The Role of GH/IGF Axis in Dento-Alveolar Complex from Development to Aging and Therapeutics: A Narrative Review.

The GH/IGF axis is a major regulator of bone formation and resorption and is essential to the achievement of normal skeleton growth and homeostasis. Beyond its key role in bone physiology, the GH/IGF axis has also major pleiotropic endocrine and autocrine/paracrine effects on mineralized tissues throughout life. This article aims to review the literature on GH, IGFs, IGF binding proteins, and their respective receptors in dental tissues, both epithelium (enamel) and mesenchyme (dentin, pulp, and tooth-supporting periodontium). The present review re-examines and refines the expression of the elements of the GH/IGF axis in oral tissues and their in vivo and in vitro mechanisms of action in different mineralizing cell types of the dento-alveolar complex including ameloblasts, odontoblasts, pulp cells, cementoblasts, periodontal ligament cells, and jaw osteoblasts focusing on cell-specific activities. Together, these data emphasize the determinant role of the GH/IGF axis in physiological and pathological development, morphometry, and aging of the teeth, the periodontium, and oral bones in humans, rodents, and other vertebrates. These advancements in oral biology have elicited an enormous interest among investigators to translate the fundamental discoveries on the GH/IGF axis into innovative strategies for targeted oral tissue therapies with local treatments, associated or not with materials, for orthodontics and the repair and regeneration of the dento-alveolar complex and oral bones.

Insulin-Like Growth Factor 2 As a Possible Neuroprotective Agent and Memory Enhancer-Its Comparative Expression, Processing and Signaling in Mammalian CNS.

A number of studies performed on rodents suggest that insulin-like growth factor 2 (IGF-2) or its analogs may possibly be used for treating some conditions like Alzheimer's disease, Huntington's disease, autistic spectrum disorders or aging-related cognitive impairment. Still, for translational research a comparative knowledge about the function of IGF-2 and related molecules in model organisms (rats and mice) and humans is necessary. There is a number of important differences in IGF-2 signaling between species. In the present review we emphasize species-specific patterns of IGF-2 expression in rodents, humans and some other mammals, using, among other sources, publicly available transcriptomic data. We provide a detailed description of Igf2 mRNA expression regulation and pre-pro-IGF-2 protein processing in different species. We also summarize the function of IGF-binding proteins. We describe three different receptors able to bind IGF-2 and discuss the role of IGF-2 signaling in learning and memory, as well as in neuroprotection. We hope that comprehensive understanding of similarities and differences in IGF-2 signaling between model organisms and humans will be useful for development of more effective medicines targeting IGF-2 receptors.

An urological cause of hypoglycaemia: A case report of the Doege-Potter syndrome.

The Doege-Potter syndrome is a rare paraneoplastic syndrome presenting with hypoglycaemia due to ectopic secretion of insulin-like growth factor II (IGF-II) from a solitary fibrous tumor. The underlying tumor can be benign or malignant and rarely present in extrapleural sites. We describe the case of a 83-year-old male diagnosed with a Doege-Potter syndrome due to a kidney tumor.

Gene expression of the IGF hormones and IGF binding proteins across time and tissues in a model reptile.

The insulin and insulin-like signaling (IIS) network regulates cellular processes including pre- and postnatal growth, cellular development, wound healing, reproduction, and longevity. Despite their importance in the physiology of vertebrates, the study of the specific functions of the top regulators of the IIS network, insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs), has been mostly limited to a few model organisms. To expand our understanding of this network, we performed quantitative gene expression of IGF hormones in liver and qualitative expression of IGFBPs across tissues and developmental stages in a model reptile, the brown anole lizard (Anolis sagrei). We found that lizards express IGF2 across all life stages (preoviposition embryos to adulthood) and at a higher level than IGF1, which is opposite to patterns seen in laboratory rodents but similar to those seen in humans and other vertebrate models. IGFBP expression was ubiquitous across tissues (brain, gonad, heart, liver, skeletal muscle, tail, and regenerating tail) in adults, apart from IGFBP5, which was variable. These findings provide an essential foundation for further developing the anole lizard as a physiological and biomedical reptile model, as well as expanding our understanding of the function of the IIS network across species.

