Abstract

The objective of this proposal is to investigate the role for insulin-like growth factor I (IGF-I) in the growth regulation of human cancer. IGF-I is a polypeptide hormone expressed by many tissues during normal growth and has been reported to be expressed by cancer cells. However, these reports are difficult to interpret due to the expression of cross-reacting mRNA species with the IGF-I cDNA on Northern analysis. This problem can be circumvented by using the sensitive and specific ribonuclease protection assay to detect IGF-I mRNA. When 45 epithelial cancer cell lines were examined using this technique, only neuroepithelioma and ovarian cancer cell lines were found to express authentic IGF-I mRNA. Since IGF-I is a potent mitogen for these cells, endogenously produced IGF-I could interact with its receptor (type I IGF receptor) and stimulate autocrine growth. Neuroepithelioma cells were found to secrete IGF-I protein. Moreover, antibody blockade of the type I IGF receptor inhibited basal cellular growth. These finding suggest that IGF-I is an important growth factor for neuroepithelioma and that it may act via an autocrine pathway. Neuroepithelioma and ovarian cancer are ideal model systems in which to study growth regulation of solid tumors by IGF-I. If IGF-I is an important growth factor for these cells, then interference with the IGF-I/type I IGF receptor interaction should inhibit tumor growth. This proposal will directly examine this hypothesis by developing methods to block receptor/ligand interactions and inhibit expression of their genes. The possibility that IGF-I mediates autocrine growth will also be addressed.
The specific aims are: 1) to determine the frequency of IGF-I expression in ovarian cancer, 2) to inhibit autocrine growth by antagonizing receptor/ligand interactions with IGF-I neutralizing and receptor blocking antibodies delivered extracellularly or intracellularly by microinjection, 3) to inhibit gene expression of IGF-I and its receptor by inducible anti-sense mRNA and anti-sense oligonucleotides and thereby inhibit tumor growth, 4) to develop these anti-IGF-I strategies for the treatment of cancer using an in vivo mouse model of ovarian carcinomatosis. These studies will provide information on the importance of IGF-I in tumor growth regulation and will test the therapeutic potential of this new form of endocrine therapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA052592-04
Application #
3459927
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
University of Texas Health Science Center San Antonio
Department
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229

  Publications

Cheng, H L; Randolph, A; Yee, D et al. (1996) Characterization of insulin-like growth factor-I and its receptor and binding proteins in transected nerves and cultured Schwann cells. J Neurochem 66:525-36
Figueroa, J A; Lee, A V; Jackson, J G et al. (1995) Proliferation of cultured human prostate cancer cells is inhibited by insulin-like growth factor (IGF) binding protein-1: evidence for an IGF-II autocrine growth loop. J Clin Endocrinol Metab 80:3476-82
Yee, D; Jackson, J G; Von Hoff, D D et al. (1994) Case report: use of insulin-like growth factor-I gene expression to distinguish between breast and ovarian cancer. Am J Med Sci 307:108-11
McGuire, S E; Hilsenbeck, S G; Figueroa, J A et al. (1994) Detection of insulin-like growth factor binding proteins (IGFBPs) by ligand blotting in breast cancer tissues. Cancer Lett 77:25-32
Yee, D; Jackson, J G; Kozelsky, T W et al. (1994) Insulin-like growth factor binding protein 1 expression inhibits insulin-like growth factor I action in MCF-7 breast cancer cells. Cell Growth Differ 5:73-7
Figueroa, J A; Sharma, J; Jackson, J G et al. (1993) Recombinant insulin-like growth factor binding protein-1 inhibits IGF-I, serum, and estrogen-dependent growth of MCF-7 human breast cancer cells. J Cell Physiol 157:229-36
Krywicki, R F; Figueroa, J A; Jackson, J G et al. (1993) Regulation of insulin-like growth factor binding proteins in ovarian cancer cells by oestrogen. Eur J Cancer 29A:2015-9
Figueroa, J A; Jackson, J G; McGuire, W L et al. (1993) Expression of insulin-like growth factor binding proteins in human breast cancer correlates with estrogen receptor status. J Cell Biochem 52:196-205
McGuire Jr, W L; Jackson, J G; Figueroa, J A et al. (1992) Regulation of insulin-like growth factor-binding protein (IGFBP) expression by breast cancer cells: use of IGFBP-1 as an inhibitor of insulin-like growth factor action. J Natl Cancer Inst 84:1336-41
Martin, D M; Yee, D; Feldman, E L (1992) Gene expression of the insulin-like growth factors and their receptors in cultured human retinal pigment epithelial cells. Brain Res Mol Brain Res 12:181-6

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