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1.  Serum Levels of Free Insulin-Like Growth Factor (IGF)-I in Normal Children 
Serum levels of free insulin-like growth factor (IGF)-I were measured by immunoradiometric assay (IRMA) in fasting sera of 137 normal boys and 120 normal girls aged from 8 to 15 yr to study relationships between free IGF-I levels and ages, total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit (ALS) levels. In both sexes, serum free IGF-I levels and the ratios of free IGF-I to total IGF-I were significantly higher in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-I showed a significant positive correlation with those of total IGF-I, IGFBP-3 and ALS, while they showed a significant negative correlation with those of IGFBP-1. These observations suggest that increase in serum free IGF-I levels during puberty is caused by a dramatic increase in total IGF-I, rather than IGFBP-3, and a decrease in IGFBP-1. Also, high free IGF-I levels may play an important role in pubertal growth spurt.
doi:10.1297/cpe.13.71
PMCID: PMC4004917  PMID: 24790301
free insulin-like growth factor (IGF)-I; total IGF-I; IGF binding protein (IGFBP)-1; IGFBP-3; acid-labile subunit (ALS)
2.  Effects of quercetin on insulin-like growth factors (IGFs) and their binding protein-3 (IGFBP-3) secretion and induction of apoptosis in human prostate cancer cells 
Background
Quercetin, the predominant flavonoid, has been reported to lower the risk of several cancers. This flavonoid found in onion, grapes, green vegetables, etc. has been shown to possess potent antiproliferative effects against various malignant cells. This study was designed to investigate its effects on insulin-like growth factors (IGFs) and their binding protein-3 (IGFBP-3) proteins secretion and also apoptosis induction in the human prostate cancer cell line, PC-3.
Methods
We evaluated the secretion of IGF-I, -II and IGFBP-3 in quercetin treated cells by immunoradiometric (IRMA) method. Apoptosis was studied in quercetin treated cells by TUNEL and DNA fragmentation. Protein expressions of Bcl-2, Bcl-xL, Bax and caspase-3 were studied by western blot.
Results
At a dose of 100 μM concentration, we observed increased IGFBP-3 accumulation in PC-3 cells conditioned medium with a dose dependent increase with 2 fold over a base line, and significantly reduced the both IGF-I and IGF-II levels. Apoptosis induction was also confirmed by TUNEL assay. Bcl-2 and Bcl-xL protein expressions were significantly decreased and Bax and caspase-3 were increased.
Conclusion
These results suggest that the decreased level of IGFs could be due to the increased levels of IGFBP-3, because of the high binding affinity towards IGFs, thereby decreasing the cell proliferation. The increased level of IGFBP-3 was associated with increased pro-apoptotic proteins and apoptosis in response to quercetin, suggesting it may be a p53-independent effector of apoptosis in prostate cancer cells.
doi:10.1186/1477-3163-5-10
PMCID: PMC1482693  PMID: 16600019
3.  Insulin-like growth factor-I mitigates motor coordination deficits associated with neonatal alcohol exposure in rats 
Neurotoxicology and teratology  2008;31(1):40-48.
Prenatal alcohol exposure can affect brain development, leading to behavioral problems, including overactivity, motor dysfunction and learning deficits. Despite warnings about the effects of drinking during pregnancy, rates of fetal alcohol syndrome remain unchanged and thus, there is an urgent need to identify interventions that reduce the severity of alcohol’s teratogenic effects. Insulin-like growth factor I (IGF-I) is neuroprotective against ethanol-related toxicity and promotes white matter production following a number of insults. Given that prenatal alcohol leads to cell death and white matter deficits, the present study examined whether IGF-I could reduce the severity of behavioral deficits associated with developmental alcohol exposure. Sprague-Dawley rat pups received ethanol intubations (5.25 g/kg/day) or sham intubations on postnatal days (PD) 4–9, a period of brain development equivalent to the third trimester. On PD 10–13, subjects from each treatment received 0 or 10 μg IGF-I intranasally each day. Subjects were then tested on a series of behavioral tasks including open field activity (PD 18–21), parallel bar motor coordination (PD 30–32) and Morris maze spatial learning (PD 45–52). Ethanol exposure produced overactivity, motor coordination impairments, and spatial learning deficits. IGF-I treatment significantly mitigated ethanol’s effects on motor coordination, but not the other two behavioral deficits. These data indicate that IGF-I may be a potential treatment for some of ethanol’s damaging effects, a finding that has important implications for children of women who drink alcohol during pregnancy.
doi:10.1016/j.ntt.2008.08.001
PMCID: PMC3164874  PMID: 18755266
fetal alcohol; open field activity; cerebellum; motor coordination; spatial learning
4.  Impact of Insulin Resistance on Insulin-Like Growth Factor-1/Insulin Like Growth Factor-Binding Protein-3 Axis and on Early Weight Gain in Small for Gestational Age Infants 
Objective: To assess insulin-like growth factor-1 (IGF-1)/IGF-binding protein-3 (IGFBP-3) axis and insulin resistance (IR) and the relationship of these parameters with growth in appropriate for gestational age (AGA) and small for gestational age (SGA) infants at birth and in early infancy.
Methods: Postnatal blood samples for measurement of glucose, insulin, IGF-1, and IGFBP-3 were taken from 60 infants (30 AGA and 30 SGA) at birth and at one, three, and six months of age. Both SGA and AGA infants were divided into two groups: growing well and not growing well. Blood glucose, insulin, IGF-1, and IGFBP-3 values were assessed in all infants.