The developmental and experience-dependent expression of IGF-2 in mice visual cortex.

The circuitry associated with the visual cortex is particularly sensitive to experiences during the early stages of life, which are collectively known as critical periods. Critical period of ocular dominance plasticity is regulated by both environmental and genetic factors. Previous studies demonstrated that IGF-1 significantly influenced the regulation of visual cortex synaptic plasticity. IGF-2 can reportedly regulate synapse formation, dendritic spine maturation, and memory consolidation in rodents. Association between IGF-2 and the regulation of visual cortex synaptic plasticity remains unclear. Here, we first aimed to elucidate the normal expression patterns of IGF-2 and its laminar expression pattern during the process of visual cortex development in mice. This confirmed that IGF-2 may influence the regulation of ocular dominance plasticity in mice. We further elucidated the role of IGF-2 in the regulation of visual cortex synaptic plasticity by examining the effect of monocular deprivation (MD) on IGF-2 expression in the visual cortex. Interestingly, we observed that MD remarkably reduced IGF-2 expression in the visual cortex. Rodents reared in an enriched environment, with enhanced sensory, motor, and social experiences, were capable of effectively accelerating the development of the visual system and could restore normal visual acuity. Although the enriched environment facilitated the restoration of normal visual acuity in the MD mice, IGF-2 expression levels in the visual cortex remained unchanged. Therefore, we considered the possibility that IGF-2 may have a different role with regard to the modulation of plasticity in the visual cortex of the mice, which we aim to study in the future.

The effect of thyroid dysfunction and treatment on adropin, asprosin and preptin levels in rats.

OBJECTIVES: Thyroid hormones have important roles in normal development and energy regulating mechanisms as well as signaling mechanisms that affect energy consumption through central and peripheral pathways. The aim of this study was to determine the effects of thyroid dysfunction on adropin, asprosin and preptin levels in rat. METHODS: The study was performed on the 38 male Wistar-albino rats. Experiment groups were designed as follows. 1-Control, 2-Hypothyroidism; To induce hypothyroidism PTU was applied by intraperitoneal as 10 mg/kg/day for 2 weeks. 3-Hypothyroidism + Thyroxine; Previously animals were made with hypothyroidism by 1 week PTU application and then 1 week l-thyroxine was given by intraperitoneal as 1.5 mg/kg/day. 4-Hyperthyroidism; Rats were made with hyperthyroidism by 3 weeks l-thyroxine (0.3 mg/kg/day). 5-Hyperthyroidism + PTU; Animals were made hyperthyroisim by l-thyroxine as groups 4, then 1 week PTU was applied to treatment of hiperthyrodism. At the end of supplementation animals were sacrificed and blood samples were collected for FT3, FT4, adropin, asprosin, preptin analysis. RESULTS: FT3 ve FT4 levels were reduced significantly in hypothyroidism while increased in hyperthyroidism (p<0.001). Hipothyrodism led to reduces adropin, asprosin and preptin levels. And also hyperthyroidism reduced adropin and preptin levels (p<0.001). CONCLUSIONS: The results of study show that experimental hypothyroidism and hyperthyroidism lead to significantly change to adropin, asprosin and preptin levels. However, correction of thyroid function caused to normals levels in asprosin and preptin.

Childhood adrenocortical tumor: A clinical and immunohistochemical study of 13 cases.

