Special Issue "Insulin-Like Growth Factors in Development, Cancers and Aging"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (31 March 2020).

Special Issue Editor

Prof. Haim Werner
Website
Guest Editor
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Israel
Interests: insulin-like growth factors; IGF1 receptor; mechanisms of transcription; tumor suppressors
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Since their discovery in the late 1950s, insulin-like growth factors (IGF) have generated a significant level of interest in many areas of biology and medicine, including endocrinology, pediatrics, growth and development, metabolism, nutrition, aging and longevity and, finally, cancer research. IGF1, which was initially identified as the mediator of growth hormone action, is regarded as a key player in numerous cellular and organismal processes. The signaling pathways elicited by IGF1 have been extensively characterized in biochemical and molecular terms over the past 40 years. However, fundamental questions regarding basic differences between mechanisms of action of IGF1 and the closely related insulin molecule are yet to be resolved. IGF1 displays one of the most potent anti-apoptotic and pro-survival activities amongst all growth factors identified to date. Therefore, the IGF1 axis and, in particular, the IGF1 receptor emerged as a promising therapeutic target in oncology. In addition, the IGF1 system plays an important role in aging processes and abrogation of the growth hormone-IGF1 endocrine axis is associated with increased lifespan. This Special Issue of Cells will provide a collection of modern articles dealing with the role of IGF1 action in cancer biology, aging, and development. The articles explore basic and clinical aspects of the IGF1 system, including post-genomic analyses as well as novel, personalized approaches to target the IGF1R in oncology.

Prof. Haim Werner
Guest Editor

Manuscript Submission Information

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Keywords

  • insulin-like growth factors (IGF1, IGF2)
  • IGF1 receptor
  • IGF binding proteins
  • mechanisms of cancer
  • personalized medicine
  • targeted therapy
  • longevity
  • aging
  • development

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Published Papers (11 papers)

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Editorial

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Open AccessEditorial
Insulin-Like Growth Factors in Development, Cancers and Aging
Cells 2020, 9(10), 2309; https://doi.org/10.3390/cells9102309 - 17 Oct 2020
Abstract
Since their discovery in the late 1950s, insulin-like growth factors (IGFs) have attracted significant interest in multiple areas of biology and medicine, including endocrinology, pediatrics, growth, metabolism, nutrition, aging, and oncology [...] Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)

Research

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Open AccessArticle
Overlap of Peak Growth Activity and Peak IGF-1 to IGFBP Ratio: Delayed Increase of IGFBPs Versus IGF-1 in Serum as a Mechanism to Speed up and down Postnatal Weight Gain in Mice
Cells 2020, 9(6), 1516; https://doi.org/10.3390/cells9061516 - 22 Jun 2020
Cited by 2
Abstract
Forced expression of insulin-like growth factor binding proteins (IGFBPs) in transgenic mice has clearly revealed inhibitory effects on somatic growth. However, by this approach, it cannot be solved if or how IGFBPs rule insulin-like growth factor (IGF)-dependent growth under normal conditions. In order [...] Read more.
Forced expression of insulin-like growth factor binding proteins (IGFBPs) in transgenic mice has clearly revealed inhibitory effects on somatic growth. However, by this approach, it cannot be solved if or how IGFBPs rule insulin-like growth factor (IGF)-dependent growth under normal conditions. In order to address this question, we have used growth-selected mouse models (obese and lean) and studied IGF-1 and IGFBPs in serum with respect to longitudinal growth activity in males and females compared with unselected controls. In mice of both genders, body weights were recorded and daily weight gains were calculated. Between 2 and 54 weeks of age, serum IGF-1 was determined by ELISA and intact IGFBP-2, -3 and -4 were quantified by Western ligand blotting. The molar ratio of IGF-1 to the sum of IGFBP-2 to -4 was calculated for all groups and plotted against the daily weight gain curve. Growth-selected mice are characterized by higher daily weight gains and extended periods of elevated growth activity if compared to matched unselected controls. Therefore, adult mice from the obese and lean groups can achieve more than twofold increased body weight in both genders (p < 0.001). Between 2 and 11 weeks of age, in obese and lean mice of both genders, serum IGF-1 concentrations are increased more prominently if compared to unselected controls (p < 0.001). Instead, substantial decreases of IGFBPs, particularly of IGFBP-2, are observed in males and females of all groups at the age of 2 to 4 weeks (p < 0.001). Due to the strong increase of IGF-1 but not of IGFBPs between two and four weeks of age, the ratio of IGF-1 to IGFBP-2 to -4 in serum significantly increased in all groups and genders (p < 0.05). Notably, the IGF-1 to IGFBP ratio was higher in male and female obese mice if compared to unselected controls (p < 0.05). Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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Open AccessFeature PaperArticle
Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults
Cells 2020, 9(6), 1368; https://doi.org/10.3390/cells9061368 - 01 Jun 2020
Cited by 1
Abstract
While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of [...] Read more.
While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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Review

