Soluble IGF2 receptor rescues Apc(Min/+) intestinal adenoma progression induced by Igf2 loss of imprinting.

Journal article

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 beta-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.

Authors: Harper, J; Burns, J; Foulstone, E; Pignatelli, M; Zaina, S

• Publication status: Published
• Journal: Cancer research
• Volume: 66
• Issue: 4
• Pages: 1940-1948
• Publication date: 2006-02-01
• DOI: 10.1158/0008-5472.can-05-2036
• EISSN: 1538-7445
• ISSN: 0008-5472
• Language: English
• Keywords: Insulin-Like Growth Factor II; Adenomatous Polyposis Coli; Transgenes; Alleles; beta Catenin; Receptor, IGF Type 2; Mice; Male; Animals; Female; Crosses, Genetic; Cell Growth Processes; Ligands; Gene Dosage; Genomic Imprinting; Disease Progression; Mice, Inbred C57BL