The aim of the study was to investigate the molecular mechanisms in childhood adrenocortical tumors (ACTs), which is still unclear.A total of 9 girls and 4 boys with ACTs were enrolled. Relevant clinical features were obtained from records. Immunohistochemistry of vimentin, chromogranin A, S100, synaptophysin, cytokeratin (CK), type 2 3ß-hydroxysteroid dehydrogenase (3ßHSD), cytochrome P45017α, p53, p21, p27, cyclin D1, Ki-67, insulin growth facter-2 (IGF-2), and ß-catenin were undertaken for 13 tumors and 3 adjacent normal tissues. TP53 mutations in exon 2-11 were analyzed for 6 tumors and 3 blood samples.Virilization was the most common presentation (8/13, 61.5%). Immunohistochemically, p53 was positive in 8 of 13 ACTs and none in controls while p21 was positive in 12 of 13 ACTs and none in controls (P = .0036). Ki-67 was positive in 10 of 13 ACTs, but not in normal tissues (P = .0089). Although the expression of p27, cyclin D1, IGF-2 and ß-catenin were similar between the ACTs and controls, ß-catenin was noted in nuclear of 3 ACTs but not in controls. The difference of type 2 3ßHSD and P450c17α was not significant (P > .05, respectively). Four variants of TP53 were identified in the 6 tumors. C215G variant was found in 5 of 6 while A701G and G743A variants were found in 1 case, respectively. A novel C680G variant was also noted in 1 case. It was notable that C215G variant was found in the blood mononuclear cell of 3 patients.In conclusion, p53 variant and p21 overexpression, and abnormal ß-catenin distribution may be involved in the etiology and mechanism of childhood ACTs.

The extent of DNA methylation anticipation due to a genetic defect in ICR1 in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder. Gain of methylation at imprinting control region 1 (ICR1-GOM), leading to the biallelic expression of IGF2 and silencing of H19, is one of the causative alterations in BWS. Twenty percent of BWS patients with ICR1-GOM have genetic defects in ICR1. Evidence of methylation anticipation in familial BWS patients with ICR1 genetic defects has been reported. However, the precise methylation pattern and extent of anticipation in these patients remain elusive. In addition, although age-related IGF2-DMR0 hypomethylation has been reported in the normal population, the period of its occurrence is unknown. In this study, we analyzed 10 sites (IGF2-DMR0, IGF2-DMR2, CTCF binding sites 1-7, and the H19 promoter) within the IGF2/H19 domain in familial BWS patients harboring a pathogenic variant in ICR1. We found that sites near the variant had relatively higher methylation in the first affected generation and observed methylation anticipation through maternal transmission in the next generation. The extent of anticipation was greater at sites far from the variant than nearby sites. The extended and severe GOM might be due to the insufficient erasure/demethylation of pre-acquired ICR1-GOM in primordial germ cells or during the preimplantation stage. In the normal population, age-related IGF2-DMR0 hypomethylation occurred; it became established by young adulthood and continued to old age. Further studies are needed to clarify (1) the precise mechanism of anticipation in patients with familial BWS and (2) the mechanism and biological significance of constitutive hypomethylation of IGF2-DMR0 and/or other imprinted differentially methylated regions.

IGF2 is Deregulated During the Development of Uterine Cervical Carcinoma in Indian Patients.

Uterine cervical carcinoma (CACX) is one of the leading causes of deaths in Indian women. Chromosomal alterations including 11p15.5 locus were reported in CACX. Consequently, we strived for the first time to understand the molecular status of the candidate gene Insulin-like growth factor 2, IGF2 (11p15.5) in Indian CACX patients (n = 128). DNA copy number (CN) analysis using CGH-SNP analysis showed no genetic alteration and it was further validated by comparison with publicly available CN datasets. But promoter hypo-methylation during the progression of CACX was observed and also found to be concordant with publicly available DNA methylation datasets. Interestingly, we found diverse expression of IGF2 transcript in both normal cervical epithelium (NCE) and CACX tumors. Similar heterogeneous expression pattern was seen in publicly available expression datasets as well. Finally, protein expression analysis in NCE showed concordance with transcript expression but tumors showed frequent low expression. Log-rank test showed a difference (p-value = 0.057) in overall survival between cases with and without alteration for IGF2 in Indian CACX patients. Collectively, our study proposes that regulation of IGF2 expression in NCE appeared to be multifaceted and deregulation during the development of CACX resulted in the differential expression.

Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1.

