Insulin-Like Growth Factor Signaling in Colorectal Cancer

Insulin-like growth factors (IGFs) and their associated network of receptors, binding proteins and intracellular adaptors form a critical axis in the development and progression of colorectal cancer. IGF-1 and IGF-2 engage the IGF-1 receptor (IGF-1R), triggering downstream cascades such as the PI3K–AKT and RAS–RAF–MEK–ERK pathways, which promote cell proliferation, survival and resistance to apoptosis. Dysregulation of IGF-binding proteins (IGFBPs) alters ligand availability and bioactivity, further modulating tumour growth and metastatic potential. Epigenetic events, notably loss of imprinting of the IGF2 gene, result in IGF2 overexpression and enhanced autocrine stimulation. Elevated activity of hybrid insulin/IGF receptors and adaptor proteins such as IRS1 and IRS2 contributes to chemoresistance and cross-talk with other growth-factor systems. Collectively, these alterations define a multifaceted signalling network with clinical relevance for prognosis, stratification of therapeutic response and the design of targeted interventions aimed at disrupting key nodes in the IGF axis.

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Insulin-Like Growth Factor Signaling in Colorectal Cancer publication trend

The graph below shows the total number of articles in insulin-like growth factor signaling in colorectal cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Insulin-like growth factors (IGFs): Peptide hormones that regulate cell growth, differentiation and survival through endocrine, paracrine and autocrine mechanisms.

IGF-1 receptor (IGF-1R): A transmembrane tyrosine kinase receptor that mediates the biological effects of IGF-1 and IGF-2 by activating intracellular signalling cascades.

IGF-binding proteins (IGFBPs): A family of six high-affinity proteins that bind IGFs in circulation and tissues, modulating ligand availability, half-life and receptor interactions.

Loss of imprinting (LOI): An epigenetic alteration in which the normal parent-specific expression of imprinted genes is disrupted, leading to biallelic expression and potential overproduction of growth factors such as IGF2.

PI3K–AKT pathway: A central intracellular signalling cascade activated by receptor tyrosine kinases, including IGF-1R, that promotes cell survival, growth and metabolic adaptation.

References

1. The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy. Frontiers in Oncology (2015).
2. Insulin-Like Growth Factor 2 (IGF2) Signaling in Colorectal Cancer—from Basic Research to Potential Clinical Applications. International Journal of Molecular Sciences (2019).
3. The Insulin-like Growth Factor System and Colorectal Cancer. Life (2022).
4. Identification of Candidate Biomarkers and Prognostic Analysis in Colorectal Cancer Liver Metastases. Frontiers in Oncology (2021).
5. The Insulin Receptor Substrate 1 (Irs1) in Intestinal Epithelial Differentiation and in Colorectal Cancer. PLOS ONE (2012).
6. IRS2 is a candidate driver oncogene on 13q34 in colorectal cancer. International Journal of Experimental Pathology (2013).
7. IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas. Signal Transduction and Targeted Therapy (2020).
8. Gene therapy for colorectal cancer by an oncolytic adenovirus that targets loss of the insulin-like growth factor 2 imprinting system. Molecular Cancer (2012).