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Open AccessFeature PaperReview
Understanding IGF-II Action through Insights into Receptor Binding and Activation
Cells 2020, 9(10), 2276; https://doi.org/10.3390/cells9102276 - 12 Oct 2020
Cited by 1
Abstract
The insulin-like growth factor (IGF) system regulates metabolic and mitogenic signaling through an intricate network of related receptors and hormones. IGF-II is one of several hormones within this system that primarily regulates mitogenic functions and is especially important during fetal growth and development. [...] Read more.
The insulin-like growth factor (IGF) system regulates metabolic and mitogenic signaling through an intricate network of related receptors and hormones. IGF-II is one of several hormones within this system that primarily regulates mitogenic functions and is especially important during fetal growth and development. IGF-II is also found to be overexpressed in several cancer types, promoting growth and survival. It is also unique in the IGF system as it acts through both IGF-1R and insulin receptor isoform A (IR-A). Despite this, IGF-II is the least investigated ligand of the IGF system. This review will explore recent developments in IGF-II research including a structure of IGF-II bound to IGF-1R determined using cryo-electron microscopy (cryoEM). Comparisons are made with the structures of insulin and IGF-I bound to their cognate receptors. Finally discussed are outstanding questions in the mechanism of action of IGF-II with the goal of developing antagonists of IGF action in cancer. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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Open AccessReview
Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy
Cells 2020, 9(9), 1970; https://doi.org/10.3390/cells9091970 - 26 Aug 2020
Cited by 1
Abstract
Insulin-like growth factor-1 (IGF-1) is a key growth factor that regulates both anabolic and catabolic pathways in skeletal muscle. IGF-1 increases skeletal muscle protein synthesis via PI3K/Akt/mTOR and PI3K/Akt/GSK3β pathways. PI3K/Akt can also inhibit FoxOs and suppress transcription of E3 ubiquitin ligases that [...] Read more.
Insulin-like growth factor-1 (IGF-1) is a key growth factor that regulates both anabolic and catabolic pathways in skeletal muscle. IGF-1 increases skeletal muscle protein synthesis via PI3K/Akt/mTOR and PI3K/Akt/GSK3β pathways. PI3K/Akt can also inhibit FoxOs and suppress transcription of E3 ubiquitin ligases that regulate ubiquitin proteasome system (UPS)-mediated protein degradation. Autophagy is likely inhibited by IGF-1 via mTOR and FoxO signaling, although the contribution of autophagy regulation in IGF-1-mediated inhibition of skeletal muscle atrophy remains to be determined. Evidence has suggested that IGF-1/Akt can inhibit muscle atrophy-inducing cytokine and myostatin signaling via inhibition of the NF-κΒ and Smad pathways, respectively. Several miRNAs have been found to regulate IGF-1 signaling in skeletal muscle, and these miRs are likely regulated in different pathological conditions and contribute to the development of muscle atrophy. IGF-1 also potentiates skeletal muscle regeneration via activation of skeletal muscle stem (satellite) cells, which may contribute to muscle hypertrophy and/or inhibit atrophy. Importantly, IGF-1 levels and IGF-1R downstream signaling are suppressed in many chronic disease conditions and likely result in muscle atrophy via the combined effects of altered protein synthesis, UPS activity, autophagy, and muscle regeneration. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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Open AccessReview
Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production
Cells 2020, 9(8), 1844; https://doi.org/10.3390/cells9081844 - 06 Aug 2020
Cited by 1
Abstract
Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled [...] Read more.
Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. However, even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF–GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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Open AccessReview
