<header style="border: 0px; outline: 0px; font-size: 14px; vertical-align: baseline; margin: 0px; padding: 0px; color: rgb(68, 68, 68); font-family: 'Open Sans', Arial, Helvetica, sans-serif; line-height: 23px; ">[h=1]IGF-1 Technical Mode of Action on Proliferation and Neoplasia- Everything you need to know[/h]<center>IGF-1 Technical Mode of Action on Proliferation and Neoplasia- Everything you need to know </center></header>
Figure 1. Regulation of circulating and tissue levels of insulin-like growth factors. Most circulating insulin-like growth factors are produced in the liver. Hepatic IGF1 production is subject to complex regulation by hormonal and nutritional factors. Growth hormone (GH), which is produced in the pituitary gland under control of the hypothalamic factors growth-hormone-releasing hormone (GHRH) and somatostatin (SMS), is a key stimulator ofIGF1production. Various IGF-binding proteins (IGFBPs) are also produced in the liver. In IGF-responsive tissues, the ligands IGF1 and IGF2 as well as IGFBPs can be delivered through the circulation from the liver (an ‘endocrine’ source), but IGFs and IGFBPs can also be locally produced through autocrine or paracrine mechanisms. These mechanisms often involve interactions between stromal- and epithelial-cell subpopulations.
Figure 2. Overview of insulin-like growth factor 1 receptor activation and downstream signalling. The insulin-like growth factor 1 receptor (IGF1R) is a tyrosine kinase cell-surface receptor that binds either IGF1 or IGF2. The local bioavailability of ligands is subject to complex physiological regulation and is probably abnormally high in many cancers. Ligands can be delivered from remote sites of production through the circulation or be locally produced. IGF-binding proteins (IGFBPs) and IGFBP proteases have key roles in regulating ligand bioavailability. IGFBPs prolong the half-life of IGFs, which has the potential to increase IGF1R activation. On the other hand, these proteins have affinity for IGFs comparable to IGF1R and there is competition between IGFBPs and IGF1R for available ligands in tissue microenvironments. This provides a basis for the inhibitory roles of IGFBPs on IGF1 signalling observed in many situations. There is evidence that certain IGFBPs also have direct, IGF-independent growth-regulatory actions. The IGF2R binds IGF2, but has no tyrosine kinase domain and appears to act as a negative influence on proliferation by reducing the amount of IGF2 available for binding to IGF1R. Certain IGFBP proteases (often produced by neoplastic cells) that cleave IGFBPs can release free ligand and thereby increase IGF1R activation. Following ligand binding to IGF1R, its tyrosine kinase activity is activated, and this stimulates signalling through intracellular networks that regulate cell proliferation and cell survival. Key downstream networks include the PI3K-AKT-TOR system and the RAF-MAPK systems. Activation of these pathways stimulates proliferation and inhibits apoptosis. This figure simplifies complex interacting regulatory networks. For many cell types, the key effects of signalling downstream to AKT relate to regulation of cell survival and mRNA translation, while the principal effect of signalling downstream to RAS involves regulation of cellular proliferation. 4EBP1, eukaryotic translation initiation factor 4E binding protein 1; eIF4E, eukaryotic translation initiation factor 4E; ERK, extracellular signal-regulated kinase; GRB2, growth-factor-receptor-bound protein 2; IRS1, insulin-receptor substrate 1; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; PI3K, phosphatidylinositol 3-kinase; PIP, phosphatidylinositol; PTEN, phosphatase and tensin homologue; S6K, S6 kinase; SHC, SRC-homology-2-domain transforming protein; SHP2, phosphatidylinositol 3-kinase regulatory subunit; SRF, serum response factor; TOR, target of rapamycin.
Figure 3. Model of the influence of insulin-like growth factor 1 signalling on the stepwise accumulation of somatic-cell genetic damage in carcinogenesis. The model of stepwise accumulation of genetic damage leading to carcinogenesis can be extended to include influences of insulin-like growth factor 1 (IGF1) signalling. These include favouring cellular proliferation over arrest and cellular survival over apoptosis. This model provides a preliminary biological framework to account for the observed association of higher levels of IGF1, or IGF1 receptor (IGF1R) activation, with cancer risk in epidemiological and laboratory studies. The model predicts that stepwise accumulation of genetic damage is facilitated in individuals with higher IGF1 levels because in these individuals there is a slightly higher rate of cell division (increasing the risk of errors) and, perhaps more importantly, because the probability of appropriate apoptosis of cells with a small number of ‘hits’ would be slightly reduced in a microenvironment with higher levels of IGF1R activation. The figure greatly exaggerates the magnitude of the hypothesized differences between ‘high IGF’ and ‘low IGF’ individuals in proliferation and apoptosis for purposes of illustration. Very small differences in these parameters, if applied to the very large renewing cell populations of organs such as the colon over a timespan of decades could influence the probability of emergence of a fully transformed clone. Colours indicate the following: yellow, normal cells; pale blue, cells containing one mutation or hit; dark blue, cells containing two mutations or hits; purple, apoptotic cells.
