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Modifying IGF1 Activity: an Approach to Treat Endocrine Disorders, Atherosclerosis and Cancer

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Modifying IGF1 Activity: an Approach to Treat Endocrine Disorders, Atherosclerosis and Cancer REVIEWS Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer David R. Clemmons Abstract | Insulin-like growth factor 1 (IGF1) is a polypeptide hormone that has a high degree of structural similarity to human proinsulin. Owing to its ubiquitous nature and its role in promoting cell growth, strategies to inhibit IGF1 actions are being pursued as potential adjunctive measures for treating diseases such as short stature, atherosclerosis and diabetes. In addition, most tumour cell types possess IGF1 receptors and conditions in the tumour microenvironment, such as hypoxia, can lead to enhanced responsiveness to IGF1. Therefore, inhibiting IGF1 action has been proposed as a specific mechanism for potentiating the effects of existing anticancer therapies or for directly inhibiting tumour cell growth. Stromal cells Insulin-like growth factor 1 (IGF1), a small polypeptide IGF1 inhibition is being pursued as a potential adjunctive Connective tissue cells, (7,500 kDa) involved in cellular growth, and is a member measure for treating atherosclerosis. Inhibiting IGF1 primarily fibroblasts, that are of a family of structurally related peptides that also include action has been proposed as a specific treatment either present in nearly every organ. insulin-like growth factor 2 (IGF2) and human proinsulin. for potentiating the effects of other forms of anticancer IGF1 circulates in relatively high concentrations (150–400 therapies or for directly inhibiting tumour cell growth. ng per ml) in plasma, predominantly as the protein-bound This Review will encompass a discussion of the factors form, with the free active peptide representing only a small that regulate IGF1 synthesis and secretion, and focus percentage (less than 1%) of the total1. Despite structural on the strategies that have been used to modify IGF1 similarities between family members, each peptide binds actions in tissues principally for developing drugs for selectively to distinct cell surface receptors, which accounts the treatment of growth disorders, catabolism, diabetes, for much of the specificity of each peptide’s actions. The atherosclerosis and cancer. type 1 IGF receptor is a heterotetramer composed of two α subunits that contain the hormone binding domain, IGF1 synthesis and tissue growth which are linked to two β subunits that contain tyrosine IGF1 is synthesized in multiple tissues including liver, kinase catalytic activity domains by disulphide bonds2. skeletal muscle, bone and cartilage. The changes in Upon ligand occupancy the receptor undergoes a confor- blood concentrations of IGF1 reflect changes in its mational change that activates the tyrosine kinase activity, synthesis and secretion from the liver, which accounts which then activates downstream signalling molecules by for 80% of the total serum IGF1 in experimental protein phosphorylation. The regulation and synthesis of animals4. The remainder of the IGF1 is synthesized in the IGF1, IGF2 and insulin is quite distinct3. IGF1 synthesis is periphery, usually by connective tissue cell types, such controlled by several factors, including the human pitui- as stromal cells that are present in most tissues. IGF1 that tary growth hormone (GH, also known as somatotropin), is synthesized in the periphery can function to regulate whereas insulin concentrations are controlled primarily cell growth by autocrine and paracrine mechanisms3. by changes in blood glucose. IGF2 concentrations are Within these tissues, the newly synthesized and secreted high during fetal growth but are less GH-dependent IGF1 can bind to receptors that are present either on the Division of Endocrinology, in adult life compared with IGF1. These three peptides connective tissue cells themselves and stimulate growth Department of Medicine, have complementary roles in growth regulation. Because (autocrine), or it can bind to receptors on adjacent cell University of North Carolina, of its anabolic and insulin-like properties, strategies are types (often epithelial cell types) that do not actually Chapel Hill, North Carolina 27599-7170, USA. being pursued for treating short stature, catabolism and synthesize IGF1 but are stimulated to grow by locally e-mail: [email protected] controlling blood glucose in diabetes. IGF1 also has an secreted IGF1 (paracrine) (FIG. 1). Several experimental doi:10.1038/nrd2359 important role in promoting cell growth and consequently animal model systems have been analysed to determine NAturE REVIEws | DRUG DISCOVERY VOLUME 6 | OCTOBER 2007 | 821 © 2007 Nature Publishing Group REVIEWS in birth weight and a 70% reduction in final adult size16. GH Blood vessel GH By