SurveyThe role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: Lessons from animal models
Introduction
Insulin-like growth factors (IGFs) are growth-promoting polypeptides, which play an essential role in growth and development. The IGF family of peptides includes IGF-I, IGF-II and insulin. These factors directly regulate cellular functions by interacting with specific cell surface receptors and activating various intracellular signaling cascades. IGF-I and IGF-II are the products of two separate genes, which are regulated independently and distinctly. Liver IGF-I gene-expression is regulated mainly by growth hormone (GH) and it is the major constituent of circulating IGF-I [1]. However, nutrition and insulin also play a regulatory role [2]. In extrahepatic tissues, IGF-I gene expression is regulated by tissue specific factors as well as by GH [3]. IGF-II is widely expressed in the developing mouse embryo but its expression declines progressively post-natally and adult rodent tissues are virtually devoid of IGF-II transcripts [4]. Unlike the IGF-I, the expression of the IGF-II gene is not regulated by GH but by other hormones and tissue specific growth factors. The multiplicity of mechanisms that exist to regulate IGF-II expression, underline the importance of tightly regulated physiological levels of IGF-II [5], [6]. In rodents, IGF-II is functional in fetal growth and development whereas IGF-I is active in post-natal and adult animals. In humans, however, both IGF-I and IGF-II are functional pre- and post-natally.
The cellular responses to the IGFs are mediated primarily by the IGF-I receptor. The IGF-I receptor is a member of the family of tyrosine kinase growth factor receptors, and is highly homologous (70%) to the insulin receptor (IR), especially in the tyrosine kinase domain. Upon ligand binding to the extracellular region, the intrinsic tyrosine kinase domain of the receptor is activated. This initiates various signaling cascades that result either in cellular proliferation or in a particular differentiated function [3]. Insulin binds the insulin receptor in a similar manner but stimulates primarily metabolic responses [7].
In the circulation, IGFs are protected from degradation by forming a complex with a family of high affinity IGF-binding proteins (IGFBPs) [8]. Most of the circulating IGF-I and IGF-II are associated with a high molecular weight complex ∼150 kDa consisting of IGFBP-3 and the acid labile subunit (ALS) [8]. Once the ternary complex dissociates, the binary complexes of IGFBP–IGF are removed from the circulation and cross the endothelium to reach the target tissues and to interact with cell surface receptors. In the tissues, IGFBPs may inhibit the interaction of the IGFs with their receptors, as the IGFBPs have a higher affinity for the IGFs than the receptors. In some cases, IGFBPs can enhance IGF action in the local microenvironment by acting as a reservoir that can slowly release the ligands. In addition, some IGFBPs can have IGF-independent effects on cells [8].
Section snippets
The GH/IGF axis in growth and development
The critical role of the GH/IGF system in somatic growth has been established in mice models where the genes for the GH receptor, the IGFs and their receptors have been ablated through homologous recombination technology. Deletion of the GH receptor gene resulted in a mouse model of Laron-type dwarfism [9]. These mice showed elevated serum GH levels, reduced IGF-I levels and growth retardation. The reduction in circulating IGF-I levels was due to a complete loss of the stimulatory effect of GH
The GH/IGF-I axis and cancer
The mouse models of IGF deficiency or IGF-IR gene ablation clearly demonstrated the role of the GH/IGF axis in normal mammalian growth and development. However, the role of the IGF system in abnormal cellular proliferation and transformation appears to be more complex. Many in vitro studies have shown that IGF-IR signaling leads to cell proliferation and the inhibition of apoptosis and because various types of tumors overexpress the IGF-IR it is assumed that the IGFs play a major role in tumor
The role of the IGF-I receptor in tumorigenesis
There is a large body of evidence based on in vitro and in vivo studies demonstrating the importance of IGF-IR signaling in mammalian cell transformation and the development of tumors. In 1994, Sell et al. demonstrated that fibroblasts derived from IGF-IR null mice could not be transformed by several oncogenes such as SV40-LTA [48], activated H-ras [49], bovine papillovirus [50], v-src [51], Raf-1 [51], or the overexpression of the platelet derived growth factor (PDGF) [52]. This protection
The IGF-IR as a target for cancer treatment
The large body of experimental evidence summarized above demonstrates that the inhibition of IGF-IR signaling and or downregulation of receptor levels lead to decreased tumor growth and metastasis. Collectively, this evidence identified the IGF-IR as a novel target for cancer treatment. However, the IGF-I system is complex and its targeting in vivo may pose a few challenges. One of these challenges is the high degree of homology between the IGF-I and insulin receptors. Thus, when targeting the
Conclusions
Animal studies have conclusively shown that the GH/IGF system is involved in tumor growth and metastasis. A number of human studies confirmed the importance of this system in malignant progression. Taken together, these studies identify the IGFs and their receptor as therapeutic targets for cancer therapy. The questions that emerge at this point are not whether IGF-IR and its ligands are playing a role in tumor development but rather, at what time point in tumor growth does IGF-I play a rate
Acknowledgements
We thank Dr. Louis Scavo (Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892-1758, USA) for helpful discussions and Bethel Stannard and Christine Biser (Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892-1758, USA) for assistance in preparation of the manuscript. Dr. Pnina Brodt is supported by grant #MOP-13646 from the Canadian Institute for Health Research and by a Terry Fox New Frontiers Initiative grant from the National Cancer Institute of
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