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The insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development, metabolism and growth, through the type 1 IGF receptor (IGF-1R). The growth hormone (GH)-IGF-I axis is the major regulator of longitudinal growth. IGF-II is expressed in many tissues, notably the placenta, to regulate human pre- and post-natal growth and development. This review provides a brief introduction to the IGF system and summarizes findings from reports arising from recent larger genomic sequencing studies of human genetic mutations in IGF1 and IGF2 and genes of proteins regulating IGF action, namely the IGF-1R, IGF-1R signaling pathway components and the IGF binding proteins (IGFBPs). A perspective on the effect of homozygous mutations on structure and function of the IGFs and IGF-1R is also given and this is related to the effects on growth., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Epidemiological studies have found that women have detectable levels of organic pollutants such as hexachlorobenzene (HCB), 2,2-dichlorodiphenyldichloroethylene (p,p'-DDE), polychlorinated biphenyl 153 (PCB153), perfluorooctanoate (PFOA), and perfluorooctane sulfonate (PFOS) in their follicular fluid. Thus, these compounds may directly affect the function of granulosa cells within the ovary and may promote granulosa cell tumor (GCT) progression. Two human GCT cell lines, COV434 and KGN, have been used as in vitro model systems to represent juvenile (JGCT) and adult (AGCT) GCT subtypes, respectively. In this study, we found that basal expression of estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), and insulin-like growth factor 1 receptor (IGF1R) was higher in the AGCT subtype than in the JGCT subtype. All of the compounds acted as mitogenic factors at low nanomolar concentrations in the JGCT and AGCT forms of GCT. Interestingly, PFOA, PFOS, and HCB stimulated cell proliferation through IGF1R, whereas p,p'-DDE acted through GPR30. Moreover, a mixture of the five compounds also significantly stimulated granulosa cell proliferation; however, the observed effect was lower than predicted. Interestingly, the proliferative effect of a mixture of these compounds was dependent on IGF1R and GPR30 but independent of the classic estrogen receptors. Taken together, our results demonstrate for the first time that mixtures of persistent organic pollutants present in follicular fluids may induce granulosa tumor progression through IGF1R and GPR30 by acting as mitogenic factors in granulosa cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Inactivation of tumor suppressor genes promotes initiation and progression of cervical cancer. This study aims to investigate the tumor suppressive effects of TROP-2 in cervical cancer cells and to explain the underlying mechanisms., Methods: The tumor suppressive functions of TROP-2 in cervical cancer cells were examined by in vitro and in vivo tumorigenic functional assays. Downstream factors of TROP-2 were screened using Human Phospho-Receptor Tyrosine Kinase Array. Small molecule inhibitors were applied to HeLa cells to test the TROP-2 effects on the oncogenicity of IGF-1R and ALK. Protein interactions between TROP-2 and the ligands of IGF-1R and ALK were detected via immunoprecipitation assay and protein-protein affinity prediction., Results: In vitro and in vivo functional assays showed that overexpression of TROP-2 significantly inhibited the oncogenicity of cervical cancer cells; while knockdown of TROP-2 exhibited opposite effects. Human Phospho-Receptor Tyrosine Kinase Array showed that the activity of IGF-1R and ALK was stimulated by TROP-2 knockdown. Small molecule inhibitors AG1024 targeting IGF-1R and Crizotinib targeting ALK were treated to HeLa cells with and without TROP-2 overexpression, and results from cell viability and migration assays indicated that the oncogenicity of vector-transfected cells was repressed to a greater extent by the inhibition of either IGF-1R or ALK than that of the TROP-2-overexpressed cells. Immunoprecipitation assay and protein-protein affinity prediction suggested protein interactions between TROP-2 and the ligands of IGF-1R and ALK., Conclusions: Collectively, our results support that TROP-2 exhibits tumor suppressor functions in cervical cancer through inhibiting the activity of IGF-1R and ALK., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Key Points: The placental insulin-like growth factor (IGF) system is critical for normal fetoplacental growth, which is dysregulated following several pregnancy perturbations including uteroplacental insufficiency and maternal obesity. We report that the IGF system was altered in placentae of mothers born growth restricted compared to normal birth weight mothers, with maternal diet- and fetal sex-specific responses. Additionally, we report increased body weight and plasma IGF1 concentrations in fetuses from chow-fed normal birth weight mothers that exercised prior to and continued during pregnancy compared to sedentary mothers. Exercise initiated during pregnancy, on the other hand, resulted in placental morphological alterations and increased IGF1 and IGF1R protein expression, which may in part be modulated by reduced Let 7f-1 miRNA abundance. Growth restriction of mothers before birth and exercise differentially regulate the placental IGF system with diet- and sex-specific responses, probably as a means to improve fetoplacental growth and development, and hence neonatal survival. This increased neonatal survival may prevent adult disease onset., Abstract: The insulin-like growth factor (IGF) system regulates fetoplacental growth and plays a role in disease programming. Dysregulation of the IGF system is implicated in several pregnancy perturbations associated with altered fetal growth, including intrauterine growth restriction and maternal obesity. Limited human studies have demonstrated that maternal exercise enhances fetoplacental growth and decreases cord IGF ligands, which may restore the placental IGF system in complicated pregnancies. This study investigated the impact maternal exercise has on the placental IGF system in placentae from mothers born growth restricted and if these outcomes are dependent on maternal diet or fetal sex. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a chow or high-fat diet from weaning, and at 16 weeks were randomly allocated an exercise protocol: Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Females were mated (20 weeks) with placentae associated with F2 fetuses collected at E20. The placental IGF system mRNA abundance and placental morphology was altered in mothers born growth restricted. Exercise increased fetal weight and Control plasma IGF1 concentrations, and decreased female placental weight. PregEx did not influence fetoplacental growth but increased placental IGF1 and IGF1R (potentially modulated by reduced Let 7f-1 miRNA) and decreased placental IGF2 protein. Importantly, these placental IGF system changes occurred with sex-specific responses. These data highlight that exercise differently influences fetoplacental growth and the placental IGF system depending on maternal exercise initiation, which may prevent the transgenerational transmission of deficits and dysfunction., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Antiestrogen resistance in estrogen receptor positive (ER + ) breast cancer is associated with increased expression and activity of insulin-like growth factor 1 receptor (IGF1R). Here, a kinome siRNA screen has identified 10 regulators of IGF1R-mediated antiestrogen with clinical significance. These include the tamoxifen resistance suppressors BMPR1B, CDK10, CDK5, EIF2AK1, and MAP2K5, and the tamoxifen resistance inducers CHEK1, PAK2, RPS6KC1, TTK, and TXK. The p21-activated kinase 2, PAK2, is the strongest resistance inducer. Silencing of the tamoxifen resistance inducing genes, particularly PAK2, attenuates IGF1R-mediated resistance to tamoxifen and fulvestrant. High expression of PAK2 in ER + metastatic breast cancer patients is correlated with unfavorable outcome after first-line tamoxifen monotherapy. Phospho-proteomics has defined PAK2 and the PAK-interacting exchange factors PIXα/β as downstream targets of IGF1R signaling, which are independent from PI3K/ATK and MAPK/ERK pathways. PAK2 and PIXα/β modulate IGF1R signaling-driven cell scattering. Targeting PIXα/β entirely mimics the effect of PAK2 silencing on antiestrogen re-sensitization. These data indicate PAK2/PIX as an effector pathway in IGF1R-mediated antiestrogen resistance.

Insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase that mediates growth, proliferation and survival. Dysregulation of IGF pathway contributes to the initiation, progression and metastasis of cancer and is also involved in diseases of glucose metabolism, such as diabetes. We have identified Ubiquilin1 (UBQLN1) as a novel interaction partner of IGF1R, IGF2R and insulin receptor (INSR). UBQLN family of proteins have been studied primarily in the context of protein quality control and in the field of neurodegenerative disorders. Our laboratory discovered a link between UBQLN1 function and tumorigenesis, such that UBQLN1 is lost and underexpressed in 50% of human lung adenocarcinoma cases. We demonstrate here that UBQLN1 regulates the expression and activity of IGF1R. Following loss of UBQLN1 in lung adenocarcinoma cells, there is accelerated loss of IGF1R. Despite decreased levels of total receptors, the ratio of active : total receptors is higher in cells that lack UBQLN1. UBQLN1 also regulates INSR and IGF2R post-stimulation with ligand. We conclude that UBQLN1 is essential for normal regulation of IGF receptors. UBQLN-1-deficient cells demonstrate increased cell viability compared with control when serum-starved and stimulation of IGF pathway in these cells increased their migratory potential by 3-fold. As the IGF pathway is involved in processes of normal growth, development, metabolism and cancer progression, understanding its regulation by Ubiquilin1 can be of tremendous value to many disciplines., (© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The insulin-like growth factor-1 receptor (IGF1R) mediates the biological actions of IGF1 and IGF2. The IGF1R is involved in both physiological and pathological activities and is usually overexpressed in most types of cancer. In addition to its classical mechanism of action, recent evidence has shown a nuclear presence of IGF1R, associated with novel genomic/transcriptional types of activities. The present study was aimed at evaluating the hypothesis that nuclear IGF1R localization is not restricted to cancer cells and might constitute a novel physiologically relevant regulatory mechanism. Our data shows that nuclear translocation takes place in a wide array of cells, including normal diploid fibroblasts. In addition, we provide evidence for a synergistic effect of a nuclear translocation blocker along with selective IGF1R inhibitors in terms of decreasing cell proliferation. Given the important role of the IGF1R in mitogenesis, the present results may be of translational relevance in cancer research. In conclusion, results are consistent with the concept that nuclear IGF1R fulfills important physiological and pathological roles.

Annual killifishes exhibit a number of unique life history characters including the occurrence of embryonic diapause, unique cell movements associated with dispersion and subsequent reaggregation of the embryonic blastomeres, and a short post-embryonic life span. Insulin-like growth factor (IGF) signaling is known to play a role in the regulation of metabolic dormancy in a number of animals but has not been explored in annual killifishes. The abundance of IGF proteins during development and the developmental effects of blocking IGF signaling by pharmacological inhibition of the insulin-like growth factor I receptor (IGF1R) were explored in embryos of the annual killifish Austrofundulus limnaeus Blocking of IGF signaling in embryos that would normally escape entrance into diapause resulted in a phenotype that was remarkably similar to that of embryos entering diapause. IGF-I protein abundance spikes during early development in embryos that will not enter diapause. In contrast, IGF-I levels remain low during early development in embryos that will enter diapause II. IGF-II protein is packaged at higher levels in escape-bound embryos compared with diapause-bound embryos. However, IGF-II levels quickly decrease and remain low during early development and only increase substantially during late development in both developmental trajectories. Developmental patterns of IGF-I and IGF-II protein abundance under conditions that would either induce or bypass entrance into diapause are consistent with a role for IGF signaling in the regulation of developmental trajectory and entrance into diapause in this species. We propose that IGF signaling may be a unifying regulatory pathway that explains the larger suite of characters that are associated with the complex life history of annual killifishes., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Amplification of seven oncogenes: HER2, EGFR, FGFR1, FGFR2, MET, KRAS and IGF1R has been identified in gastric cancer. The first five are targeted therapeutically in patients with HER2-positivity, FGFR2- or MET-amplification but the majority of patients are triple-negative and require alternative strategies. Our aim was to evaluate the importance of the IGF1R tyrosine kinase in triple-negative gastric cancer with and without oncogenic KRAS, BRAF or PI3K3CA mutations. Cell lines and metastatic tumor cells isolated from patients expressed IGF1R, and insulin-like growth factor-1 (IGF-1) activated the PI3-kinase/Akt and Ras/Raf/MAP-kinase pathways. IGF-1 protected triple-negative cells from caspase-dependent apoptosis and anoikis. Protection was mediated via the PI3-kinase/Akt pathway. Remarkably, IGF-1-dependent cell survival was greater in patient samples. IGF-1 stimulated triple-negative gastric cancer cell growth was prevented by IGF1R knockdown and Ras/Raf/MAP-kinase pathway inhibition. The importance of the receptor in cell line and metastatic tumor cell growth in serum-containing medium was demonstrated by knockdown and pharmacological inhibition with figitumumab. The proportions of cells in S-phase and mitotic-phase, and Ras/Raf/MAP-kinase pathway activity, were reduced concomitantly. KRAS-addicted and BRAF-impaired gastric cancer cells were particularly susceptible. In conclusion, IGF1R and the IGF signal transduction pathway merit consideration as potential therapeutic targets in patients with triple-negative gastric cancer.

