Soluble IGF2 receptor rescues Apc(Min/+) intestinal adenoma progression induced by Igf2 loss of imprinting.
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.
Harper
James
J
Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol, United Kingdom.
Burns
Jason L
JL
Foulstone
Emily J
EJ
Pignatelli
Massimo
M
Zaina
Silvio
S
Hassan
A Bassim
AB
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000483:Alleles; D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D003433:Crosses, Genetic; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D018392:Genomic Imprinting; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017527:Receptor, IGF Type 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D051176:beta Catenin / Q000378:metabolism
D008024:Ligands; D017527:Receptor, IGF Type 2; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II