Results: Homeostasis model assessment-IR (HOMA-IR) values in well-growing SGA infants in the third and sixth months were found to be higher than in not well-growing SGA infants (3.9±0.8 vs. 1.0±0.3 at 3 months and 3.3±0.9 vs. 2.4±0.9 at 6 months, p<0.05). IGF-1 levels in well-growing SGA infants at 3 and 6 months were found to be higher than those in not well-growing SGA infants (83.80±44.50 vs. 73.50±17.60 ng/mL at 3 months and 95.12±50.74 vs. 87.67±22.91 ng/mL at 6 months, p<0.05). The IGF-1 values were significantly lower in well-growing SGA infants than in well-growing AGA infants (83.80±44.50 vs. 103.31±30.81 ng/mL at 3 months and 95.12±50.74 vs. 110.87±26.44 ng/mL at 6 months, p<0.05).
Conclusions: This study demonstrates the effects of accelerated early infant growth on IGF-1/IGFBP-3 axis in SGA-born infants.
Conflict of interest:None declared.
doi:10.4274/Jcrpe.867
PMCID: PMC3701915  PMID: 23748063
Well-growing; insulin-like growth factor/IGFBP-3 axis; insulin resistance; small for gestational
5.  Expression of Insulin-Like Growth Factor System Genes During the Early Postnatal Neurogenesis in the Mouse Hippocampus 
Journal of neuroscience research  2007;85(8):1618-1627.
Insulin-like growth factor-1 (IGF-1) is essential to hippocampal neurogenesis and the neuronal response to hypoxia/ischemia injury. IGF (IGF-1 and -2) signaling is mediated primarily by the type 1 IGF receptor (IGF-1R) and modulated by six high-affinity binding proteins (IGFBP) and the type 2 IGF receptor (IGF-2R), collectively termed IGF system proteins. Defining the precise cells that express each is essential to understanding their roles. With the exception of IGFBP-1, we found that mouse hippocampus expresses mRNA for each of these proteins during the first 2 weeks of postnatal life. Compared to postnatal day 14 (P14), mRNA abundance at P5 was higher for IGF-1, IGFBP-2, -3, and -5 (by 71%, 108%, 100%, and 98%, respectively), lower for IGF-2, IGF-2R, and IGFBP-6 (by 65%, 78%, and 44%, respectively), and unchanged for IGF-1R and IGFBP-4. Using laser capture microdissection (LCM), we found that granule neurons and pyramidal neurons exhibited identical patterns of expression of IGF-1, IGF-1R, IGF-2R, IGFBP-2, and -4, but did not express other IGF system genes. We then compared IGF system expression in mature granule neurons and their progenitors. Progenitors exhibited higher mRNA levels of IGF-1 and IGF-1R (by 130% and 86%, respectively), lower levels of IGF-2R (by 72%), and similar levels of IGFBP-4. Our data support a role for IGF in hippocampal neurogenesis and provide evidence that IGF actions are regulated within a defined in vivo milieu.
doi:10.1002/jnr.21289
PMCID: PMC2302789  PMID: 17455296
insulin-like growth factor (IGF); hippocampus; dentate gyrus; laser capture microdissection (LCM)
6.  Ethanol inhibition of aspartyl-asparaginyl-β-hydroxylase in fetal alcohol spectrum disorder: Potential link to the impairments in central nervous system neuronal migration 
Alcohol (Fayetteville, N.Y.)  2009;43(3):225-240.
Fetal alcohol spectrum disorder (FASD) is caused by prenatal exposure to alcohol and associated with hypoplasia and impaired neuronal migration in the cerebellum. Neuronal survival and motility are stimulated by insulin and insulin-like growth factor (IGF), whose signaling pathways are major targets of ethanol neurotoxicity. To better understand the mechanisms of ethanol-impaired neuronal migration during development, we examined the effects of chronic gestational exposure to ethanol on aspartyl (asparaginyl)-β-hydroxylase (AAH) expression, because AAH is regulated by insulin/IGF and mediates neuronal motility. Pregnant Long—Evans rats were pair-fed isocaloric liquid diets containing 0, 8, 18, 26, or 37% ethanol by caloric content from gestation day 6 through delivery. Cerebella harvested from postnatal day 1 pups were used to examine AAH expression in tissue, and neuronal motility in Boyden chamber assays. We also used cerebellar neuron cultures to examine the effects of ethanol on insulin/IGF—stimulated AAH expression, and assess the role of GSK-3β—mediated phosphorylation on AAH protein levels. Chronic gestational exposure to ethanol caused dose-dependent impairments in neuronal migration and corresponding reductions in AAH protein expression in developing cerebella. In addition, prenatal ethanol exposure inhibited insulin and IGF-I—stimulated directional motility in isolated cerebellar granule neurons. Ethanol-treated neuronal cultures (50 mM × 96 h) also had reduced levels of AAH protein. Mechanistically, we showed that AAH protein could be phosphorylated on Ser residues by GSK-3β, and that chemical inhibition of GSK-3β and/or global Caspases increases AAH protein in both control- and ethanol-exposed cells. Ethanol-impaired neuronal migration in FASD is associated with reduced AAH expression. Because ethanol increases the activities of both GSK-3β and Caspases, the inhibitory effect of ethanol on neuronal migration could be mediated by increased GSK-3β phosphorylation and Caspase degradation of AAH protein.
doi:10.1016/j.alcohol.2008.09.009
PMCID: PMC2893031  PMID: 19393862
Aspartyl (asparaginyl)-β-hydroxylase; Fetal alcohol syndrome; Neuronal migration; Insulin; Central nervous system; Glycogen synthase kinase 3β
7.  Pharmacodynamic Considerations with Recombinant Human Insulin-Like Growth Factor-I in Children 
Hormone research  2005;63(5):220-227.
