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.
