The insulin-like growth factor-I plays a role in most functions of the body. It is produced by the liver, released to the circulation, and utilized locally by most non-hepatic tissues. To study the roles of circulating versus paracrine effects of IGF-I, we gene-deleted the IGF-I from the liver using the cre/loxP system. These mice showed a marked reduction in circulating IGF-I, but no obvious phenotype. When these mice were crossed with mice with an acid labile subunit gene-deletion, the circulating levels fell further. The crossed mice showed growth retardation and a reduction in bone density, suggesting an important role for circulating "endocrine" IGF-I. What remains to be determined are the roles for paracrine IGF-I. Liver IGF-I-deleted mice also showed a delayed onset of, and reduction in growth and metastases of an orthotopic colon cancer that is introduced by implanting the tumor onto the cecum. In a second model, DMBA-induced breast cancer and a genetically introduced breast cancer (SV40TAg mice) also delayed the appearance of tumors, reduced the growth and number of tumors in liver IGF-I-deleted mice. These results suggest that circulating IGF-I levels may be important in the risk for cancer growth and metastases. We have extended these studies to include a tamoxifen-inducible albumin Cre expressing mouse line. This allows us to induce the reduction of circulating IGF-1 at various post-natal days, even following the tumor appearance, to determine specifically if the previous data are due to chronic IGF-1 reductions from an early age or more specifically within the period of tumor appearance and growth. Crossing these mice with mice carrying the null allele for the acid-labile subunit (ALS) led to mice that had post-natal retardation associated with a further reduction in circulating IGF-I levels. Furthermore, their skeletons demonstrated osteoporosis to a greater degree than their growth retardation and suggested that circulating IGF-I, while important for longitudinal growth during puberty, was even more important for bone formation. We have also crossed these mice with the IGF-BP-3 knockout thereby reducing the circulating IGF-I to virtually zero and are investigating the effect of this triple knockout.