Emerging Concepts in the Role of IGFs and Cancer

The insulin-like growth factors (IGFs) are a ubiquitous family of ligands, binding proteins and receptors that are critical during early development and continue to play important functions during adult life. The IGFs have achieved widespread recognition in the endocrine scientific community over the years due to their pleotropic functions in virtually all organs of the body. More recently the IGF system has gained recognition due to its association with cancer. Recent epidemiological studies have shown an association between plasma IGF-I levels and the relative risk for cancer development including prostate, breast, colon, lung and bladder cancers. Furthermore, there is great interest in developing an inhibitor to the IGF-I receptor to block cancer growth. These include antibodies and small peptides to block the ligand binding domain or small molecules that inhibit the tyrosine kinase domain. For all of the above reasons it was felt that an issue in the journal covering the effects of the IGF-I receptor and cell function related to cancer was timely. In this issue we have asked various experts to address their work on two major related areas; the effects of the IGF system on cellular mechanisms that relate to cell cycle, proliferation and apoptosis as well as the importance of the IGF system in cancer.

In the first section, the articles which include original contributions as well as reviews describe some general topics on the IGF system, including the response of tumor tissue to circulating IGF-I, IGFs and the thymic system, and the effects of malignancy on skeletal muscle.

The second section deals with cellular signaling and describes the exciting new concept of the nuclear localization and effect of IRS-1. IRS-1 normal binds to the insulin and IGF-I receptors and was considered a cytosolic adapter protein; the article by Tu and colleagues describes how IRS-I may function in the nucleus. Other studies include p38 MAP kinase, a stress kinase, and its involvement in apoptosis in prostate cell lines that express a truncated IGF-I receptor. Dupont has reviewed the cross-talk between the IGF-I receptor and estrogen receptor signaling in breast cancer cell lines, whereas Koda describes the co-expression of the IGF-I receptor and the estrogen receptors in breast cancers and lymph nodes.

Regarding the epidemiology of the IGF system and cancer risk, Giovannucci reviews the evidence for nutrition, hyperinsulinemia, IGFs and their relationship to cancer development, whereas Sell reviews the issues of aging and caloric restriction and cancer risk. The potential association of acromegaly and colorectal cancer, a hotly debated issue is reviewed by Renehan.

In those articles concentrating on the role of the insulin-like growth factor binding proteins (IGFBPs), Perks and Holly suggest that the independent effects of IGFBPs on epithelial cancer cells make it a target for cancer therapeutics, as does Ali who focuses on IGFBP-3. Gallicchio demonstrates that IGFBP-6 (a relatively understudied IGFBP) can inhibit rhabdomyosarcoma growth when used with a rapamycin analog. In the review by Flint, the actions of IGFBP-5 on the mammary gland are summarized.

Articles dealing with specific targeting of the IGF-I receptor include a review by Salisbury and Macaulay, the demonstration of the use of a new monoclonal antibody that down-regulates the IGF-I receptor by Jackson-Booth and other articles on potential tools for targeting the IGF-I receptor in cancer.

On behalf of the journal I would personally like to thank all the authors for their outstanding contributions which will make this issue an extraordinary addition to the journal and surely will be of great value to those researchers both in academics and in industry who are interested in the latest developments in IGFs and cancer.

References

• 1 Rajaram S, David J. Baylink, and Subburaman Mohan Insulin-Like Growth Factor-Binding Proteins in Serum and Other Biological Fluids: Regulation and Functions.  J Endocr Rev. 1997;  18 801-831
• 2 Firth S M, Baxter R C. Cellular Actions of the Insulin-Like Growth Factor Binding Proteins.  Endocr Rev. 2002;  23 824-854
• 3 LeRoith D, Werner H, Beitner-Johnson D, Roberts C T Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor.  Endocr Rev. 1995;  16 143-163