The insulin-like growth factor type 1 receptor and colo-rectal neoplasia: modelling the somatic evolution of cancers

Abstract

This thesis examines the temporal expression of the Insulin-like growth factor type 1 receptor gene (IGF-1R) in the evolution of human colo-rectal cancer. The IGF-IR is a highly conserved transmembrane receptor tyrosine kinase that is expressed at high levels in embryonic stem cells and in many cancer phenotypes. However, the IGF-IR is expressed at lower levels in some advanced cancers. The reasons for this and the timing of these changes in expression during neoplasia are not understood. Herein these studies examine IGF-IR expression in human colo¬ rectal neoplasia by means of Northern blotting and Immunohistochemistry validated by tissue and reagent controls and by Western blotting. The studies show that in the normal human colon, adult stem cells in the basal crypt region express high IGF-IR levels which decrease to low levels when these cells migrate to and differentiate in the mid and upper crypt regions. In the aberrant crypt focus, the transformed cells express high IGF-IR levels throughout the crypt axis despite showing varying degrees of differentiation. This pattern of high IGF-IR expression occurring de novo in colo-rectal neoplasia continues with neoplastic progression in adenomatous polyps and cancers. However, reduced IGF-IR expression is seen in some advanced cancer phenotypes - in epithelial-type cancer cells that show a fully polarised morphology in areas with epithelial-mesenchymal type transformation (EMT) and in invasive mesenchymal-type cancer cells that show a loss of cellbasement membrane or cell-cell adhesion after EMT. These morphological changes account for the low levels of IGF-IR expression seen in advanced invasive cancers in the current studies. These studies provide basic insights into how IGF-IR expression in normal cellular development is disrupted at tumour initiation and progression and into how this process might be involved in later stage cancers during EMT and invasion.