A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis

Abstract

TRANSGENIC mice expressing the simian virus-40 large T-antigen (Tag) under the control of the insulin gene regulatory region offer a useful model for tumorigenesis^1,2. All the islets of Langerhans express Tag, although there is at first no aberrant proliferation. Over half of the islets become hyperplastic, however, and neovascu-larization of a further subset (about 10%)³ leads eventually to formation of highly vascularized solid tumours in 1–2% of islets by about 14 weeks of age. Here we show that the initial prolifer-ative switch is correlated with focal activation of insulin-like growth factor II (IGF-II). Transfection with an antisense oligo-nucleotide to the IGF-II messenger RNA interferes with tumour cell proliferation in vitro, and transgenic mice homozygous for a disruption of the IGF-II gene develop tumours with reduced malignancy and a higher incidence of apoptosis. Several signals, in this case including an oncoprotein and a growth/survival factor, thus appear to be needed to elicit hyperproliferation.