Insulin-like Growth Factor II Supply Modifies Growth of Intestinal Adenoma in ApcMin/+ Mice

Insulin-like growth factor-II (IGF-II) is an embryonic growth promoter and cell survival factor. IGF-II supply is normally limited by gene expression because transcription occurs predominantly from the paternal allele in mouse and man (maternal imprinting). Excess IGF-II has detrimental systemic and local effects in vivo , promoting somatic overgrowth and an increased frequency of tumors. IGF2 mRNA is overexpressed in colorectal and many other human cancers. In this paper, we show that altered IGF-II supply modifies intestinal tumor growth. Mice genetically altered in the IGF-II system were combined in crosses with Apc Min/+, a murine model of human familial adenomatous polyposis. Depending on genetic background, Apc Min/+ acquires multiple small intestinal adenoma before becoming moribund with anemia. Mice that express excess IGF-II delivered using a bovine keratin 10 promoter ( k10Igf2/+ ) develop a disproportionate overgrowth of colon, uterus, and skin. Combination with Apc Min/+ leads to a 10-fold increase in the number and the diameter of colon adenoma ( P < 0.0001) compared to Apc Min/+ littermate controls (postnatal day 80), an increased susceptibility to rectal prolapse (41%), and a histological progression to carcinoma. Mice with reduced IGF-II supply, secondary to the disruption of the paternal Igf2 allele ( Igf2 +m/−p), are 60% the weight of wild-type littermates. Combination with Apc Min/+ leads to a 3-fold reduction in small intestinal adenoma number ( P < 0.0001) compared to Apc Min/+ littermate controls (postnatal day 150), and a significant decrease in adenoma diameter ( P < 0.001). With in situ hybridization, we show that Igf2 was expressed in all adenoma irrespective of IGF-II supply. This suggests that there is an increased maternal allele expression of Igf2 (loss of imprinting) in adenoma which form, despite paternal Igf2 allele disruption. We conclude that IGF-II supply is a modifier of intestinal adenoma growth, and we provide genetic evidence for its functional role in colorectal cancer progression.

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