Implications of Insulin-Like Growth Factor-1 in Skeletal Muscle and Various Diseases
Cells 2020, 9(8), 1773; https://doi.org/10.3390/cells9081773 - 24 Jul 2020
Cited by 2
Abstract
Skeletal muscle is an essential tissue that attaches to bones and facilitates body movements. Insulin-like growth factor-1 (IGF-1) is a hormone found in blood that plays an important role in skeletal myogenesis and is importantly associated with muscle mass entity, strength development, and [...] Read more.
Skeletal muscle is an essential tissue that attaches to bones and facilitates body movements. Insulin-like growth factor-1 (IGF-1) is a hormone found in blood that plays an important role in skeletal myogenesis and is importantly associated with muscle mass entity, strength development, and degeneration and increases the proliferative capacity of muscle satellite cells (MSCs). IGF-1R is an IGF-1 receptor with a transmembrane location that activates PI3K/Akt signaling and possesses tyrosine kinase activity, and its expression is significant in terms of myoblast proliferation and normal muscle mass maintenance. IGF-1 synthesis is elevated in MSCs of injured muscles and stimulates MSCs proliferation and myogenic differentiation. Mechanical loading also affects skeletal muscle production by IGF-1, and low IGF-1 levels are associated with low handgrip strength and poor physical performance. IGF-1 is potentially useful in the management of Duchenne muscular dystrophy, muscle atrophy, and promotes neurite development. This review highlights the role of IGF-1 in skeletal muscle, its importance during myogenesis, and its involvement in different disease conditions. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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Open AccessReview
Effects of GH/IGF on the Aging Mitochondria
Cells 2020, 9(6), 1384; https://doi.org/10.3390/cells9061384 - 02 Jun 2020
Cited by 1
Abstract
The mitochondria are key organelles regulating vital processes in the eukaryote cell. A decline in mitochondrial function is one of the hallmarks of aging. Growth hormone (GH) and the insulin-like growth factor-1 (IGF-1) are somatotropic hormones that regulate cellular homeostasis and play significant [...] Read more.
The mitochondria are key organelles regulating vital processes in the eukaryote cell. A decline in mitochondrial function is one of the hallmarks of aging. Growth hormone (GH) and the insulin-like growth factor-1 (IGF-1) are somatotropic hormones that regulate cellular homeostasis and play significant roles in cell differentiation, function, and survival. In mammals, these hormones peak during puberty and decline gradually during adulthood and aging. Here, we review the evidence that GH and IGF-1 regulate mitochondrial mass and function and contribute to specific processes of cellular aging. Specifically, we discuss the contribution of GH and IGF-1 to mitochondrial biogenesis, respiration and ATP production, oxidative stress, senescence, and apoptosis. Particular emphasis was placed on how these pathways intersect during aging. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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Open AccessReview
IGFBP-3/IGFBP-3 Receptor System as an Anti-Tumor and Anti-Metastatic Signaling in Cancer
Cells 2020, 9(5), 1261; https://doi.org/10.3390/cells9051261 - 20 May 2020
Cited by 1
Abstract
Insulin-like growth factor binding protein-3 (IGFBP-3) is a p53 tumor suppressor-regulated protein and a major carrier for IGFs in circulation. Among six high-affinity IGFBPs, which are IGFBP-1 through 6, IGFBP-3 is the most extensively investigated IGFBP species with respect to its IGF/IGF-I receptor [...] Read more.
