make them, or pathways that they regulate, attractive targets for drug development.

Abstract

The six members of the family of insulin-like growth factor (IGF) binding proteins (IGFBPs) were originally characterized as passive reservoirs of circulating IGFs, but they are now understood to have many actions beyond their endocrine role in IGF transport. IGFBPs also function in the pericellular and intracellular compartments to regulate cell growth and survival — they interact with many proteins, in addition to their canonical ligands IGF-I and IGF-II. Intranuclear roles of IGFBPs in transcriptional regulation, induction of apoptosis and DNA damage repair point to their intimate involvement in tumour development, progression and resistance to treatment. Tissue or circulating IGFBPs might also be useful as prognostic biomarkers.

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Figure 1: Relationships between 'free' and IGFBP-bound IGFs in the circulation.
Figure 2: Proposed mechanisms for growth-inhibitory actions of IGFBPs.
Figure 3: Proposed scheme for the role of sphingolipids in mediating the dual growth-inhibitory and growth-stimulatory effects of IGFBPs in cancer.

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Acknowledgements

The author acknowledges project grants from the National Health & Medical Research Council, the Australian Research Council, and the Cancer Council New South Wales.

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  1. Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, 2065, New South Wales, Australia

    Robert C. Baxter

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Correspondence to Robert C. Baxter.

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Supplementary information S1 (table)

Association between circulating levels of IGFBPs and cancer risk or prognosis (PDF 151 kb)

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Association between tumor levels of IGFBPs and cancer prognosis (PDF 139 kb)

Glossary

Signal peptide

A short, amino-terminal peptide sequence that directs newly synthesized proteins that are destined for secretion into the secretory pathway.

Non-islet cell tumour hypoglycaemia

(NICTH). A condition of tumour-associated low blood glucose that is caused by hypersecretion of insulin-like growth factor 2 (IGF-II) (rather than by hypersecretion of insulin); the IGF-II is often secreted from the tumour tissue in a precursor form.

Hypermethylation

The addition of methyl groups to clustered cytosine residues in regulatory regions of DNA, which leads to the inhibition of gene transcription.

Endocytic receptor

A receptor that mediates the cellular uptake of proteins from the extracellular space.

Non-homologous end-joining

(NHEJ). A common mechanism of repairing double-strand DNA breaks that involves ligation of the broken DNA strands without the use of a DNA template to ensure faithful restoration of the original sequence.

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Baxter, R. IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer 14, 329–341 (2014). https://doi.org/10.1038/nrc3720

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