Data from Soluble IGF2 Receptor Rescues <i>Apc</i><sup><i>Min/</i>+</sup> Intestinal Adenoma Progression Induced by <i>Igf2</i> Loss of Imprinting

<div>Abstract<p>The potent growth-promoting activity of insulin-like growth factor-II (IGF-II) is highly regulated during development but frequently up-regulated in tumors. Increased expression of the normally monoallelic (paternally expressed) mouse (<i>Igf2</i>) and human (<i>IGF2</i>) genes modify progression of intestinal adenoma in the <i>Apc<sup>Min/+</sup></i> mouse and correlate with a high relative risk of human colorectal cancer susceptibility, respectively. We examined the functional consequence of <i>Igf2</i> allelic dosage (null, monoallelic, and biallelic) on intestinal adenoma development in the <i>Apc<sup>Min/+</sup></i> by breeding with mice with either disruption of <i>Igf2</i> paternal allele or <i>H19</i> maternal allele and used these models to evaluate an IGF-II–specific therapeutic intervention. Increased allelic <i>Igf2</i> expression led to elongation of intestinal crypts, increased adenoma growth independent of systemic growth, and increased adenoma nuclear β-catenin staining. By introducing a transgene expressing a soluble form of the full-length IGF-II/mannose 6-phosphate receptor (sIGF2R) in the intestine, which acts as a specific inhibitor of IGF-II ligand bioavailability (ligand trap), we show rescue of the <i>Igf2</i>-dependent intestinal and adenoma phenotype. This evidence shows the functional potency of allelic dosage of an epigenetically regulated gene in cancer and supports the application of an IGF-II ligand–specific therapeutic intervention in colorectal cancer. (Cancer Res 2006; 66(4): 1940-8)</p></div>