The insulin-like growth factor type 1 receptor and colorectal neoplasia: insights into invasion

This study examines the expression of the insulin-like growth factor type 1 receptor (IGF-1R) in colorectal neoplasia. Previous studies have shown that the IGF-1R is expressed at high levels in normal embryonic stem cells and in many cancer phenotypes. However, lower IGF-1R levels are expressed in some advanced cancer phenotypes. The timing of and the reasons for these changes in expression during the evolution of a cancer are not understood. Here, we examine IGF-1R expression in the evolution of colorectal cancer by means of Northern blotting and immunohistochemistry validated by tissue and reagent controls and Western blotting. We show for the first time that (1) in normal colorectal crypts, epithelial stem cells in the basal crypt region express high IGF-1R levels, which decrease to low levels when these cells migrate to and differentiate in the mid and upper crypt regions; (2) in tumor initiation in aberrant crypt foci, all of the transformed cells express high levels of the IGF-1R at stem cell levels throughout the crypt axis; (3) in tumor progression in adenomatous and cancerous crypts, tumor cells of an epithelial type morphology express high levels of the IGF-1R; (4) in advanced cancers, low levels of the IGF-1R are expressed in invasive foci where cancer cells dedifferentiate to a mesenchymal-type morphology and show a loss of cell adhesion. Interestingly, these cells can form an alternating pattern with mesenchymal type cells that show cell adhesion and high levels of IGF-1R expression. In summary, this study shows that high-level IGF-1R expression in colorectal neoplasia is initiated by an abnormality of stem cell programed differentiation in the aberrant crypt focus. However, low-level IGF-1R expression is found in some invasive cancers where it is consequent to cancer cell dedifferentiation to a mesenchymal type morphology with loss of cell adhesion.