A 2ND SIGNAL SUPPLIED BY INSULIN-LIKE GROWTH-FACTOR-II IN ONCOGENE-INDUCED TUMORIGENESIS

TRANSGENIC mice expressing the simian virus-40 large T-antigen (Tag) u nder 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 t he islets become hyperplastic, however, and neovascularization of a fu rther subset (about 10%)(3) leads eventually to formation of highly va scularized solid tumours in 1-2% of islets by about 14 weeks of age. H ere we show that the initial proliferative switch is correlated with f ocal activation of insulin-like growth factor II (IGF-II). Transfectio n with an antisense oligonucleotide to the IGF-II messenger RNA interf eres with tumour cell proliferation in vitro, and transgenic mice homo zygous for a disruption of the IGF-II gene develop tumours with reduce d 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.