Aim
To report effects of weight-based recombinant human insulin-like growth factor-I (rhIGF-I) on IGF axis parameters in children with hyperinsulinism.
Methods
Open label trial with subcutaneous rhIGF-I (40 μg/kg/dose). Patients studied were children (1 month to 11 years) with diffuse hyperinsulinism (n = 7). Serial serum IGF and insulin-like growth factor binding protein (IGFBP) concentrations were measured by RIA and analyzed by linear Pearson regression.
Results
Following the initial rhIGF-I dose, total insulin-like growth factor-I (IGF-I) rose by 56% at 30 min (p < 0.01) and 85% at 120 min (p < 0.02). Serum IGF-II, IGFBP-2, and IGFBP-3 levels did not change. Peak serum IGF-I levels within 12 h of the initial rhIGF-I dose were 167–700 mg/ml. The variable peak IGF-I response is attributable in part to IGFBP-3 differences across this pediatric age range. Models of rhIGF-I dosing based upon body surface area (BSA) or initial IGFBP-3 resulted in predictable peak serum IGF-I levels (r = 0.78; p < 0.03). Recalculating rhIGF-I dosing based upon the BSA · IGFBP-3 product correlated closely with peak IGF-I level (r = 0.85; p < 0.007).
Conclusions
Weight-based IGF-I dosing in this cohort resulted in variable IGF-I levels. Considering BSA and serum IGFBP-3 concentration in children is appropriate for subcutaneous IGF-I administration. A combination of these values may yield predictable individualization of rhIGF-I dosing.
doi:10.1159/000085682
PMCID: PMC3102299  PMID: 15886488
Hyperinsulinism; IGF-I dosing; rhIGF-I dosing; Pharmacokinetics; IGF-I; IGFBP
8.  Apigenin Suppresses Insulin-like Growth Factor I Receptor Signaling in Human Prostate Cancer: An In Vitro and In Vivo Study 
Molecular carcinogenesis  2009;48(3):243-252.
Deregulation of insulin-like growth factor (IGF)-I/IGF-IR signaling has been implicated in the development and progression of prostate cancer. Agents that can suppress the mitogenic activity of the IGF/IGF-IR growth axis may be of preventive or therapeutic value. We have previously demonstrated that apigenin, a plant flavone, modulates IGF signaling through upregulation of IGFBP-3. In this study, we investigated the mechanism(s) of apigenin action on the IGF/IGF-IR signaling pathway. Exposure of human prostate cancer DU145 cells to apigenin markedly reduced IGF-I-stimulated cell proliferation and induced apoptosis. Apigenin inhibited IGF-I-induced activation of IGF-IR and Akt in DU145 cells. Similar growth inhibitory and apoptotic responses were observed in PC-3 cells, which constitutively over-express this pathway. This effect of apigenin appears to be due partially to reduced autophosphorylation of IGF-IR. Inhibition of p-Akt by apigenin resulted in decreased phosphorylation of GSK-3β along with decreased expression of cyclin D1 and increased expression of p27/kip1. In vivo administration of apigenin to PC-3 tumor xenografts inhibited tumor growth, resulted in IGF-IR inactivation and dephosphorylation of Akt and its downstream signaling. These results suggest that inhibition of cell proliferation and induction of apoptosis by apigenin are mediated, at least in part, by its ability to inhibit IGF/IGF-IR signaling and the PI3K/Akt pathway.
doi:10.1002/mc.20475
PMCID: PMC2647985  PMID: 18726972
prostate cancer; apigenin; IGF-I; IGF-IR; PI3K-Akt; glycogen synthase kinase-3
9.  The IGF axis and hepatocarcinogenesis 
Molecular Pathology  2001;54(3):138-144.
Deregulation of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs), IGFBP proteases, and the expression of the IGF receptors, has been identified in the development of hepatocellular carcinoma (HCC). Characteristic alterations detected in HCC and hepatoma cell lines comprise the increased expression of IGF-II and the IGF-I receptor (IGF-IR), which have emerged as crucial events in malignant transformation and the growth of tumours. Alterations of IGFBP production and the proteolytic degradation of IGFBPs resulting in an excess of bioactive IGFs, as well as the defective function of the IGF degrading IGF-II/mannose 6-phosphate receptor (IGF-II/M6PR), may further potentiate the mitogenic effects of IGFs in the development of HCC.
PMCID: PMC1187051  PMID: 11376124
insulin-like growth factors; insulin-like growth factor binding proteins; insulin-like growth factor I receptor; insulin-like growth factor II/mannose 6-phosphate receptor; hepatocarcinogenesis; hepatocellular carcinoma
10.  Racial variation in umbilical cord blood leptin concentration in male babies 
Background
We hypothesize that racial differences in utero contribute to the racial disparity in prostate cancer risk. Leptin is a candidate for evaluating this hypothesis because it influences fetal development and newborn growth.