contrast, selective deletion of IGF1 synthesis in the liver (which leaves peripheral synthesis intact), decreases serum IGF1 by 80% but results in less than a 10% GH reduction in adult size13. These results imply that IGF1 receptor produced in the periphery is the main determinant of somatic growth in mice, whereas hepatic synthesis is the IGF1 primary determinant of plasma concentrations3. Hepatic Paracrine IGF1 Autocrine synthesis of IGF1 is regulated by several hormones, action action IGF1 principally GH, but the ability of GH to stimulate IGF1 receptor is strongly influenced by nutritional status. Following GH administration there is a major increase in blood IGF1 concentrations17. This increase in blood IGF1 acts IGF1 Extracellular to suppress GH synthesis in the pituitary gland through matrix a process termed negative-feedback regulation18, which synthesis IGFBP5 reservoir represents an important homeostatic mechanism for maintaining normal plasma IGF1 concentrations. After 5 days of fasting, hepatic synthesis of IGF1 is relatively Extracellular matrix refractory to GH stimulation and plasma IGF1 declines IGF1 receptor GH receptor by 50% (REF. 19). Upon refeeding, GH sensitivity is restored within 72 hours. Other hormones, including Figure 1 | Autocrine and paracrine actions of IGF1. Insulin-like growth factor 1 thyroxine, cortisol, oestradiol and testosterone20 par- (IGF1) is synthesized in peripheral tissues by connective tissueNatur celle Re typesviews |such Drug asDisc overy ticipate with GH in regulating hepatic IGF1 synthesis. fibroblasts. These cells contain growth hormone receptors and can respond to growth hormone (GH) that enters the tissues from blood vessels. Newly synthesized IGF1 is Thyroxine enhances sensitivity to GH, whereas cortisol secreted and transported to adjacent cells (paracrine action), where it stimulates acts to inhibit IGF1 synthesis. High cortisol concentra- coordinated cellular growth. It can also be secreted and then rebind to the cell of tions can lead to growth attenuation by this mecha- origin, where it stimulates cell growth (autocrine action). Similarly, locally produced nism. Oestradiol inhibits IGF1 synthesis in the liver by IGF1 can bind to IGF binding proteins (IGFBPs) such as IGFBP5 localized in the inducing suppressor of cytokine signalling 3 (SOCS3), extracellular matrix where a reservoir of IGF1, which can be released following tissue which inhibits GH stimulated signal transduction21. injury or during repair, is created. Stimuli other than GH, such as platelet-derived Testosterone not only enhances hepatic IGF1 synthesis, growth factor, can increase IGF1 synthesis; these factors are important for initiating but also alters the sensitivity of the pituitary gland to the response of tissue repair after injury. negative-feedback regulation of GH secretion, thus lead- ing to increases in GH and IGF1. IGF2 concentrations in blood, which are threefold greater than IGF1, are mini- the variables that regulate autocrine and paracrine secre- mally increased by GH22 and are significantly decreased tion of IGF1 and its actions5,6. Following tissue or cellular by prolonged fasting. injury there is a wave of IGF1 synthesis that stimulates Following either local secretion or transport through reparative cell types to replicate; this response has been the circulation to target tissues, IGF1 and IGF2 bind to shown to occur in injured blood vessels6, skeletal mus- the type 1 IGF1 receptor. IGF1 binds to the receptor with cle5, cartilage7 and in the brain8. Other growth factors sixfold to eightfold higher affinity than IGF2 and both that are involved in the repair process, such as platelet- peptides have affinities that are more than 100-fold greater derived growth factor (PDGF), fibroblast growth factor than insulin23. Conversely, insulin has a much higher (FGF) and epidermal growth factor (EGF), can stimulate affinity for its receptor. Following receptor activation, local synthesis of IGF1 (REfs 9–11). When transplanted the tyrosine kinase autophosphorylates tyrosine residues into experimental animal models, tumour cell types pro- that serve as important docking sites for the signalling duce IGF1 and/or IGF2, which can stimulate tumour proteins SRC homology 2 domain-containing protein growth. Additionally the mesenchymal cells surrounding (SHC) and insulin receptor substrate family 1 (IRS1)24. the tumour also provide an important paracrine source Both of these signalling intermediates are important for of IGF112. Autocrine and paracrine IGF1 signalling is the activation of the phosphoinositide 3 kinase (PI3K) believed to be important in determining normal fetal and mitogen-activated protein (MAP) kinase pathways growth13, and fetal brain expression of IGF1 is thought that mediate the metabolic and growth promoting to be crucial for determining brain growth and head actions of IGF1 and
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