Soluble IGF2 Receptor Rescues Apc Min/+ Intestinal Adenoma Progression Induced by Igf2 Loss of Imprinting
- 15 February 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 66 (4) , 1940-1948
- https://doi.org/10.1158/0008-5472.can-05-2036
Abstract
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 ApcMin/+ 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 ApcMin/+ 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 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 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)Keywords
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