Methods
We measured leptin concentration by ELISA in venous cord blood collected from 70 African-American and 37 white male full-term births. We measured sex steroid hormones and insulin-like growth factor (IGF) axis concentrations previously. Separately by race, we calculated the geometric mean leptin concentration and estimated the geometric mean adjusted for birth and placental weights, mother’s age and parity, time of day and season of birth, and sex steroid hormone and IGF-axis concentrations using linear regression.
Results
Leptin was positively correlated with birth (r=0.34) and placental (r=0.25) weights, IGF-1 (r=0.21), and IGF binding protein-3 (r=0.29) adjusting for race. Unadjusted geometric mean leptin did not differ (p=0.92) between African Americans (5,280 pg/mL; 95% CI: 4,322-6,451) and whites (5,187 pg/mL; 95% CI: 3,938-6,832). Adjusted geometric mean leptin was nonstatistically significantly higher (p=0.15) in African Americans (5,954 pg/mL; 95% CI: 4,725-7,502) than whites (4,133 pg/mL; 95% CI: 2,890-5,910).
Conclusion
We observed a non-significantly higher adjusted cord blood leptin concentration in African-American compared with white male babies, although unadjusted levels were similar.
Impact
These findings do not support the hypothesis that leptin level in utero contributes to the racial disparity in prostate cancer risk in adulthood.
doi:10.1158/1055-9965.EPI-10-0283
PMCID: PMC3070060  PMID: 21307303
Leptin; in utero; race; male
11.  Alterations in the insulin-like growth factor system during treatment with diethylstilboestrol in patients with metastatic breast cancer 
British Journal of Cancer  2001;85(2):147-151.
Alterations in the insulin-like growth factor (IGF)-system were evaluated in 16 patients treated with diethylstilboestrol 5 mg 3 times daily. Fasting blood samples were obtained before treatment and after 2 weeks, 1 month and/or 2–3 months on therapy. Insulin-like growth factor (IGF)-I, IGF-II, free IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3 were measured by radioimmuno-/immunoradiometric-assays. All samples were subjected to Western ligand blotting as well as immunoblotting for IGFBP-3. We observed a significant decrease (percentage of pretreatment levels with 95 confidence intervals of the mean) in IGF-I [2 weeks 63% (49–79); 1 month 56% (44–73); 2–3 months 66% (53–82)], IGF-II [2 weeks 67% (56–80); 1 month 60% (52–68); 2–3 months 64% (55–75)], free IGF-I [2 weeks 29% (19–42); 1 month 25% (18–36); 2–3 months 31% (21–46)], IGFBP-2 [2 weeks 53% (18–156); 1 month 69% (61–78); 2–3 months 66% (57–78)], IGFBP-3 [2 weeks 74% (63–85); 1 month 69% (62–76); 2–3 months 71% (63–80)], as well as IGFBP-3 protease activity [2 weeks 71% (54–95); 1 month 78% (64–94); 2–3 months 71% (54–93)]. Contrary, the plasma levels (percentage of pretreatment levels with 95 confidence intervals of the mean) of IGFBP-1 [2 weeks 250% (127–495); 1 month 173% (138–542); 2–3 months 273% (146–510)] and IGFBP-4 [2 weeks 146% (112–192); 1 month 140% (116–169); 2–3 months 150% (114–198)] increased significantly. While this study confirms previous observations during treatment with oral oestrogens in substitution doses, the reduction in plasma IGF-II, free IGF-I, IGFBP-2 and -3 are all novel findings. A profound decrease in free IGF-I suggests a reduced bioavailability of IGFs from plasma to the tissues. These observations may be of significance to understand the mechanisms of the antitumour effect of diethylstilboestrol in pharmacological doses. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1871
PMCID: PMC2364048  PMID: 11461068
high dose oestrogens; breast cancer therapy; IGF-system
12.  White Matter Damage After Chronic Subclinical Inflammation in Newborn Mice 
Journal of child neurology  2009;24(9):1171-1178.
Preterm infants exposed to inflammation are at increased risk of white matter injury and/or cerebral palsy. To investigate the effect of chronic inflammation on developing white matter, we administered low-dose lipopolysaccharide once a day from postnatal day 3 to 11 examined white matter changes at postnatal day 12, and monitored serum levels of insulin-like growth factor 1 (IGF-1) and insulin-like factor binding protein-3 (IGFBP-3). A single injection of lipopolysaccharide decreased the serum IGF-1 level but not the IGFBP-3 level. At postnatal day 12, quantification of immunohistochemical staining for axonal, myelin, and oligodendrocyte markers revealed impaired myelination in subcortical white matter. In addition, brain grey matter volume decreased and spleen and liver weight increased at postnatal day 12. These data suggest chronic subclinical inflammation hampers development of white and grey matter in early life, which may be associated with IGF-1 deficiency.
doi:10.1177/0883073809338068
PMCID: PMC3674559  PMID: 19745089
white matter damage; inflammation; neonatal brain injury; IGF-1
13.  Growth hormone axis in chronic kidney disease 
Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation. Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality. Renal failure is a state of GH resistance and not GH deficiency. Some mechanisms of GH resistance are: reduced density of GH receptors in target organs, impaired GH-activated post-receptor Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins (IGFBPs). Treatment with recombinant human growth hormone (rhGH) has been proven to be safe and efficacious in children with CKD. Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height, the final adult height is still significantly below the genetic target. Growth retardation may persist after renal transplantation due to multiple factors, such as steroid use, decreased renal function and an abnormal GH–IGF1 axis. Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear growth. Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 (rhIGF-1), recombinant human IGFBP3 (rhIGFBP3) and IGFBP displacers are under investigation and may prove to be more effective in treating growth failure in CKD.
doi:10.1007/s00467-007-0527-x
PMCID: PMC2100434  PMID: 17676425
Growth hormone; Insulin-like growth factor; Chronic kidney failure; Growth failure; Treatment
14.  Prenatal modulation of breast density and breast stem cells by insulin-like growth factor-1 
American Journal of Stem Cells  2012;1(3):239-252.