Insulin-like growth factor binding protein-3 (IGFBP-3) is a p53 tumor suppressor-regulated protein and a major carrier for IGFs in circulation. Among six high-affinity IGFBPs, which are IGFBP-1 through 6, IGFBP-3 is the most extensively investigated IGFBP species with respect to its IGF/IGF-I receptor (IGF-IR)-independent biological actions beyond its endocrine/paracrine/autocrine role in modulating IGF action in cancer. Disruption of IGFBP-3 at transcriptional and post-translational levels has been implicated in the pathophysiology of many different types of cancer including breast, prostate, and lung cancer. Over the past two decades, a wealth of evidence has revealed both tumor suppressing and tumor promoting effects of IGF/IGF-IR-independent actions of IGFBP-3 depending upon cell types, post-translational modifications, and assay methods. However, IGFBP-3′s anti-tumor function has been well accepted due to identification of functional IGFBP-3-interacting proteins, putative receptors, or crosstalk with other signaling cascades. This review mainly focuses on transmembrane protein 219 (TMEM219), which represents a novel IGFBP-3 receptor mediating antitumor effect of IGFBP-3. Furthermore, this review delineates the potential underlying mechanisms involved and the subsequent biological significance, emphasizing the clinical significance of the IGFBP-3/TMEM219 axis in assessing both the diagnosis and the prognosis of cancer as well as the therapeutic potential of TMEM219 agonists for cancer treatment. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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Open AccessReview
Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug
Cells 2020, 9(5), 1098; https://doi.org/10.3390/cells9051098 - 29 Apr 2020
Cited by 3
Abstract
The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical [...] Read more.
The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap—a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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Open AccessReview
New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations
Cells 2020, 9(4), 862; https://doi.org/10.3390/cells9040862 - 02 Apr 2020
Cited by 3
Abstract
Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) play a crucial factor in the growth, differentiation and survival of cells in health and disease. IGF-I and IGF-II primarily activate the IGF-I receptor (IGF-IR), which is present on the cell surface. Activation of [...] Read more.
Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) play a crucial factor in the growth, differentiation and survival of cells in health and disease. IGF-I and IGF-II primarily activate the IGF-I receptor (IGF-IR), which is present on the cell surface. Activation of the IGF-IR stimulates multiple pathways which finally results in multiple biological effects in a variety of tissues and cells. In addition, activation of the IGF-IR has been found to be essential for the growth of cancers. The conventional view in the past was that the IGF-IR was exclusively a tyrosine kinase receptor and that phosphorylation of tyrosine residues, after binding of IGF-I to the IGF-IR, started a cascade of post-receptor events. Recent research has shown that this view was too simplistic. It has been found that the IGF-IR also has kinase-independent functions and may even emit signals in the unoccupied state through some yet-to-be-defined non-canonical pathways. The IGF-IR may further form hybrids with the insulin receptors but also with receptor tyrosine kinases (RTKs) outside the insulin-IGF system. In addition, the IGF-IR has extensive cross-talk with many other receptor tyrosine kinases and their downstream effectors. Moreover, there is now emerging evidence that the IGF-IR utilizes parts of the G-protein coupled receptor (GPCR) pathways: the IGF-IR can be considered as a functional RTK/GPCR hybrid, which integrates the kinase signaling with some IGF-IR mediated canonical GPCR characteristics. Like the classical GPCRs the IGF-IR can also show homologous and heterologous desensitization. Recently, it has been found that after activation by a ligand, the IGF-IR may be translocated into the nucleus and function as a transcriptional cofactor. Thus, in recent years, it has become clear that the IGF-IR signaling pathways are much more complex than first thought. Therefore a big challenge for the (near) future will be how all the new knowledge about IGF-IR signaling can be translated into the clinical practice and improve diagnosis and treatment of diseases. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factors in Development, Cancers and Aging)
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