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

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 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: James Harper, Jason L Burns, Emily J Foulstone, Massimo Pignatelli, Silvio Zaina, A Bassim Hassan
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 4 Pg. 1940-8 (Feb 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16488992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Receptor, IGF Type 2
• beta Catenin
• Insulin-Like Growth Factor II

Topics

• Adenomatous Polyposis Coli (genetics, metabolism, pathology)
• Alleles
• Animals
• Cell Growth Processes (genetics)
• Crosses, Genetic
• Disease Progression
• Female
• Gene Dosage
• Genomic Imprinting
• Insulin-Like Growth Factor II (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Ligands
• Male
• Mice
• Mice, Inbred C57BL
• Receptor, IGF Type 2 (biosynthesis, genetics, metabolism)
• Transgenes
• beta Catenin (metabolism)