Biological determinants of breast density, a strong predictor of human breast cancer risk, are postulated to be influenced by prenatal exposures to mitogens. We investigated the extent to which prenatal exposures to insulin-like growth factor-1 (IGF-1) would affect body weight, breast density, and levels of breast stem/progenitor cells in the prepubescent offspring of wild type C57BL/6J and IGF-1 deficient mice. We found that administration of IGF-1 to pregnant mice resulted in significantly heavier birth and postnatal body weights of the offspring when compared to PBS controls. Morphometric analysis of whole mount carmine alum staining of the left fourth inguinal mammary gland revealed that a prenatal dose of 5 μg IGF-1 resulted in significantly longer ductal elongation in wild type mice and significantly higher breast density in both mouse strains. Furthermore, 5 μg IGF-1 also resulted in the highest number of putative CD49f+CD24+ and CD49f+CD24+CD29+ breast stem/progenitor cells in the wild type offspring when compared to PBS controls, as assessed by flow cytometric analysis of dissociated cells from the right fourth inguinal mammary gland, while significantly higher numbers of these cell populations as well as CD24+CD29+ and CD49f+EpCAM+ cells were observed in IGF-1 deficient mice. These findings provide direct evidence for a prenatal modulation of breast density in the offspring by IGF-1, possibly involving populations of breast stem/progenitor cells.
PMCID: PMC3636733  PMID: 23671811
Alveolar bud; birth weight; breast cancer risk; epithelial ducts; fetal origin of disease; flow cytometry; in utero environment; mammary gland; mouse model; terminal end bud
15.  IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors 
Molecular Cancer  2012;11:9.
Background
Hepatoblastoma (HB) is an embryonal liver neoplasm of early childhood with a poor prognosis for patients with distant metastases and vascular invasion. We and others have previously shown that the overexpression of insulin-like growth factor 2 (IGF2), loss of imprinting at the IGF2/H19 locus, and amplification of pleomorphic adenoma gene 1 (PLAG1) are common features in HB, suggesting a critical role of the IGF axis in hepatoblastomagenesis. In this study, we investigated the role of the insulin-like growth factor binding protein 3 (IGFBP3), a known competitor of the IGF axis, in pediatric liver cancers.
Results
The IGFBP3 gene was highly expressed in normal pediatric livers but was heavily downregulated in four HB cell lines and the majority of HB primary tumors (26/36). Detailed methylation analysis of CpG sites in the IGFBP3 promoter region by bisulfite sequencing revealed a high degree of DNA methylation, which is causatively associated with the suppression of IGFBP3 in HB cell lines. Consequently, the treatment of HB cell lines with 5-aza-2'-deoxycytidine resulted in DNA demethylation and reactivation of the epigenetically silenced IGFBP3 expression. Interestingly, IGFBP3 promoter methylation predominantly occurred in metastatic HB with vascular invasion. Restoring IGFBP3 expression in HB cells resulted in reduced colony formation, migration, and invasion.
Conclusion
This study provides the first direct evidence that the reactivation of IGFBP3 decreases aggressive properties of pediatric liver cancer cells and that IGFBP3 promoter methylation might be used as an indicator for vessel-invasive tumor growth in HB patients.
doi:10.1186/1476-4598-11-9
PMCID: PMC3349592  PMID: 22401581
Hepatoblastoma; Epigenetics; Methylation; Invasion; IGF2
16.  Polymorphisms in the Insulin-Like Growth Factor Axis Are Associated with Gastrointestinal Cancer 
PLoS ONE  2014;9(3):e90916.
Introduction
Numerous factors influence the development of gastrointestinal (GI) cancer. The insulin-like growth factor (IGF) axis plays a role in embryonic and postnatal growth and tissue repair. Elevated levels of IGFs, low levels of IGF binding proteins (IGFBPs) and over-expression of IGF receptor (IGFR-I) were associated with several stages of cancer. Here, the prevalence of the single nucleotide polymorphisms (SNPs) rs6214 in the IGF type I (IGF-I) gene and rs6898743 in the growth hormone receptor (GHR) gene in patients with GI cancer and controls was studied.
Materials & Methods
In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC), 475 with esophageal cancer (EC) and 544 with colorectal cancer (CRC) and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction. The association between these SNPs and GI cancer, HNC, esophageal adenocarcinoma (EAC), esophageal squamous-cell carcinoma (ESCC) and proximal or distal CRC was studied. Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated via unconditional logistic regression.
Results
Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05), using the most common genotypes GG as reference. An OR of 1.54 (95% CI, 1.05–2.27) was found for EC for genotype AA of rs6214. The ORs for EAC were 1.45 (95% CI, 1.04–2.01) and 1.71 (95% CI, 1.10–2.68), for genotypes GA and AA, respectively. Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26–0.86) for ESCC.