Many childhood Wilms tumors are driven by mutations in the microRNA biogenesis machinery, but the mechanism by which these mutations drive tumorigenesis is unknown. Here we show that the transcription factor pleomorphic adenoma gene 1 (PLAG1) is a microRNA target gene that is overexpressed in Wilms tumors with mutations in microRNA processing genes. Wilms tumors can also overexpress PLAG1 through copy number alterations, and PLAG1 expression correlates with prognosis in Wilms tumors. PLAG1 overexpression accelerates growth of Wilms tumor cells in vitro and induces neoplastic growth in the developing mouse kidney in vivo. In both settings, PLAG1 transactivates insulin-like growth factor 2 (IGF2), a key Wilms tumor oncogene, and drives mammalian target of rapamycin complex 1 (mTORC1) signaling. These data link microRNA impairment to the PLAG1-IGF2 pathway, providing new insight into the manner in which common Wilms tumor mutations drive disease pathogenesis.

Vitrification Has an Effect like Culture on Gene Expression and Histone Modification In Mouse Embryos.

BACKGROUND: OBJECTIVE: This paper reports results from studies on modifications of histone marks in transcriptional regulatory regions of H19, Igf2 and Mest genes in vitrified-warmed and cultured mouse embryos. MATERIALS AND METHODS: Non vitrified and vitrified-warmed 8-cell embryos were cultured in Ham's F10+10% BSA into blastocyst stage in two experimental groups. Gene expression level was assessed by quantitative PCR and histone modifications were evaluated by ChIP assay method. RESULTS: The expression levels of the selected genes in vitrified embryos were found to be markedly reduced compared to the control group. Significant increase in H3K9me2 as a gene silencer was seen in the regulatory regions of all genes in vitrified group. Furthermore, H3K4me3 and H3K9ac decreased in some regulatory regions but not in all of them. Additionally, H3K9me2 in regulatory regions of Igf2 and H19 significantly increased in group I, whereas, there was no change in Mest compared to the control group. CONCLUSIONS: Vitrification and culture condition affects gene down regulation of Igf2 and H19. Although changes in each histone mark are not always the same as gene expression, the total pattern and sum of their changes are in line with gene down regulation upon vitrification and culture.

Rapamycin-independent IGF2 expression in Tsc2-null mouse embryo fibroblasts and human lymphangioleiomyomatosis cells.

Lymphangioleiomyomatosis (LAM) is a rare, almost exclusively female lung disease linked to inactivating mutations in tuberous sclerosis complex 2 (TSC2), a tumor suppressor gene that controls cell metabolic state and growth via regulation of the mechanistic target of rapamycin (mTORC1) signaling. mTORC1 is frequently activated in human cancers and, although the mTORC1 inhibitor rapamycin has a cytostatic effect, it is, in general, unable to elicit a robust curative effect or tumor regression. Using RNA-Seq, we identified (1) Insulin-like Growth Factor (IGF2) as one of the genes with the highest fold-change difference between human TSC2-null and TSC2-expressing angiomyolipoma cells from a patient with LAM, and (2) the mouse IGF2 homolog Igf2, as a top-ranking gene according to fold change between Tsc2-/- and Tsc2+/+ mouse embryo fibroblasts (MEFs). We extended transcript-level findings to protein level, observing increased Igf2 protein expression and Igf2 secretion by Tsc2-/- MEFs. Increased Igf2 expression was not due to epigenetic imprinting, but was partially mediated through the Stat3 pathway and was completely insensitive to rapamycin treatment. An siRNA-mediated decrease of Igf2 resulted in decreased Stat3 phosphorylation, suggesting presence of an autocrine Igf2/Stat3 amplification cycle in Tsc2-/- MEFs. In human pulmonary LAM lesions and metastatic cell clusters, high levels of IGF2 were associated with mTORC1 activation. In addition, treatment of three primary IGF2-expressing LAM lung cell lines with rapamycin did not result in IGF2 level changes. Thus, targeting of IGF2 signaling may be of therapeutic value to LAM patients, particularly those who are unresponsive to rapamycin.

Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat.

The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also glutamatergic transmission, including receptors such as the N-methyl-d-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.

Vitrification, not cryoprotectant exposure, alters the expression of developmentally important genes in in vitro produced porcine blastocysts.