A growing body of evidence suggests that microRNA-494 (miR-494) could act as tumor-suppressive or oncogenic microRNAs (miRNAs) in different types of tumors. However, the biological roles and underlying mechanisms of miR-494 remain unknown in human epithelial ovarian carcinoma (EOC). Therefore, the aims of this study were to investigate the miR-494 expression and the significance of its clinical diagnosis in patients suffering EOC and to analyze its role and underlying molecular mechanism on the carcinogenesis of EOC. Here, we found that miR-494 was significantly decreased in EOC cell lines and tissues and its expression was negatively correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, high pathological grade, and lymph node metastasis (all P < 0.01). Functional studies showed that overexpression of miR-494 in EOC cells could remarkably inhibit proliferation, colony formation, migration, and invasion and induce cell apoptosis, G0/G1 phase arrest. An in vivo analysis revealed that the overexpression of miR-494 suppressed tumor growth in a nude mouse xenograft model system. Bioinformatic assay and dual-luciferase assay confirmed that insulin-like growth factor 1 receptor (IGF1R) was as a direct target of miR-494 in EOC cells. Western blot assay showed that overexpression of miR-494 inhibited IGF1R expression and its downstream signal protein expression. In addition, downregulation of IGF1R has similar effects with miR-494 overexpression on EOC cells and overexpression of IGF1R effectively rescued the inhibition of overexpressed miR-494 in EOC cells. These data suggested that miR-494 functions as a tumor suppressor in EOC by targeting IGF1R.

The somatotropic signaling pathway has been implicated in aging and longevity studies in mice and other species. The physiology and lifespans of a variety of mutant mice, both spontaneous and genetically engineered, have contributed to our current understanding of the role of growth hormone and insulin-like growth factor I on aging-related processes. Several other mice discovered to live longer than their wild-type control counterparts also exhibit differences in growth factor levels; however, the complex nature of the phenotypic changes in these animals may also impact lifespan. The somatotropic axis impacts several pathways that dictate insulin sensitivity, nutrient sensing, mitochondrial function, and stress resistance as well as others that are thought to be involved in lifespan regulation., (Copyright © 2015 the American Physiological Society.)

Among various auto/paracrine growth-regulating signaling pathways an important role belongs to that of insulin-like growth factors (IGFs) and insulin. IGF-signaling system is actively involved in the regulation of both normal ovarian function and ovarian tumor growth. On the one hand, all members of this system are expressed in malignant ovarian epithelial cells, and the prognostic significance of this expression has been revealed for some of them in ovarian cancer patients in several studies. On the other hand, circulating IGFs/IGFBPs levels have not been undoubtedly associated with ovarian cancer risk or disease progression, but some of them can be regarded as supplementary serological ovarian cancer markers. An important route to the clinical application of IGF-signaling system studies in ovarian cancer is the growing possibility of using specific molecular targeted agents to suppress its growth-stimulating and other activities. However, the introduction of such agents to practical oncology has met serious problems, with the main difficulties resulting from the absence of reliable predictive molecular markers and metabolic side effects due to the tight connection between IGF-signaling and insulin-regulated processes. The prognostic and diagnostic values of various IGF system components and the current state of corresponding molecular targeted therapies development for ovarian cancer are reviewed.

Inhibition of histone deacetylases (HDACs) has emerged as a new target for cancer therapies. The present study examined the antitumor effect and molecular mechanism of the HDAC inhibitor apicidin in YD-15 human salivary mucoepidermoid carcinoma (MEC) cells. The cells were treated with apicidin and cell death was quantified using an MTT assay. Apoptosis and autophagy were measured using flow cytometry, immunoblot analysis and cell staining. Regulation of the signaling pathways was monitored using immunoblot analysis and co-treatment with specific inhibitors. Insulin-like growth factor 1 receptor (IGF-1R) was knocked down using specific siRNA. Apicidin significantly inhibited the proliferation of MEC cells. Apicidin also induced apoptosis through the inactivation of extracellular signal-regulated kinase (ERK) and AKT/mTOR signaling and activation of c-Jun NH2-terminal kinase (JNK), whereas apicidin promoted autophagy through inactivation of the AKT/mTOR signaling. These effects may be mediated by the inhibition of IGF-1R, an upstream regulator of MAPK and AKT/mTOR pathways. These results suggested that apicidin is an attractive chemotherapeutic agent against salivary MEC and may be a good candidate for targeting IGF-1R for cancer therapies.

The involvement of insulin, the insulin-like growth factors (IGF1, IGF2) and their receptors in central nervous system development and function has been the focus of scientific interest for more than 30 years. The insulin-like peptides, both locally-produced proteins as well as those transported from the circulation into the brain via the blood-brain barrier, are involved in a myriad of biological activities. These actions include, among others, neuronal survival, neurogenes, angiogenesis, excitatory and inhibitory neurotransmission, regulation of food intake, and cognition. In recent years, a linkage between brain insulin/IGF1 and certain neuropathologies has been identified. Epidemiological studies have demonstrated a correlation between diabetes (mainly type 2) and Alzheimer׳s disease. In addition, an aberrant decline in IGF1 values was suggested to play a role in the development of Alzheimer׳s disease. The present review focuses on the expression and function of insulin, IGFs and their receptors in the brain in physiological and pathological conditions., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Background: Several microRNAs (miRs) have been shown to regulate gene expression in the heart, and dysregulation of their expression has been linked to cardiac disease. miR-378 is strongly expressed in the mammalian heart but so far has been studied predominantly in cancer, in which it regulates cell survival and tumor growth., Methods and Results: Here, we report tight control of cardiomyocyte hypertrophy through miR-378. In isolated primary cardiomyocytes, miR-378 was found to be both necessary and sufficient to repress cardiomyocyte hypertrophy. Bioinformatic prediction suggested that factors of the mitogen-activated protein kinase (MAPK) pathway are enriched among miR-378 targets. Using mRNA and protein expression analysis along with luciferase assays, we validated 4 key components of the MAPK pathway as targets of miR-378: MAPK1 itself, insulin-like growth factor receptor 1, growth factor receptor-bound protein 2, and kinase suppressor of ras 1. RNA interference with these targets prevented the prohypertrophic effect of antimiR-378, suggesting their functional relation with miR-378. Because miR-378 significantly decreases in cardiac disease, we sought to compensate for its loss through adeno-associated virus-mediated, cardiomyocyte-targeted expression of miR-378 in an in vivo model of cardiac hypertrophy (pressure overload by thoracic aortic constriction). Restoration of miR-378 levels significantly attenuated thoracic aortic constriction-induced cardiac hypertrophy and improved cardiac function., Conclusions: Our data identify miR-378 as a regulator of cardiomyocyte hypertrophy, which exerts its activity by suppressing the MAPK signaling pathway on several distinct levels. Restoration of disease-associated loss of miR-378 through cardiomyocyte-targeted adeno-associated virus-miR-378 may prove to be an effective therapeutic strategy in myocardial disease.

