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Soluble IGF2 Receptor Rescues Apc^Min/+ Intestinal Adenoma Progression Induced by Igf2 Loss of Imprinting

¹ Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol, United Kingdom and ² Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark

Requests for reprints: A. Bassim Hassan, Department of Cellular and Molecular Medicine (formerly Pathology and Microbiology), School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, United Kingdom. Phone: 44-117-928-7555; Fax: 44-117-928-7896; E-mail: Bass.Hassan{at}Bristol.ac.uk.

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 (Igf2) and human (IGF2) genes modify progression of intestinal adenoma in the Apc^Min/+ mouse and correlate with a high relative risk of human colorectal cancer susceptibility, respectively. We examined the functional consequence of Igf2 allelic dosage (null, monoallelic, and biallelic) on intestinal adenoma development in the Apc^Min/+ by breeding with mice with either disruption of Igf2 paternal allele or H19 maternal allele and used these models to evaluate an IGF-II–specific therapeutic intervention. Increased allelic Igf2 expression led to elongation of intestinal crypts, increased adenoma growth independent of systemic growth, and increased adenoma nuclear ß-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 Igf2-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)

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