The growth hormone–insulin-like growth factor-I axis and colorectal cancer

doi:10.1016/S1471-4914(01)02104-9

Trends in Molecular Medicine

Volume 7, Issue 10, 1 October 2001, Pages 447-454

https://doi.org/10.1016/S1471-4914(01)02104-9 Get rights and content

Abstract

The growth hormone (GH)–insulin-like growth factor (IGF)-I axis is an important modulator of growth and development, but in addition to their classical role as endocrine hormones, its components also regulate a wide range of biological functions through paracrine and autocrine mechanisms. Their potent mitogenic and anti-apoptotic effects play a critical role in the regulation of rapidly renewing epithelial cell populations such as those found in the colon. Recent evidence suggests an association between inappropriate regulation of the GH–IGF-I axis and the development of colorectal cancer. However, the molecular mechanisms and signalling pathways responsible are only beginning to be unravelled, as are the relative contributions of the endocrine and autocrine or paracrine effects.

Section snippets

Colorectal cancer

Most colorectal cancers develop as a result of the pathologic transformation of normal colonic epithelium to an adenomatous polyp and, ultimately, an invasive cancer. Inactivation of the adenomatous polyposis coli (APC) tumour suppressor gene on chromosome 5q is one of the earliest events in colorectal tumorigenesis. Activating mutations of the K-ras proto-oncogene are another frequent early event, followed by loss of heterozygosity on 18q, resulting in the inactivation of two tumour-suppressor

Evidence for a role of the GH–IGF-I axis in colorectal tumorigenesis

The colonic epithelium is arranged in crypts with actively dividing stem cells located towards the base, and differentiating daughter cells moving up the crypt towards the lumen to undergo apoptosis (Fig. 2). Beneath the epithelial cells lies the connective tissue, comprising fibroblasts, myofibroblasts, endothelial and neuroendocrine cells, and these are separated from the epithelial cells by a basement membrane composed of extracellular matrix (ECM). IGF-I expressed by and secreted from

Regulation of the GH–IGF-I axis in the colon

Surprisingly little is known about the regulation of the GH–IGF-I axis in the colon, both in terms of the expression of GH and IGF-I themselves, but also with respect to the role of the various IGFBPs and proteases, as well as the intracellular signalling pathways. This is important, because cellular responses to various stimuli are usually cell-type specific, and pathways activated in a particular tissue might not be the ones relevant to colorectal tumour development. Furthermore, it is

Downstream effects of IGF-IR activation

Signalling through the IGF-IR is effected through a complex series of pathways (Fig. 4), with the often contradictory effects on cellular behaviour dependent on the availability of downstream transducing molecules ⁵⁴. This results in cell type-specific variation in the signalling pathways involved in cellular transformation ⁵⁵. Choice of signalling pathway is also stimulus dependent: IGF-I can protect colon cancer cells from TNF-α-induced apoptosis by potentiating the MAPK and NF-κB signalling

Signalling specificity

There is increasing evidence that the various signal transduction pathways interact with one another to generate complex networks with synergistic properties that the individual pathways lack ⁶⁰. The IGF-IR appears to be at a convergence point in the control of cell growth, and a functional IGF-I/IGF-IR autocrine loop is required for the mitogenic effects of other growth factors (e.g. the epidermal growth factor EGF) ¹. Therefore, it is interesting that GH can alter the phosphorylation status

Clinical benefits of understanding the GH–IGF-I signalling pathway

In this review, we have discussed the considerable evidence in support of an important role for the GH–IGF-I axis in the development and growth of colorectal cancer. Further knowledge of the mechanisms regulating this influence and the downstream signalling pathways by which these components exert their effects might have important clinical applications. For instance, confirmation of the link between the prospective development of colon cancer and circulating IGF-I levels might allow the

Conclusion

In vivo, signalling pathways initiated by IGF1-receptor activation in the colon are extremely complex: several ligands bind to the IGF-IR, which itself can heterodimerise with at least two other receptors, but perhaps most importantly, activation occurs contemporaneously with signalling from numerous other hormone and cytokine receptors. Therefore, signals are transduced along networks that involve multiple interacting components, many of which are shared and are intermediates for numerous

Acknowledgements

The authors’ work is supported by grants from the London Immunotherapy Cancer Trust and the Joint Research Board of St Bartholomew's Hospital.

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Trends in Molecular Medicine

ReviewThe growth hormone–insulin-like growth factor-I axis and colorectal cancer

Abstract

Section snippets

Colorectal cancer

Evidence for a role of the GH–IGF-I axis in colorectal tumorigenesis

Regulation of the GH–IGF-I axis in the colon

Downstream effects of IGF-IR activation

Signalling specificity

Clinical benefits of understanding the GH–IGF-I signalling pathway

Conclusion

Acknowledgements

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Growth Horm. IGF. Res.

Eur J. Cancer

Hum. Pathol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

The somatomedin hypothesis: 2001

Endocr. Rev.

Autocrine and paracrine actions of intestinal fibroblast-derived insulin-like growth factors

Am. J. Physiol.

The effects of insulin-like growth factors on tumorigenesis and neoplastic growth

Endocr. Rev.

Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3

J. Natl. Cancer Inst.

IGF-I and IGF-II in relation to colorectal cancer

Int. J. Cancer

A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women

Cancer Epidemiol. Biomarkers Prev.

Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women

J. Natl. Cancer Inst.

Serum concentrations of insulin-like growth factor 1 in colonic neoplasia

Acta Oncol.

More about: prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3

J. Natl. Cancer Inst.

Alterations in serum levels of insulin-like growth factors and insulin- like growth-factor-binding proteins in patients with colorectal cancer 120

Int. J. Cancer

Increased levels of insulin-like growth factor binding protein-2 in sera and tumours from patients with colonic neoplasia with and without acromegaly

Clin. Endocrinol. (Oxf)

Acromegaly and cancer: a problem

J. Clin. Endocrinol. Metab.

Increased epithelial cell proliferation in the colon of patients with acromegaly

Cancer Res.

Insulin-like growth factor I and the development of colorectal neoplasia in acromegaly

J. Clin. Endocrinol. Metab.

Restoration of epithelial cell polarity in a colorectal cancer cell line by suppression of β-catenin/T-cell factor 4-mediated gene transactivation

Cancer Res.

Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation

Oncogene

Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of β-catenin

Proc. Natl. Acad. Sci. U. S. A.

Induction of transforming growth factor β 1 by insulin-like growth factor-1 in dermal fibroblasts

J. Cell Physiol.

Differential sensitivity of human colonic adenoma and carcinoma cells to transforming growth factor β (TGF-β): conversion of an adenoma cell line to a tumorigenic phenotype is accompanied by a reduced response to the inhibitory effects of TGF-beta

Oncogene

A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor beta1

Cancer Epidemiol. Biomarkers Prev.

Down-regulation of TGF-beta receptors in human colorectal cancer: implications for cancer development

Br. J. Cancer

IGF-II/IGF-I receptor pathway up-regulates COX-2 mRNA expression and PGE2 synthesis in Caco-2 human colon carcinoma cells

Oncogene

The role of cyclooxygenases in inflammation, cancer, and development

Oncogene

Review
The growth hormone–insulin-like growth factor-I axis and colorectal cancer