The major issue currently being faced in the management of prostate cancer is the inability to distinguish between indolent prostate tumors that will not present clinically from more aggressive and metastatic prostate cancers that will impact on men's lives. Only a small proportion of prostate cancers can be accounted for by unmistakable hereditary cancer syndromes and the predominant contribution to the progression of most sporadic cancers is thought to be environmental, with nutrition having the greatest influence. Population studies have clearly implicated metabolic factors as contributors to disease progression and poor response to therapy. It is well established that the IGF system is key in regulating growth and metabolism and mediates the effects of nutrition on these processes. It consists of two ligands (IGF-I and IGF-II), two receptors [type 1 IGF-IR and IGF-II/mannose 6-phosphate receptor], and six high affinity IGF-binding proteins (IGFBP-1 to -6). This review provides evidence from in vitro, in vivo, clinical and epidemiology studies that indicates an important role for the IGF axis in the development of prostate cancer and the likely role that it plays in mediating the effects of nutrition on disease progression. We suggest that the IGF axis is central to understanding how lifestyle impacts on prostate cancer and we highlight this by describing numerous strategies being developed to target this axis.

Although very similar to insulin and its receptor; the modus operandi of the insulin-like growth factors (IGFs) within the body is very different from that of the traditional peptide hormone. The IGF-binding proteins bind the IGFs with greater affinity than the cell surface receptors, enabling them to tightly control tissue activity. In addition to their role in fetal and childhood growth, IGFs play an important role in metabolic regulation. This article describes the basic underlying human physiology of IGFs, how this differs from that of experimental models, and why some information can only be learned from human clinical studies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Insulin-like growth factors (IGFs) play an integral role in development, growth, and survival. This article details the current understanding of the effects of IGFs in the peripheral nervous system (PNS) during health and disease, and introduces how the IGF system regulates PNS development and impacts growth and survival of PNS cells. Also discussed are implications of IGF signaling in neurodegeneration and the status and prospects of IGF therapies for PNS conditions. There is substantial support for the application of IGF therapies in the treatment of PNS injury and disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The insulin-like growth factor (IGF) signaling pathway consists of multiple IGF ligands, IGF receptors, and IGF-binding proteins (IGFBPs). Studies in a variety of animal and cellular systems suggest that the IGF signaling pathway plays a key role in regulating skeletal muscle growth, differentiation, and in maintaining homeostasis of the adult muscle tissues. Intriguingly, IGFs stimulate both myoblast proliferation and differentiation, which are two mutually exclusive biological events during myogenesis. Both of these actions are mediated through the same IGF-1 receptor. Recent studies have shed new insights into the molecular mechanisms underlying these paradoxical actions of IGFs in muscle cells. In this article, we provide a brief review of our current understanding of the IGF signaling system and discuss recent findings on how local oxygen availability and IGFBPs act to specify IGF actions in muscle cells., ((c) 2010 Elsevier Inc. All rights reserved.)

Development of the post-hatching conceptus in ruminants involves a period of morphological expansion that is driven by complex interactions between the conceptus and its intrauterine environment. As a result of these interactions, endometrial physiology is altered, leading to establishment of the pregnancy and continued development of the placenta. Disruption of normal fetal and placental development can occur when embryos are exposed to manipulations in vitro or when inappropriate endocrine sequencing occurs in vivo during the pre- and peri-implantation periods. The present review addresses the development of the post-hatching bovine conceptus, its interactions with the maternal system and changes in development that can occur as a result of in vivo and in vitro manipulations of the bovine embryo.

Insulin-like growth factor-1 (IGF-1) signaling has recently been implicated in the development of cardiac hypertrophy after long-term endurance training, via mechanisms that may involve energetic stress. Given the potential overlap of insulin and IGF-1 signaling we sought to determine if both signaling pathways could contribute to exercise-induced cardiac hypertrophy following shorter-term exercise training. Studies were performed in mice with cardiac-specific IGF-1 receptor (IGF1R) knockout (CIGFRKO), mice with cardiac-specific insulin receptor (IR) knockout (CIRKO), CIGFRKO mice that lacked one IR allele in cardiomyocytes (IGFR-/-IR+/-), and CIRKO mice that lacked one IGF1R allele in cardiomyocytes (IGFR+/-IR-/-). Intravenous administration of IGF-1 or 75 hours of swimming over 4 weeks increased IGF1R tyrosine phosphorylation in the heart in control and CIRKO mice but not in CIGFRKO mice. Intriguingly, IR tyrosine phosphorylation in the heart was also increased following IGF-1 administration or exercise training in control and CIGFRKO mice but not in CIRKO mice. The extent of cardiac hypertrophy following exercise training in CIGFRKO and CIRKO mice was comparable to that in control mice. In contrast, exercise-induced cardiac hypertrophy was significantly attenuated in IGFR-/-IR+/- and IGFR+/-IR-/- mice. Thus, IGF-1 and exercise activates both IGF1R and IR in the heart, and IGF1R- and IR-mediated signals may serve redundant roles in the hypertrophic responses of the heart to exercise training.

Context: Term-born children conceived by in vitro fertilisation (IVF) are reportedly taller than naturally conceived (NC) children. High levels of growth promoting hormones and epigenetic imprinting have been suggested as pathogenetic mechanisms., Hypothesis: Tall stature in prematurely born IVF-conceived (IVF-C) children suggests pre- or early implantation imprinting rather than a postnatal effect., Methods: We studied 334 very low birthweight (VLBW: birth weight <1500 g) children born prematurely during 1995-1999 and obtained their anthropometric measures at 6-10 years of age. Perinatal and neonatal data were obtained from the Israeli VLBW database. We compared IVF-C, ovulating agents conceived (OA-C) and naturally conceived (NC) groups of children with respect to their and their parents' anthropometry and their perinatal/neonatal variables., Results: Childhood height standard deviation scores (SDSs) were greatest in IVF-C (-0.12 (SD 1.25); p<0.022) and insignificantly greater in OA-C (-0.37 (SD 1.02)) as compared to NC (-0.58 (SD 1.36)) children. The IVF-C and NC groups were significantly different regarding 17 parental and perinatal variables; however, multiple regression analysis including these variables showed that, as compared with NC, IVF-C children had significantly older mothers at birth with earlier follow-up during pregnancy and more multi-fetal pregnancies., Conclusions: IVF-C and to a lesser extent OA-C prematurely born children are taller than otherwise NC children. After ruling out postnatal and parental causes, we speculate that pre- or early implantation factors might have contributed to the taller stature of IVF-C children.