Figure 4. Insulin-like growth factor 1 receptor targeting: therapeutic strategies. Work is underway by many groups to develop pharmacological strategies to reduce signalling at and downstream of the insulin-like growth factor 1 receptor (IGF1R), in the hope that this will lead to compounds that are useful in cancer treatment. Approaches that will soon be tested clinically following demonstration of antineoplastic activity in laboratory studies include the use of blocking antibodies directed against the extracellular portion of the receptor and small-molecule tyrosine kinase inhibitors with specificity for IGF1R. Small interfering RNA (siRNA) and antisense strategies to reduce receptor expression, as well as transfection of altered or truncated IGF1R proteins that act in a dominant-negative fashion to interfere with receptor function are additional approaches that have been effective in laboratory studies. There is also great interest in therapeutic strategies that target signalling pathways downstream of IGF1R. Important examples include AKT inhibitors, and TOR inhibitors such as rapamycin and its analogues. IRS1, insulin-receptor substrate 1; PI3K, phosphatidylinositol 3-kinase; TOR, target of rapamycin.
Figure 5. Why is life expectancy increased when insulin-like growth factor 1 levels are reduced? Experimental results provide convincing evidence that in several experimental organisms, decreased insulin-like growth factor 1 (IGF1) signalling is associated with increased lifespan, even though in cell-culture systems reduced IGF1-receptor (IGF1R) activation increases the likelihood of cell death. A model to account for the increased lifespan associated with reduced IGF1 signalling is related to the classic ‘rate of living’ hypothesis. It is plausible that the process of ageing is related to the number of cell divisions since conception (although other factors are also involved). If the rate of cell turnover increases with higher levels of activation of IGF1R or related receptors, then at any fixed chronological age, there will have been more cell divisions in the ancestry of IGF-responsive cells of individuals with higher levels of receptor activation, compared with individuals with lower levels of activation. By the measure of ‘number of cell divisions since conception’, at an arbitrary number of years since conception, the individual on the right has aged faster than the individual on the left. If the process of ageing proceeds at least in part as a function of the number of cell divisions since conception, rather than as a function of elapsed time since conception, the individual on the left would live longer.
Medscape [Nat Rev Cancer 4(7):505-518, 2004. © 2004 Nature Publishing Group]
Figure 1. Regulation of circulating and tissue levels of insulin-like growth factors. Most circulating insulin-like growth factors are produced in the liver. Hepatic IGF1 production is subject to complex regulation by hormonal and nutritional factors. Growth hormone (GH), which is produced in the pituitary gland under control of the hypothalamic factors growth-hormone-releasing hormone (GHRH) and somatostatin (SMS), is a key stimulator ofIGF1production. Various IGF-binding proteins (IGFBPs) are also produced in the liver. In IGF-responsive tissues, the ligands IGF1 and IGF2 as well as IGFBPs can be delivered through the circulation from the liver (an ‘endocrine’ source), but IGFs and IGFBPs can also be locally produced through autocrine or paracrine mechanisms. These mechanisms often involve interactions between stromal- and epithelial-cell subpopulations.
Figure 2. Overview of insulin-like growth factor 1 receptor activation and downstream signalling. The insulin-like growth factor 1 receptor (IGF1R) is a tyrosine kinase cell-surface receptor that binds either IGF1 or IGF2. The local bioavailability of ligands is subject to complex physiological regulation and is probably abnormally high in many cancers. Ligands can be delivered from remote sites of production through the circulation or be locally produced. IGF-binding proteins (IGFBPs) and IGFBP proteases have key roles in regulating ligand bioavailability. IGFBPs prolong the half-life of IGFs, which has the potential to increase IGF1R activation. On the other hand, these proteins have affinity for IGFs comparable to IGF1R and there is competition between IGFBPs and IGF1R for available ligands in tissue microenvironments. This provides a basis for the inhibitory roles of IGFBPs on IGF1 signalling observed in many situations. There is evidence that certain IGFBPs also have direct, IGF-independent growth-regulatory actions. The IGF2R binds IGF2, but has no tyrosine kinase domain and appears to act as a negative influence on proliferation by reducing the amount of IGF2 available for binding to IGF1R. Certain IGFBP proteases (often produced by neoplastic cells) that cleave IGFBPs can release free ligand and thereby increase IGF1R activation. Following ligand binding to IGF1R, its tyrosine kinase activity is activated, and this stimulates signalling through intracellular networks that regulate cell proliferation and cell survival. Key downstream networks include the PI3K-AKT-TOR system and the RAF-MAPK systems. Activation of these pathways stimulates proliferation and inhibits apoptosis. This figure simplifies complex interacting regulatory networks. For many cell types, the key effects of signalling downstream to AKT relate to regulation of cell survival and mRNA translation, while the principal effect of signalling downstream to RAS involves regulation of cellular proliferation. 4EBP1, eukaryotic translation initiation factor 4E binding protein 1; eIF4E, eukaryotic translation initiation factor 4E; ERK, extracellular signal-regulated kinase; GRB2, growth-factor-receptor-bound protein 2; IRS1, insulin-receptor substrate 1; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; PI3K, phosphatidylinositol 3-kinase; PIP, phosphatidylinositol; PTEN, phosphatase and tensin homologue; S6K, S6 kinase; SHC, SRC-homology-2-domain transforming protein; SHP2, phosphatidylinositol 3-kinase regulatory subunit; SRF, serum response factor; TOR, target of rapamycin.