The vitrification of embryos is common practice in advanced livestock breeding programs and in human fertility clinics. Recent studies have revealed that vitrification results in aberrant expression of a number of stress related genes. However, few studies have examined the effect that vitrification has on developmentally important genes, and none have been conducted in porcine embryos. The aim of this study was to determine the effects that different vitrification procedures and cryoprotectant combinations have on the expression of imprinted genes in in vitro produced (IVP) porcine blastocysts. The transcript levels of insulin-like growth factor 2 (IGF2) were lower in all groups of vitrified blastocysts compared to that in non-vitrified control blastocysts (P < 0.05). Expression levels of IGF2 and IGF2 receptor (IGF2R) in blastocysts that had been exposed to cryoprotectants without being vitrified were similar to that in non-vitrified control blastocysts (P > 0.05). Furthermore, blastocysts vitrified using ethylene glycol and propanediol combined, and those vitrified in a closed device, had IGF2R transcript levels similar to that in non-vitrified control blastocysts (P > 0.05). In conclusion, vitrification, but not exposure to cryoprotectants, caused aberrant expression of the imprinted genes IGF2 and IGF2R. Vitrification protocols that incorporated propanediol or a closed device were found to be least disruptive of gene expression in IVP porcine blastocysts.

Gestational 3,3',4,4',5-pentachlorobiphenyl (PCB 126) exposure disrupts fetoplacental unit: Fetal thyroid-cytokines dysfunction.

Exposure to polychlorinated biphenyls (PCBs) is related to several endocrine disorders. This study examined the effect of maternal exposure of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) on the fetoplacental unit and fetal thyroid-cytokine axis during the pregnancy. Pregnant albino rats received PCB 126 (20 or 40µg/kgb.wt.) by oral gavage from gestation day (GD) 1 to 20. Potential effects of PCB 126 were evaluated by following the histopathological changes in the placenta by Haematoxylin and Eosin (H&E) stain and measuring the maternofetal thyroid axis (ELIZA), maternofetal body weight, and fetal growth markers (ELIZA), and cytokines (ELIZA) at embryonic day (ED) 20. Placental tissues of both treated groups showed hyperemia, hemorrhage, degeneration and apoptosis in labyrinth layer and spiral artery at GD 20. Both administrations of PCB 126 elevated serum thyrotropin (TSH) concentration, and decreased free thyroxine (FT4) and free triiodothyronine (FT3) concentrations, resulting in a maternofetal hypothyroidism. The presence of hypothyroidism increased fetal serum concentration of transforming growth factor-ß (TGF-ß), leptin (LEP), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and decreased the fetal serum insulin growth factor-I (IGF-I), IGF-II, insulin, adiponectin (ADP), and growth hormone (GH) in both treated groups at ED 20. However, the increase in resistin (RETN) and interferon-γ (IFN-γ) was non-significant in low-dose group and highly significant in high-dose group. Simultaneously, the reduction in body weight of the dams and fetuses was observed in both PCB 126 groups of examined day with respect to the control group. The maternal PCB 126 distorted the fetoplacental unit might disrupt the fetal thyroid-cytokines axis and prenatal development.

Increased motor neuron resilience by small molecule compounds that regulate IGF-II expression.

The selective vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS) is evident by sparing of a few subpopulations during this fast progressing and debilitating degenerative disease. By studying the gene expression profile of resilient vs. vulnerable motor neuron populations we can gain insight in what biomolecules and pathways may contribute to the resilience and vulnerability. Several genes have been found to be differentially expressed in the vulnerable motor neurons of the cervical spinal cord as compared to the spared motor neurons in CNIII/IV. One gene that is differentially expressed and present at higher levels in less vulnerable motor neurons is insulin-like growth factor II (IGF-II). The motor neuron protective effect of IGF-II has been demonstrated both in vitro and in SOD1 transgenic mice. Here, we have screened a library of small molecule compounds and identified inducers of IGF-II mRNA and protein expression. Several identified compounds significantly protected motor neurons from glutamate excitotoxicity in vitro. One of the compounds, vardenafil, resulted in a complete motor neuron protection, an effect that was reversed by blocking receptors of IGF-II. When administered to naïve rats vardenafil was present in the cerebrospinal fluid and increased IGF-II mRNA expression in the spinal cord. When administered to SOD1 transgenic mice, there was a significant delay in motor symptom onset and prolonged survival. Vardenafil also increased IGF-II mRNA and protein levels in motor neurons derived from healthy subject and ALS patient iPSCs, activated a human IGF-II promoter and improved survival of ALS-patient derived motor neurons in culture. Our findings suggest that modulation of genes differentially expressed in vulnerable and resilient motor neurons may be a useful therapeutic approach for motor neuron disease.