The authors review the antineoplastic effect of mammalian target of rapamycin (mTOR) inhibitors and their biological basis. mTOR is an intracellular serine/threonine kinase that is a central controller of cell growth and proliferation. mTOR integrates signals from sources such as nutrients and growth factors. mTOR regulation can affect angiogenesis, cell growth, nutrient uptake and utilization, and metabolism. Growth factors such as insulin growth factor, epidermal growth factor, platelet-derived growth factor and vascular endothelial growth factor bind to and activate receptors located on the cell surface. Receptors activate intracellular signaling cascades phosphatidylinositol 3 kinase-serine-threonine kinase-mTOR (PI3K-AKT-mTOR) leading to protein synthesis. Activation of the mTOR pathway is linked to increased protein synthesis by modulating elements that are important in cellular processes, including growth, proliferation, angiogenesis and nutrient uptake. Many growth factor receptors and signaling pathway components are deregulated in cancer. Deregulations in mTOR-linked pathways increase the risk of developing cancer or have been identified in many human cancers. Deregulations include overexpression of growth factors, overexpression or mutations of growth factor receptors, loss of tumor suppressor genes, and gain-of-function mutations in mTOR-linked pathways. These deregulations permit the survival, growth, proliferation and migration of cancer cells and promote tumor angiogenesis. Targeting them has been a successful anticancer strategy. Targeting mTOR as well as these deregulated pathways could provide enhanced anticancer activity. The efficacy of mTOR inhibitors in preventing several types of cancers in transplanted patients or in recovering cancers developed in transplant patients has been documented in both trials and single reports.

IGF-I and -II are potent neuronal mitogens and survival factors. The actions of IGF-I and -II are mediated via the type I IGF receptor (IGF-IR) and IGF binding proteins regulate the bioavailability of the IGFs. Cell viability correlates with IGF-IR expression and intact IGF-I/IGF-IR signaling pathways, including activation of MAPK/phosphatidylinositol-3 kinase. The expression of IGF-I and -II, IGF-IR, and IGF binding proteins are developmentally regulated in the central and peripheral nervous system. IGF-I therapy demonstrates mixed therapeutic results in the treatment of peripheral nerve injury, neuropathy, and motor neuron diseases such as amyotrophic lateral sclerosis. In this review we discuss the role of IGFs during peripheral nervous system development and the IGF signaling system as the potential therapeutic target for the treatment of nerve injury and motor neuron diseases.

Hereditary breast cancers affect women who have an increased risk of developing tumors because of a familial history. In most cases, they can be attributed to mutations in the breast cancer associated gene 1 and 2 (BRCA1 and BRCA2). Recent studies have demonstrated a link between the insulin-like growth factor (IGF) signaling pathway and familial breast cancer incidence. IGF and IGF receptors represent a family of biological growth factors and transducers, which have been involved in both physiological and pathological processes. It has been shown that BRCA1 regulates expression of several members of the IGF family. Here, we will examine our understanding of the functions of IGF/IGF-receptor signaling, the development of new inhibitors of this pathway and the related mechanisms of familial breast cancer formation.

The IGF-II/mannose 6-phosphate receptor (IGF2R) function in extracellular matrix (ECM) remodeling is known to occur as a result of transforming growth factor-beta (TGF-beta) activation and plasmin in the proteolytic cleavage level caused by the interaction between latent TGF-beta and urokinase plasminogen activator receptor (uPAR) respectively. In one of our previous studies, we found IGF-II and IGF2R dose-dependently correlated with the progression of pathological hypertrophy remodeling following complete abdominal aorta ligation. However, how this IGF2R signaling pathway responds specifically to IGF-II and regulates the myocardial ECM remodeling process is unclear. We found that IGF2R was aberrantly expressed in myocardial infarction scars. The matrix metalloproteinase-9 (MMP-9) zymographic activity was elevated in H9c2 cardiomyoblast cells treated with IGF-II, but not IGF-I. Treatment with Leu27IGF-II, an IGF2R specifically binding IGF-II analog, resulted in significant time-dependent increases in the MMP-9, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA); and a reduction in the tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) protein expression. Furthermore, IGF2R expression inhibition by siRNA blocked the IGF-II-induced MMP-9 activity. We hypothesize that after IGF-II is bound with IGF2R, the resulting signal disrupts the balance in the MMP-9/TIMP-2 expression level and increases plasminogen activator (PAs) expression involved in the development of myocardial remodeling. If so, IGF2R signaling inhibition may have potential use in the development of therapies preventing heart fibrosis progression.

It is well known that the insulin-like growth factor (IGF) axis is an important regulator of foetal growth and in recent years, it has been suggested that the ligands IGF-I and IGF-II may, in part, mediate this effect by promoting proper placental development and function. In other tissues, IGF effects on metabolism, proliferation and differentiation are primarily mediated via IGF binding protein-regulated interaction of IGFs with the type 1 IGF receptor and therefore here, we review the placental expression and postulated role, of each of the IGF axis components and discuss the cellular mechanisms through which these effects are exerted., ((c) 2008 S. Karger AG, Basel)

In congenital diaphragmatic hernia (CDH), both mortality and morbidity are mainly caused by pulmonary hypoplasia and persistent pulmonary hypertension. Insulin-like growth factors (IGFs) are one of the growth factors that may play an important role in the fetal lung development. Elucidating the roles of these growth factors regarding fetal lung development would thus provide new insight regarding the optimal therapy for CDH patients. The aim of this study is to investigate the role of IGFs in the fetal lung development. The mRNA expression of IGFs and its receptors was analyzed by real-time RT-PCR from embryonic day (E) 11.5 to E18.5 mice. In addition, the lungs dissected from the E17.5 mice were divided into the following three groups; lungs cultured only in the serum-free medium (group I n = 5), lungs cultured in medium containing either IGF-I (group II n = 5), or IGF-II (group III n = 5). All cultures were investigated by immunohistochemistry, using the antibodies of thyroid transcription factor (TTF)-1, prosurfactant protein (proSp)-C, alpha smooth muscle actin (alpha-SMA), and anti-proliferating cell nuclear antigen (PCNA). The mRNA expression level of both IGF-I and IGF-II was higher during the earlier stage than that of later stage. In contrast, the mRNA expression of both IGF-I receptor (IGF-IR) and IGF-II receptor (IGF-IIR) was higher from the E17.5 to E18.5 than that at any other stage. The number of positive cells for TTF-1, proSp-C, alpha-SMA and PCNA increased more in both groups II and III than in group I. Based on our findings, IGFs are suggested to induce alveolar and vascular maturation in the late stages of fetal lung development. Therefore, the administration of IGFs to the fetal CDH lung may thus be able to effectively improve the symptoms of hypoplastic lung.

