ALTERED BODY-COMPOSITION AND INCREASED FREQUENCY OF DIVERSE MALIGNANCIES IN INSULIN-LIKE GROWTH FACTOR-II TRANSGENIC MICE

The physiological role of insulin-like growth factor (IGF) II (IGF-II) in adult humans is poorly understood. Rather high levels of IGF-II pe rsist in adult human serum, whereas, in rodents, IGF-II levels are ver y low. To investigate the physiological and carcinogenic effects of pe rsistently elevated IGF-II in adults, we have produced two lines of tr ansgenic mice in which high levels of IGF-II (20- or 30 fold increase above normal) are persistently maintained in the blood. The transgene is driven by the major urinary protein promoter, and it is highly expr essed in the liver and perputial glands in both lines. The adult trans genic mice are smaller than controls, and their body composition is al tered. Their lean body mass is reduced by 5-8%, whereas fat mass is re duced between 44 and 77%. The mice expressing the highest level of IGF -II (30x) develop hypoglycemia and hypoinsulinemia and IGF-I levels ar e normal. Mice in the lower expression line (20-fold elevated IGF-II) develop hypoglycemia progressively over their lifetime. Mice from both lines also develop a diverse spectrum of tumors at a higher frequency than controls after 18 months of age, and the most frequent types of tumors are hepatocellular carcinomas and lymphomas. Squamous cell carc inoma, sar coma, and thyroid carcinomas also occurred in our test grou p. The long latent period before tumors arise and the wide spectrum of tumor types suggest that IGF-II may function primarily as a tumor pro gression factor in mice via autocrine and endocrine mechanisms of acti on.