Figure 3. Model of the influence of insulin-like growth factor 1 signalling on the stepwise accumulation of somatic-cell genetic damage in carcinogenesis. The model of stepwise accumulation of genetic damage leading to carcinogenesis can be extended to include influences of insulin-like growth factor 1 (IGF1) signalling. These include favouring cellular proliferation over arrest and cellular survival over apoptosis. This model provides a preliminary biological framework to account for the observed association of higher levels of IGF1, or IGF1 receptor (IGF1R) activation, with cancer risk in epidemiological and laboratory studies. The model predicts that stepwise accumulation of genetic damage is facilitated in individuals with higher IGF1 levels because in these individuals there is a slightly higher rate of cell division (increasing the risk of errors) and, perhaps more importantly, because the probability of appropriate apoptosis of cells with a small number of ‘hits’ would be slightly reduced in a microenvironment with higher levels of IGF1R activation. The figure greatly exaggerates the magnitude of the hypothesized differences between ‘high IGF’ and ‘low IGF’ individuals in proliferation and apoptosis for purposes of illustration. Very small differences in these parameters, if applied to the very large renewing cell populations of organs such as the colon over a timespan of decades could influence the probability of emergence of a fully transformed clone. Colours indicate the following: yellow, normal cells; pale blue, cells containing one mutation or hit; dark blue, cells containing two mutations or hits; purple, apoptotic cells.
Figure 4. Insulin-like growth factor 1 receptor targeting: therapeutic strategies. Work is underway by many groups to develop pharmacological strategies to reduce signalling at and downstream of the insulin-like growth factor 1 receptor (IGF1R), in the hope that this will lead to compounds that are useful in cancer treatment. Approaches that will soon be tested clinically following demonstration of antineoplastic activity in laboratory studies include the use of blocking antibodies directed against the extracellular portion of the receptor and small-molecule tyrosine kinase inhibitors with specificity for IGF1R. Small interfering RNA (siRNA) and antisense strategies to reduce receptor expression, as well as transfection of altered or truncated IGF1R proteins that act in a dominant-negative fashion to interfere with receptor function are additional approaches that have been effective in laboratory studies. There is also great interest in therapeutic strategies that target signalling pathways downstream of IGF1R. Important examples include AKT inhibitors, and TOR inhibitors such as rapamycin and its analogues. IRS1, insulin-receptor substrate 1; PI3K, phosphatidylinositol 3-kinase; TOR, target of rapamycin.
Figure 5. Why is life expectancy increased when insulin-like growth factor 1 levels are reduced? Experimental results provide convincing evidence that in several experimental organisms, decreased insulin-like growth factor 1 (IGF1) signalling is associated with increased lifespan, even though in cell-culture systems reduced IGF1-receptor (IGF1R) activation increases the likelihood of cell death. A model to account for the increased lifespan associated with reduced IGF1 signalling is related to the classic ‘rate of living’ hypothesis. It is plausible that the process of ageing is related to the number of cell divisions since conception (although other factors are also involved). If the rate of cell turnover increases with higher levels of activation of IGF1R or related receptors, then at any fixed chronological age, there will have been more cell divisions in the ancestry of IGF-responsive cells of individuals with higher levels of receptor activation, compared with individuals with lower levels of activation. By the measure of ‘number of cell divisions since conception’, at an arbitrary number of years since conception, the individual on the right has aged faster than the individual on the left. If the process of ageing proceeds at least in part as a function of the number of cell divisions since conception, rather than as a function of elapsed time since conception, the individual on the left would live longer.
Medscape [Nat Rev Cancer 4(7):505-518, 2004. © 2004 Nature Publishing Group]