Pathogens cause damage, and their elimination requires activation of the costly immune response. A highly economic defense strategy should thus be the behavioral avoidance of pathogens, as manifested in humans by all aspects of hygiene or revulsion at pathogen-rich material. Despite its potential importance, behavioral defenses have as yet received only little attention in biomedical research--in stark contrast to the physiological immune system. In the present study, the genetics of such behavioral defenses are elucidated in a simple model organism, the nematode Caenorhabditis elegans. We show for the first time that mutations in the insulin-like receptor (ILR) pathway lead to two distinct behavioral responses against pathogenic strains of the gram-positive bacterium Bacillus thuringiensis (BT), including the physical evasion of pathogens and their reduced oral uptake. Since this pathway also contributes to nematode stress resistance, the results surprisingly reveal a genetic link between physiological and behavioral defenses. Considering that many signaling pathways have conserved their functions across evolution, including the ILR pathway, this signaling cascade may represent an interesting candidate regulator for behavioral defenses in more complex organisms, including humans.

The insulin-like growth factor (IGF) signaling system plays indispensable roles in pre- and post-natal brain growth and development. A large body of studies using both in vivo null mutant and transgenic mice and in vitro neuronal culture techniques indicate that IGF-I acts directly on the brain while IGF-II effects are mediated to a large extent by IGF-II control of placental growth. It appears that all of the mechanisms, except migration, that are involved in normal brain development, e.g., proliferation, apoptosis, maturation and differentiation, are influenced by IGF-I. While IGF system members are produced in the brain, recent reports in post-natal animals indicate that normal brain health and function are dependent upon transfer of circulating IGF-I from the liver and its transfer across the blood brain barrier. Data showing that this phenomenon applies to pre-natal brain growth and development would make an important contribution to fetal physiology. A number of kinase pathways are able to participate in IGF signaling in brain with respect to nutrient restriction; among the most important are the PI3K/AKT, Ras-Raf-MEK-ERK and mTOR-nutrient sensing pathways. Both maternal and fetal IGF-I peripheral plasma concentrations are greatly reduced in nutrient restriction while IGF-II does not appear to be affected. Nutrient restriction also affects IGF binding protein concentrations while effects on the IGF-I receptor appear to vary with the paradigm. Studies on the effects of nutrient restriction on the fetal primate brain in relation to activity of the IGF system are needed to determine the applicability of rodent studies to humans.

The biological activity of IGF-I and -II is controlled by six binding proteins (IGFBPs), preventing the IGFs from interacting with the IGF receptor. Proteolytic cleavage of IGFBPs is one mechanism by which IGF can be released to bind the receptor. The IGFBPs are usually studied individually, although the presence of more than one of the IGFBPs in most tissues suggests a cooperative function. Thus, the IGFBPs are part of regulatory networks with proteolytic enzymes in one end and the IGF receptor in the other end. We have established a model system that allows analysis of the dynamics between IGF, IGFBP-4 and -5, the IGF receptor, and the proteolytic enzyme PAPP-A, which specifically cleaves both IGFBP-4 and -5. We demonstrate different mechanisms of IGF release from IGFBP-4 and -5: cooperative binding to IGF is observed for the proteolytic fragments of IGFBP-5, but not fragments of IGFBP-4. Furthermore, we find that PAPP-A-mediated IGF-dependent cleavage of IGFBP-4 is inhibited by IGFBP-5, which sequesters IGF from IGFBP-4, and that cleavage of both IGFBP-4 and -5 is required for the release of bioactive IGF. Finally, we show that cell surface-localized proteolysis of IGFBP-4 represents the final regulatory step of efficient IGF delivery to the receptor. Our data define a regulatory system in which molar ratios between the IGFBPs and IGF and between the different IGFBPs, sequential proteolytic cleavage of the IGFBPs, and surface association of the activating proteinase are key elements in the regulation of IGF receptor stimulation.

The mitogenic signaling in mammalian cells is carried out mainly by growth factors that interact with receptors localized at the plasma membrane. Most of these receptors have a tyrosine kinase activity domain that is localized at the cytoplasmic region of the molecule. The interaction of the growth factors with the receptors, besides inducing the kinase activity of the receptor, activate signaling pathways the alter gene expression patterns and induce mitogenesis, or if deregulated are related to cancer. Among these receptors ERBB, VEGF, PDGF and IGF are attractive targets for directed therapies. ERBB receptors are frequently involved in the production of many types of cancers. Both, the over-expression of the growth factor and the receptor, besides mutations at the cytoplasmic tyrosine kinase domain contribute to constitutive signaling in human cancer. VEGF has a pivotal role in maintaining the tumor growth by facilitating growth of new blood vessels. Therefore, inhibition of tumor growth targeting of the tumor vasculature, by interfering with the activity of VEGFr is now a real alternative in combinatorial therapies. PDGF is a growth factor involved in growth of connective tissue and wound healing. Activating mutations of PDGFr have been found in gastrointestinal tumors and the autocrine signaling maintained by this receptor have been described in many tumors. Imatinib, and inhibitor of the tyrosine kinase activity of Bcr-Abl targets also the kinase of the PDGFr. Finally IGF-I an II have an important antiapoptotic and pro-mitogenic role in most tumors. Different inhibitors are now under clinical studies for the use in combination of chemotherapeutic drugs in the treatment of different tumors.

The insulin-like growth factor receptor (IGF-IR) is critical in epidermal development and IGF binding protein-3 (IGFBP-3), a modulator of cellular activity with or without IGF-dependence, co-localises with epidermal IGF-IRs. We have investigated whether the greater UV susceptibility of a human keratinocyte cell line (HaCaT) in comparison to normal human keratinocytes (NHKs) may involve differences in the IGF system. At 24 h after UV (960 mJ/cm(2) UVB), in comparison to NHKs, HaCaT keratinocytes exhibited significantly higher levels of apoptosis, refractoriness to IGF-I treatment and reduced IGF-IR phosphorylation. Secreted, intact IGFBP-3 (38-42 kDa) and IGFBP-3 mRNA abundance were reduced in HaCaT keratinocytes, but not consistently altered in NHKs. Immunoreactive IGFBP-3 fragments (16-11 kDa) were detected in both UV-exposed cultures. These data suggest that an altered IGF system contributes to HaCaT keratinocyte UV susceptibility and that following UV insult the IGF system may enhance keratinocyte viability and contribute to a return to epidermal homeostasis.