Conclusion
The A allele of SNP rs6214 in the IGF-I gene was associated with EAC, and with HNC in women. The GC genotype of rs6898743 in the GHR gene was negatively associated with ESCC.
doi:10.1371/journal.pone.0090916
PMCID: PMC3946608  PMID: 24608110
17.  Insulin-like growth factor I, IGF binding protein 3, and IGFBP protease activity: relation to anthropometric indices in solid tumours or leukaemia 
Archives of Disease in Childhood  1999;80(3):226-230.
OBJECTIVES—To measure the serum concentrations of insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3), and the level of IGFBP-3 protease activity in 38 children presenting with malignancies, and to assess their relation with auxological parameters and nutritional status.
METHODS—Height, weight, skinfold thickness, and mid-upper arm circumference (MUAC) were recorded using standard techniques. IGF-I and IGFBP-3 were measured using specific radioimmunoassays. Serum IGFBPs were also visualised on western ligand blot. IGFBP-3 protease activity was assessed by the extent of fragmentation of recombinant [125I]-IGFBP-3, compared with that induced by pregnancy serum. Anthropometric and radioimmunoassay data were expressed as standard deviation scores (SDS).
RESULTS—The median (range) IGF-I SDS was significantly reduced in all patients (−1.1 (−5.1 to 1.2)) and lower in children who were malnourished (−2.5 (−3.9 to 0.1)). IGFBP-3 SDS was within the normal range for 31 of 38 patients but IGFBP-3 protease activity was raised in all patients. Neither IGFBP-3 concentration nor protease activity was affected by nutritional status. IGF-I correlated with MUAC (r = 0.41) and subscapular skinfold thickness SDS (r = 0.38), but not with weight, height, weight for height, or triceps skinfold thickness.
CONCLUSIONS—IGF-I is low in children with malignancies, and even lower in those who are malnourished. IGFBP-3 concentrations were normal in most patients but interpretation is complicated by the presence of raised IGFBP-3 protease activity, which could lead to overestimating concentrations of intact peptide. IGF-I appears to relate to arm anthropometry as an index of nutritional status but not height, weight, or weight for height, as would be expected in normal children.


PMCID: PMC1717861  PMID: 10325701
18.  Identification of insulin-like growth factor (IGF)-I and IGF-binding protein in chylous ascites. 
Insulin-like growth factors (IGFs) are bound by several IGF-binding proteins (IGFBPs) that appear to regulate IGF transportation, receptor binding and action. In adult human serum, most of IGFs are bound in a 150 kDa complex which could not cross the capillary wall. We measured IGF-I and IGFBPs in chyle by radioimmunoassay and western ligand blot. The concentration of IGF-I in chyle was only 15% of the corresponding serum level and most of IGF-I was found in 50 kDa complex. The IGFBPs profile in chyle, especially IGFBP-3, was different from that of serum. The concentration of IGFBP-3 in chyle was much less than in serum and the size of glycosylated IGFBP-3 was different from that of serum. However, the size and relative amount of IGFBP-1 and -2 in chyle were similar to serum. This finding indicates that IGF-I and IGFBPs in chyle to a large extent originate in the vascular system and only the 50 kDa complex can cross the capillary barrier.
PMCID: PMC3054345  PMID: 9539313
19.  Growth Hormone/Insulin-Like Growth Factor-1 Axis as Related to Body Mass Index in Patients with Idiopathic Short Stature 
Objective: Idiopathic short stature (ISS) is a heterogeneous disorder. An impairment of growth hormone (GH)/insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1 R) axis is postulated. To evaluate the somatotropic axis in relation to body mass index (BMI), serum IGF-1, IGF-binding protein-3 (IGFBP-3) and the expression of IGF-1 R genes in patients with ISS.
Methods: Fifty-five ISS patients (24F/31M) aged 14.6±5.5 years (range 3.5-28.5 years) and 25 BMI- and pubertal stage-matched peers were enrolled in the study. The ISS patients underwent a four-day standard GH stimulation test to evaluate IGF-1 generation. mRNA expression of the IGF-1 R gene in peripheral blood leukocytes was evaluated. ISS patients and controls were compared with respect to anthropometric and laboratory data. The results were also analyzed after subdividing the two groups into low-normal [BMI standard deviation score (SDS) between -2 to -1)] and normal (BMI SDS between -1 to +1) BMI subgroups.
Results: Basal serum IGF-1 concentrations were lower in ISS subjects compared to controls who had similar BMI SDS values (p=0.000). Subgroup analyses revealed that there were no significant differences between low-normal BMI ISS subjects and low-normal BMI controls with respect to serum IGF-1 and IGFBP-3 concentrations. However, in the normal BMI ISS subgroup, basal and stimulated IGF-1 levels were significantly lower than the basal values in their control counterparts (basal: p=0.000; stimulated: p=0.007). mRNA expression of IGF-1 R gene was not found to be significantly different in ISS subjects and controls.
Conclusions: ISS patients were found to have lower IGF-1 concentrations than BMI-matched peers, a finding supporting presence of an impairment in the somatotropic axis. IGF-1 R expression does not seem to be impaired in ISS patients. ISS patients with low-normal BMI SDS also tend to display a relative IGF-1 resistance, whereas those with normal BMI SDS tend to be less GH-sensitive than healthy peers.
