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. Thess 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 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 growth and number of tumors in the liver IGF-I-deleted mice. These results suggest that circulating IGF-I levels may be important in the risk for cancer growth and metastases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK055019-05
Application #
6810522
Study Section
(CEB)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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Yakar, Shoshana; Leroith, Derek; Brodt, Pnina (2005) The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: Lessons from animal models. Cytokine Growth Factor Rev 16:407-20
Yakar, Shoshana; Pennisi, Patricia; Zhao, Hong et al. (2004) Circulating IGF-1 and its role in cancer: lessons from the IGF-1 gene deletion (LID) mouse. Novartis Found Symp 262:3-9; discussion 9-18, 265-8
Yakar, Shoshana; Setser, Jennifer; Zhao, Hong et al. (2004) Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J Clin Invest 113:96-105
Wu, Yiping; Cui, Karen; Miyoshi, Keiko et al. (2003) Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. Cancer Res 63:4384-8