A Hypoglycemia-inducing Giant Borderline Phyllodes Tumor Secreting High-molecular-weight Insulin-Like Growth Factor II: Immunohistochemistry and a Western Blot Analysis.

A 50-year-old woman with a large right breast mass was emergently hospitalized for generalized weakness and fatigue. A histological examination of tumor biopsy specimens revealed a phyllodes tumor (PT). She suddenly lost consciousness due to severe hypoglycemia. Non-islet cell tumor hypoglycemia (NICTH) due to the PT was suspected. The tumor was emergently resected. A histological examination revealed a borderline PT. The patient recovered from the hypoglycemic episode. High-molecular-weight insulin-like growth factor II was detected in serum that had been collected preoperatively and in the tumor tissue, but not in serum that had been collected postoperatively. We herein present a case of a borderline PT with NICTH.

Gene expression levels of the insulin-like growth factor family in patients with AMD before and after ranibizumab intravitreal injections.

PURPOSE: The present study focused on the assessment of the mRNA levels of the insulin-like growth factor (IGF) family in patients with the exudative form of age-related macular degeneration (AMD) before and after ranibizumab intravitreal injections. PATIENTS AND METHODS: An analysis of the expression profile of the IGF family of genes in patients with AMD was carried out using the oligonucleotide microarray and quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) methods. RESULTS: In the peripheral blood mononuclear cells (PBMCs) obtained from AMD group receiving ranibizumab compared to the peripheral blood mononuclear cells from AMD group before ranibizumab treatment using oligonucleotide microarray technique, six statistically significant differentially expressed transcripts related to the IGF family were detected (unpaired t-test, p<0.05, fold change >1.5). Moreover, analysis using the real-time RT-qPCR technique revealed statistically significant differences in the IGF2 and IGF2R mRNA levels (Mann-Whitney U test, p<0.05) between the two groups that were studied. Statistical analyses of both oligonucleotide microarray and real-time RT-qPCR results demonstrated a significant decreased expression only for IGF2 mRNA. CONCLUSION: Our results revealed a changed expression of IGF2 mRNA after ranibizumab treatment.

Production of insulin-like growth factor-II in hepatocellular carcinoma with recurrent hypoglycemia: a case report.

A 35-year-old woman, who was an HBV carrier, complained of fever for 2 weeks, and thus, she was admitted in our hospital. Both serum AFP and PIVKA-II levels were abnormally high, and an abdominal enhanced CT revealed the presence of multiple masses in both lobes of the liver. She was diagnosed with hepatocellular carcinoma (T4, N0, M0, and Vp4) and was treated with transcatheter arterial infusion chemotherapy. On the 4th day of her illness, her serum glucose level was 26mg/dl. Glucose infusion and intravenous hyperalimentation were not effective, and she experienced repeated hypoglycemic attacks. Based on the low levels of both insulin (0.4µU/ml) and insulin-like growth factor (IGF)-I (14ng/ml), we made a diagnosis of non-islet cell tumor hypoglycemia associated with hepatocellular carcinoma. The patient was orally administered prednisolone at a dose of 20mg/day. On the 49th day of illness, the hepatocellular carcinoma ruptured, and 2 days later, she died because of hemorrhage shock. Postmortem immunohistochemical staining for IGF-II was positive in the tumor cells of the liver. Furthermore, Western immunoblotting revealed the presence of high-molecular-weight form of IGF-II in the serum of the patient.

Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies.

Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2-overexpressing CRC patients.