The insulin-like growth factor (IGF) system plays a central role in the neuroendocrine regulation of growth in all vertebrates. Evidence from studies in a variety of vertebrate species suggest that this growth factor complex, composed of ligands, receptors, and high-affinity binding proteins, evolved early during vertebrate evolution. Among nonmammalian vertebrates, IGF signaling has been studied most extensively in fish, particularly teleosts of commercial importance. The unique life history characteristics associated with their primarily aquatic existence has fortuitously led to the identification of novel functions of the IGF system that are not evident from studies in mammals and other tetrapod vertebrates. Furthermore, the emergence of the zebrafish as a preferred model for development genetics has spawned progress in determining the requirements for IGF signaling during vertebrate embryonic development. This review is intended as a summary of our understanding of IGF signaling, as revealed through research into the expression, function, and evolution of IGF ligands, receptors, and binding proteins in fish.

This review aims to summarize experimental evidence supporting the role of the insulin-like growth factor (IGF) signalling system in the progression, maintenance, and treatment of cancer. These data implicate the IGF system as an important modifier of cancer cell proliferation, survival, growth, and treatment sensitivity. The role of the IGF system in cancer should be examined in the context of the extra-cellular and intra-cellular signalling networks, in particular: phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt/PKB), mammalian target of rapamycin (mTOR), and forkhead transcription factors (FOXO). This review highlights evidence derived from molecular structure and functional genetics with respect to how the extra-cellular components of the IGF system function normally, and their subsequent modifications in cancer. The therapeutic relevance of the research evidence described is also addressed, as the challenge is to apply this knowledge to human health.

The insulin-like growth factors (IGF) are a family of growth factors, receptors and binding proteins that are involved in numerous growth and differentiation processes, as well as in various pathological conditions. The aim of this review is to summarize data that has been accumulating in recent years linking the IGF system to a number of physiological and pathological oral processes. The IGF system fulfills an important role in growth and development of teeth, mandible, maxillae, and tongue. It has been postulated that IGF-I may be of great value in the treatment of periodontal defects and in tissue healing. Furthermore, IGF-II has been shown to be overexpressed in salivary gland adenomas, suggesting that aberrant IGF signaling may be a key factor in the etiology of oral malignancies. Understanding the role and regulation of IGF system components in salivary glands and other oral structures will be of significant basic and clinical relevance.

Objective: We have shown previously that oxidized LDL decreases insulin-like growth factor-1 (IGF-1) and IGF-1 receptor expression in vascular smooth muscle cells and that IGF-1 and IGF-1 receptor expression are reduced in the deep intima of early atherosclerotic lesions. Because oxidized LDL is potentially important for the depletion of vascular smooth muscle cells contributing to plaque destabilization, we studied the role of IGF-1 in oxidized LDL-induced apoptosis., Methods and Results: We provide evidence that oxidized LDL-induced apoptosis is caused by decreased mitochondrial membrane potential and increased cytochrome C release in human aortic vascular smooth muscle cells. Overexpression of the IGF-1 receptor by using an adenovirus completely abrogated these effects. The antiapoptotic function of the IGF-1 receptor was associated with increased Akt kinase activity and increased expression of phosphorylated Bad. Moreover, a dominant-negative p85 phosphatidylinositol 3-kinase adenovirus blocked the capacity of the IGF-1 receptor to prevent oxidized LDL-induced apoptosis., Conclusions: Our data demonstrate that IGF-1 receptor activation inhibits oxidized LDL-induced cytochrome C release and apoptosis through the phosphatidylinositol 3-kinase/Akt signaling pathway and suggest that genetic or pharmacological activation of the IGF-1 receptor may be a useful strategy to stabilize atherosclerotic plaques.

Glutamate receptors play a key role in neuronal plasticity, learning and memory, and in several neuropathologies. Short-term and long-term changes in synaptic efficacy are triggered by glutamate. Although an enhanced glutamate-dependent tyrosine phosphorylation has been described in several systems, its role in membrane-to-nuclei signaling is unclear. Taking advantage of the fact that the gene encoding the chick kainate-binding protein undergoes a glutamate-dependent transcriptional regulation via an activator protein-1 (AP-1) site, we evaluated the involvement of tyrosine kinases in this process. We describe here the participation of receptor and non-receptor tyrosine kinases in the signaling cascade triggered by glutamate. Our results suggest that in Bergmann glia cells, glutamate receptors transactivate receptor tyrosine kinases, favoring the idea of a complex network of signals activated by this excitatory neurotransmitter that results in regulation of gene expression., (Copyright 2003 Wiley-Liss, Inc.)

The receptor for the insulin-like growth factor-1 (IGF-1R) controls a wide variety of cellular functions. IGF-1R is a tyrosine kinase receptor that is activated by the binding of a ligand to the extracellular domain. There are three ligands for IGF-1R: IGF-I, IGF-II and insulin at supraphysiological concentrations. The binding of the ligand activates the catalytic activity of the tyrosine kinase domain, which in turn causes the autophosphorylation of IGF-1R. As a consequence of autophosphorylation, the activated IGF-1R sends a potent mitogenic signal to the cell nucleus. It has been clearly shown that an overexpressed and activated IGF-1R is quasi-obligatory for the establishment of a malignant cell phenotype. Interestingly, the targeting of IGF-1R can reverse the malignant phenotype in cancer cells, without affecting the biology of normal cells. For these reasons, IGF-1R seems to be a very promising candidate target for cancer therapy. In addition, IGF-1R protects cells from apoptosis and promotes cell growth and proliferation. However, more recent studies have also shown that IGF-1R regulates cell adhesion and motility, and, in certain cellular contexts, can induce differentiation. Indeed, the biology of the IGF-1R appears more complex than previously thought. The goal of this review is to describe the multiple functions displayed by IGF-1R in cell biology.

