The insulin-like growth factor system and cancer
Derek LeRoitha,*, Charles T. Roberts Jrb
Diabetes Branch, Room 8D12, Building 10, National Institutes of Health MSC 1758, Bethesda, MD 20892-1758, USA b Department of Pediatrics, Oregon Health and Science University, Portland, OR, 97239 USA Received 20 January2003; accepted 4 February 2003
Abstract The insulin-like growth factor (IGF) family of ligands, binding proteins and receptors is an important growth factor system involved in both the development of the organism and the maintenance of normal function of many cells of the body. The system also has powerful anti-apoptotic effects. More recently, evidence has accrued to demonstrate that the IGFsplay an important role in cancer. Individuals with serum IGF-II levels in the upper quartile of the normal range (and IGF binding protein-3 levels in the lower quartiles) have a relative risk for developing breast, prostate, colon and lung cancer. IGF-II is commonly expressed by tumor cells and may act as an autocrine growth factor; occasionally even reaching target tissues and causingtumor-induced hypoglycemia. The IGF-I receptor is commonly (though not always) overexpressed in many cancers, and many recent studies have identiﬁed new signaling pathways emanating from the IGF-I receptor that affect cancer cell proliferation, adhesion, migration and cell death; functions that are critical for cancer cell survival and metastases. In this review, many aspects of the IGF system and itsrelationship to cancer will be discussed. Published by Elsevier Science Ireland Ltd.
Keywords: Insulin-like growth factor; Insulin receptor; Cancer
1. Introduction The insulin-like growth factor (IGF) signaling system plays a critical role in the growth and development of many tissues and regulates overall growth, particularly prenatal growth. The IGF system has also been implicated in variouspathophysiological conditions, and is thought to play a particularly prominent role in tumorigenesis. The IGF system is
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comprised of the IGF ligands (IGF-I and IGF-II), cellsurface receptors that mediate the biological effects of the IGFs, including the IGF-I receptor (IGF-IR),the IGF-II receptor (IGF-IIR), and the insulin receptor (IR), as well as a family of IGF-binding proteins (IGFBPs). IGFBPs affect the half-lives and bioavailability of the IGFs in the circulation, in extracellular ﬂuids, and may exert IGF-independent effects under certain conditions (Fig. 1). This review will focus on the structure and function of the three components of the IGF axis, theirinteractions, and their role in tumorigenesis. For reviews on the IGF system see Refs. [1 – 3].
0304-3835/03/$ - see front matter Published by Elsevier Science Ireland Ltd. doi:10.1016/S0304-3835(03)00159-9
D. LeRoith, C.T. Roberts Jr / Cancer Letters 195 (2003) 127–137
Fig. 1. The IGF system. Shown are the ligands, cell-surface receptors, and the IGF-binding proteins that constitutethe IGF system. As indicated, IGF-I interacts with the IGF-IR and the IGFBPs, IGF-II interacts with the IGF-IR, the IGF-IIR, the exon 11-lacking (A) form of the IR, and the IGFBPs, and insulin interacts with the IR. Some of the IGFBPs exert effects that are independent of their modulation of IGF signaling through the IGF-IR and the IR, and these may involve novel IGFBP receptors.
2. The IGFligands 2.1. Structure of IGF-I and IGF-II The mature IGF-I and IGF-II peptides consist of B and A domains that are homologous to the B and A chains of insulin. Unlike insulin, the IGF peptides are not prototypically cleaved, but remain linked in the mature peptides by C domains analogous to the C peptide of insulin. Both IGF-I and IGF-II contain an additional short D domain that is not found in...