IGF Axis and Barrett’s Esophagus (Cancer Research UK – Hardie/Murray)

Information on study funded by Cancer Research UK:

The Role of the IGF axis in the development of Barrett’s metaplasia: a pooled case:control analysis from the Barrett’s Esophagus Adenocarcinoma Consortium (BEACON)

Evidence is accumulating that insulin like growth factors (IGFs) and their binding proteins (e.g. IGFBP-3, IGFBP-1) play an important role in the development of neoplastic growth through complex actions on cell proliferation, differentiation and apoptosis. Prospective studies have shown an increased risk of colorectal, prostate and pre-menopausal breast cancer in patients with high levels of circulating IGF-1. Knowledge of the role of this factor in the development of pre-neoplastic lesions is limited; but high circulating levels of IGF-1 have been associated with an increased frequency of colonic adenomas and cervical squamous intraepithelial lesions.  Reduced IGFBP-3 levels have been reported in patients with antral or corpus intestinal metaplasia.

Human esophageal cells express the IGF-1 receptor and IGF-1 stimulates proliferation and outgrowth of new mucosa in cultured esophageal explants. Subcutaneous administration of IGF-1 in rats enhances growth of columnar intestinal epithelium, and induces hyperplasia in crypt and villus compartments. Independent of IGF-1, IGFBP-3 enhances apoptosis in esophageal cells following DNA damage; a response which could be important given the DNA damaging properties of reflux constituents.

Our hypothesis is that circulating levels of IGF-1 and its associated binding proteins play an important role in the development of BE by modifying the outcome of reflux induced injury in the esophagus. As the IGF axis is influenced by sex and obesity, this may also provide an explanation for the association between these factors and Barrett’s development. The study is ongoing and involves the analysis of over three thousand samples for IGF-1, IGFBP-3 and IGFBP-1 using plasma obtained from five case control studies of Barrett’s oesophagus (Ireland, Australia, California, Seattle, North Carolina).

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