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 B-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)

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

“…These results suggest that IGF-I acts on the tumor through an endocrine manner and that IGF-II acts mainly in an autocrine or paracrine manner in the vicinity of the tumors. These data are consistent with previous reports showing that liver-specific IGF-I deficiency reduces tumor progression in an orthotopic xenograft model (10) and that the soluble form of IGF-IIR produced constitutively in the intestine reduces intestinal polyp formation in Apc Min/+ mice (18).…”

“…Loss of imprinting of the IGF-II gene increases locally produced IGF-II concentration, which correlates with colorectal carcinogenesis (11)(12)(13)(14)(15). Some studies have shown that IGF-II modifies intestinal tumor growth in Apc Min/+ mice, a close genotypic and phenotypic model of human familial adenomatous polyposis, with genetically altered IGF-II expression (16)(17)(18).…”

Functional evaluation of novel soluble insulin-like growth factor (IGF)-II–specific ligand traps based on modified domain 11 of the human IGF2 receptor

“…Àm/+p mouse model can reverse the tumor-promoting effects of biallelic expression of Igf2 in vivo (16). Alternative approaches that target deregulation of the IGF system in tumors include interruption of ligand receptor interactions by increasing the supply of binding proteins, introducing either ligand-specific or receptor antibodies (20,52), expressing soluble and ligand binding forms of IGF1R (73), disruption of IGF1R receptor supply with RNA targeting (74), and inhibition of kinase activity of the IGF1R (75,76).…”

The Efficacy of IGF-I Receptor Monoclonal Antibody against Human Gastrointestinal Carcinomas is Independent of k-ras Mutation Status

“…IGF-I can also antagonize the antiproliferative effects of cyclooxygenase-2 (COX-2) inhibitors (21). Soluble IGF-IIR salvages Apc (Min/þ) intestinal adenoma progression induced by loss of IGF-II imprinting (11). IGF-IR is also important for tumor maintenance in addition to carcinogenicity (22,23).…”