In addition to their roles in IGF transport, the six IGF-binding proteins (IGFBPs) regulate cell activity in various ways. By sequestering IGFs away from the type I IGF receptor, they may inhibit mitogenesis, differentiation, survival, and other IGF-stimulated events. IGFBP proteolysis can reverse this inhibition or generate IGFBP fragments with novel bioactivity. Alternatively, IGFBP interaction with cell or matrix components may concentrate IGFs near their receptor, enhancing IGF activity. IGF receptor-independent IGFBP actions are also increasingly recognized. IGFBP-1 interacts with alpha(5)beta(1) integrin, influencing cell adhesion and migration. IGFBP-2, -3, -5, and -6 have heparin-binding domains and can bind glycosaminoglycans. IGFBP-3 and -5 have carboxyl-terminal basic motifs incorporating heparin-binding and additional basic residues that interact with the cell surface and matrix, the nuclear transporter importin-beta, and other proteins. Serine/threonine kinase receptors are proposed for IGFBP-3 and -5, but their signaling functions are poorly understood. Other cell surface IGFBP-interacting proteins are uncharacterized as functional receptors. However, IGFBP-3 binds and modulates the retinoid X receptor-alpha, interacts with TGFbeta signaling through Smad proteins, and influences other signaling pathways. These interactions can modulate cell cycle and apoptosis. Because IGFBPs regulate cell functions by diverse mechanisms, manipulation of IGFBP-regulated pathways is speculated to offer therapeutic opportunities in cancer and other diseases.

Understanding the control of size is of fundamental biological and clinical importance. Insulin/IGF signaling during development controls growth and size, possibly by coordinating the activities of the Ras and PI 3-kinase signaling pathways. We show that in Drosophila mutating the consensus binding site for the Ras pathway adaptor Drk/Grb2 in Chico/IRS does not interfere with growth whereas mutating the binding sites of the PI 3-kinase adaptor p60 completely abrogates Chico function. Furthermore, we present biochemical and genetic evidence that loss of the homolog of the tumor suppressor gene, Pten, results in increased PtdInsP(3) levels and that these increased levels are sufficient to compensate for the complete loss of the Insulin/insulin-like growth factor receptor function. This reduction of Pten activity is also sufficient to vastly increase organism size. These results suggest that PtdInsP(3) is a second messenger for growth and that levels of PtdInsP(3) during development regulate organismal size.

Recognition of molecular pathways relevant to cancer biology have led to advances in prevention and treatment. Numerous laboratory and clinical investigations have implicated the insulin-like growth factors (IGFs) in tumourigenesis. In this review, the evidence for the involvement of IGFs in cancer is discussed. While these data are persuasive, it is clear that additional methods to regulate IGF action in cancer patients are needed to substantiate the role of this growth factor family in cancer biology., (Copyright 2001 Elsevier Science Ltd.)

The insulin-like growth factor (IGF) system, comprising insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), and their binding proteins (IGFBPs), is linked to cell growth, the development of cardiovascular disease, and several cancers. Little is known about its epidemiology. The authors studied relations of the IGF system to anthropometric and metabolic variables in three population-based ethnic groups in Manchester, England, in 1994-1998 with differing disease risks: African Caribbean (n = 193), Pakistani (n = 130), and local Europeans(n = 142). Standardized anthropometry, glucose tolerance tests, and serum assays were performed. Body mass indices (BMIs) were high in all groups. IGF-I levels were highest in normoglycemic African Caribbeans and declined with age (r = -0.28). IGF-II levels were greatest in Europeans. IGFBP-1 concentrations increased with age in Pakistanis (r = 0.20) and Europeans (r = 0.29), but not in African Caribbeans (r = 0.06), and were inversely related to BMI (r = -0.37). Age- and sex-adjusted IGFBP-1 was inversely related to fasting insulin and proinsulin in all groups; participants with newly detected diabetes were relatively insulinopenic but had higher IGFBP-1 concentrations. Nonesterified (free) fatty acid (NEFA) concentrations increased with declining glucose tolerance. In multiple regression analysis, IGFBP-1 was independently and negatively related to fasting insulin, BMI, and African-Caribbean compared with European ethnicity but positively related to age, fasting glucose, and NEFA. IGF-I was inversely related only to age, NEFA, and Pakistani ethnicity. IGF-II showed a strong ethnic difference but was unrelated to other variables. These data indicate considerable potential for exploring disease-IGF system relations in population samples.

Purpose: Preclinical animal experiments support the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor (IGF-IR/AS ODN) as an effective potential antitumor agent. We performed a human pilot safety and feasibility study using an IGF-IR/AS ODN strategy in patients with malignant astrocytoma., Patients and Methods: Autologous glioma cells collected at surgery were treated ex vivo with an IGF-IR/AS ODN, encapsulated in diffusion chambers, reimplanted in the rectus sheath within 24 hours of craniotomy, and retrieved after a 24-hour in situ incubation. Serial posttreatment assessments included clinical examination, laboratory studies, and magnetic resonance imaging scans., Results: Other than deep venous thrombosis noted in some patients, no other treatment-related side effects were observed. IGF-IR/AS ODN-treated cells, when retrieved and assessed, were < or = 2% intact by trypan blue exclusion, and none of the intact cells were viable in culture thereafter. Parallel Western blots disclosed IGF-IR downregulation to < or = 10% after ex vivo antisense treatment. At follow-up, clinical and radiographic improvements were observed in eight of 12 patients, including three cases of distal recurrence with unexpected spontaneous or postsurgical regression at either the primary or the distant intracranial site., Conclusion: Ex vivo IGF-IR/AS ODN treatment of autologous glioma cells induces apoptosis and a host response in vivo without unusual side effects. Subsequent transient and sustained radiographic and clinical improvements warrant further clinical investigations.

Observations in targeted mouse mutants and patients with genetic abnormalities grant insight into the various and distinct roles of insulin-like growth factor receptors (IGF-Rs) and insulin receptors (IRs) during early development. While IGF-1Rs (mediating both IGF-1 and IGF-2 actions) are important for embryonic and fetal growth, IRs (mediating IGF-2 rather than insulin action) play a minor role. However, it is an oversimplification to conclude that IGF-1Rs mediate growth and IRs mediate metabolic responses. Mice lacking both IRs and IGF-1Rs are more severely growth retarded than mice lacking either receptor alone. The phenotype of combined deficiency of IRs and IGF-1Rs is similar to the phenotype caused by the absence of IGF-1 and IGF-2. This provides genetic proof that these two receptors account for the entirety of the growth promoting effects of IGF-1 and IGF-2. There is little evidence that hybrid insulin/IGF-1 receptors promote embryonic growth to a significant degree. The clinical presentation regarding severity of growth retardation and metabolic disturbances observed in animal models versus in humans may differ greatly and the reasons will be reviewed in detail.