Conflict of interest:None declared.
doi:10.4274/Jcrpe.901
PMCID: PMC3628387  PMID: 23419423
Idiopathic short stature; insulin-like growth factor 1 (IGF-1); body mass index; IGF-1 receptor; IGF-binding protein 3 (IGFBP)-3; IGF-1 generation test
20.  Intranasal Administration of IGF-1 Protects against Lipopolysaccharide-induced Injury in the Developing Rat Brain 
Neuroscience  2011;194:195-207.
Our previous studies show that insulin-like growth factor-1 (IGF-1) can either protect against or increase lipopolysaccharide (LPS)-induced damage in the developing brain, depending on the dose, when it is co-administered with LPS through intracerebral injection. To further explore effects of IGF-1 on central inflammation associated brain injury, IGF-1 was administered through intranasal infusion in the current study. Postnatal day 5 (P5) rats were exposed to LPS at a dose of 1 μg/g body weight or sterile saline through intracerebral injection. Recombinant human insulin-like growth factor-1 (rhIGF-1) at a dose of 50 μg/pup or vehicle was administered intranasally 1 or 2 hr after the LPS injection. Neonatal LPS exposure resulted in oligodendrocyte (OL) and white matter injury in the P6 or P21 rat brain. The damages include dilatation of lateral ventricles, pyknotic cell death, loss of OL progenitor cells and mature OLs in the cingulum area, and impairment of myelination at the corpus callosum area. Neurological dysfunctions were observed in juvenile rats with neonatal LPS exposure. Intranasal IGF-1 treatment at either 1 or 2 hr after LPS exposure significantly attenuated LPS-induced brain injury and improved some behavioral deficits. Intranasal IGF-1 treatment also reduced infiltration of polymorphonuclear leukocytes and activation of microglia in the rat brain 24 hr after LPS exposure, but it did not prevent the elevation in concentrations of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα) in the LPS-exposed rat brain during the first 24 hr. This is an indication that direct anti-inflammation might not be the primary mechanism for the protection of IGF-1, and other mechanisms, such as anti-apoptotic effects, are likely involved in its protective effects.
doi:10.1016/j.neuroscience.2011.08.003
PMCID: PMC3183292  PMID: 21840378
insulin-like growth factor-1; intranasal administration; LPS; oligodendrocyte; apoptotic cell death; inflammatory cytokine
21.  Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer 
British Journal of Cancer  2001;85(1):74-77.
Fasting blood samples were obtained before definitive surgery or biopsy in 128 patients referred to the department of surgery with suspected or manifest breast cancer. Insulin-like growth factor (IGF)-I, IGF-II and free IGF-I were measured by radioimmunoassay/immunoradiometric assay, while IGFBP-3 proteolysis was evaluated by Western immunoblot. 12 patients had ductal carcinoma in situ benign conditions, while staging revealed metastatic disease in 15 of 16 patients with invasive cancers. IGFBP-3 proteolysis above the normal range was recorded in 19 patients with invasive cancers, but in none of the patients suffering from DCIS/benign conditions. Increased IGFBP-3 proteolysis was most frequently recorded in patients harbouring large tumours and metastatic disease (Stage I: 0/19, 0%; Stage II: 3/45, 7%, Stage III: 9/37, 24%, and Stage IV: 7/15, 47%). IGFBP-3 proteolysis was significantly higher in Stage III (P =0.01) and IV (P< 0.001) patients compared to the other stage groups (P = 0.001). IGF-I and IGF-II correlated negatively to IGFBP-3 proteolysis and age. Plasma levels of IGF-I and -II were significantly lower in patients with elevated IGFBP-3 proteolysis compared to those within the normal range. Our findings reveal alterations in the IGF-system among a substantial number of patients with large primary breast cancers. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1860
PMCID: PMC2363920  PMID: 11437405
insulin-like growth factor binding protein-3; proteolysis; insulin-like growth factor-I; primary breast cancer
22.  Adult-Onset Deficiency in Growth Hormone and Insulin-Like Growth Factor-I Alters Oligodendrocyte Turnover in the Corpus Callosum 
Glia  2009;57(10):1062-1071.
Growth hormone (GH) and insulin-like growth factor-I (IGF-I) provide trophic support during development and also appear to influence cell structure, function and replacement in the adult brain. Recent studies demonstrated effects of the GH/IGF-I axis on adult neurogenesis, but it is unclear whether the GH/IGF-I axis influences glial turnover in the normal adult brain. In the current study we used a selective model of adult-onset GH and IGF-I deficiency to evaluate the role of GH and IGF-I in regulating glial proliferation and survival in the adult corpus callosum. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete via twice daily injections of GH starting at postnatal day 28 (P28), approximately the age at which GH pulse amplitude increases in developing rodents. GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Quantitative analyses revealed that adult-onset GH/IGF-I deficiency decreased cell proliferation in the white matter and decreased the survival of newborn oligodendrocytes. These findings are consistent with the hypothesis that aging-related changes in the GH/IGF-I axis produce deficits in ongoing turnover of oligodendrocytes, which may contribute to aging-related cognitive changes and deficits in remyelination after injury.
doi:10.1002/glia.20829
PMCID: PMC2696576  PMID: 19115393
white matter; trophic factor; oligodendrocytes; demyelination; aging
23.  Immunohistochemical expression of insulin-like growth factor binding protein-3 in invasive breast cancers and ductal carcinoma in situ: implications for clinicopathology and patient outcome 
Breast Cancer Research  2004;7(1):R119-R129.
Introduction
Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial cell growth through insulin-like growth factor (IGF)-dependent and IGF-independent pathways and is a direct (IGF-independent) growth inhibitor as well as a mitogen that potentiates EGF (epidermal growth factor) and interacts with HER-2. Previously, high IGFBP-3 levels in breast cancers have been determined by enzyme-linked immunosorbent assay and immunoradiometric assay methods. In vitro, IGFBP-3's mechanisms of action may involve cell membrane binding and nuclear translocation. To evaluate tumour-specific IGFBP-3 expression and its subcellular localisation, this study examined immunohistochemical IGFBP-3 expression in a series of invasive ductal breast cancers (IDCs) with synchronous ductal carcinomas in situ (DCIS) in relation to clinicopathological variables and patient outcome.
Methods
Immunohistochemical expression of IGFBP-3 was evaluated with the sheep polyclonal antiserum (developed in house) with staining performed as described previously.
Results
IGFBP-3 was evaluable in 101 patients with a variable pattern of cytoplasmic expression (positivity of 1+/2+ score) in 85% of invasive and 90% of DCIS components. Strong (2+) IGFBP-3 expression was evident in 32 IDCs and 40 cases of DCIS. A minority of invasive tumours (15%) and DCIS (10%) lacked IGFBP-3 expression. Nuclear IGFBP-3 expression was not detectable in either invasive cancers or DCIS, with a consistent similarity in IGFBP-3 immunoreactivity in IDCs and DCIS. Positive IGFBP-3 expression showed a possible trend in association with increased proliferation (P = 0.096), oestrogen receptor (ER) negativity (P = 0.06) and HER-2 overexpression (P = 0.065) in invasive tumours and a strong association with ER negativity (P = 0.037) in DCIS. Although IGFBP-3 expression was not an independent prognosticator, IGFBP-3-positive breast cancers may have shorter disease-free and overall survivals, although these did not reach statistical significance.
Conclusions
Increased breast epithelial IGFBP-3 expression is a feature of tumorigenesis with cytoplasmic immunoreactivity in the absence of significant nuclear localisation in IDCs and DCIS. There are trends between high levels of IGFBP-3 and poor prognostic features, suggesting that IGFBP-3 is a potential mitogen. IGFBP-3 is not an independent prognosticator for overall survival or disease-free survival, to reflect its dual effects on breast cancer growth regulated by complex pathways in vivo that may relate to its interactions with other growth factors.
doi:10.1186/bcr963
PMCID: PMC1064109  PMID: 15642160
clinicopathology; ductal carcinoma in situ; IGFBP-3; immunohistochemistry; prognosis
24.  Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease 
Background
Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α). Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH). The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD). The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether these changes are related to systemic inflammation.
Methods
We measured serum leptin, IGF-I, TNF-α, interleukin 1β (IL-1β), interleukin 6 (IL-6) and interleukin 8 (IL-8) levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1) and two weeks later (Day 15). 25 healthy age-matched subjects served as controls. COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema). Serum leptin and IGF-I were measured by radioimmunoassay and TNF-α, IL-1β, IL-6 and IL-8 were measured by ELISA.
Results
Serum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p < 0.001). A positive correlation was observed between leptin and TNF-α on Day 1 (r = 0.620, p < 0.001). Emphysematous patients had significantly lower IGF-I levels compared to those with chronic bronchitis both on Day 1 and Day 15 (p = 0.003 and p < 0.001 respectively).
Conclusion
Inappropriately increased circulating leptin levels along with decreased IGF-I levels occured during acute exacerbations of COPD. Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later.
doi:10.1186/1471-2466-9-11
PMCID: PMC2670813  PMID: 19344528
25.  Race/ethnic Variation in Serum Levels of IGF-I and IGFBP-3 in US Adults 
Objectives
The IGF axis plays a significant role in normal growth and development and variation in IGFs is associated with health outcomes. Past studies report variation in IGF levels among race/ethnic groups known to differ in disease incidence. This paper reports on race/ethnic variation in serum levels of IGF-I and IGF-BP3 in a nationally representative and ethnically diverse sample of US adults.
Design
Serum IGF-I and IGFBP-3 levels from the fasting subsample (n = 6061) of respondents to the US National Health and Nutrition Examination Survey III (NHANES III) were analyzed using an IGF-I ELISA (Diagnostic Systems Laboratory (DSL) 10–5600) and an IGFBP-3 IRMA (DSL 6600). The NHANES is a combined examination and interview survey of a nationally representative sample of US adults. Regression analyses were used to estimate cross-sectional associations between the IGF axis and demographic variables.
Results
In unadjusted analyses, serum IGF-I levels were higher in males than in females, and IGFBP-3 levels were higher in females than in males. Both analytes were lower in older adults. Univariate analyses indicate that serum levels of IGF-I are lower in female Non-Hispanic Whites (NHW) (256 [4.9]) and Hispanics (249 [6.6]) than in Non-Hispanic Blacks (NHB) (281 [4.9]). However, in males, IGF levels in NHWs (287 [3.6]) and NHBs (284 [4.3]) are similar and levels in Mexican-Americans are only moderately reduced (265 [3.4]). Notably, NHB’s have the highest molar ratio of IGF-I:IGFBP-3 at all ages. After adjustment for age and BMI, gender and race/ethnicity differences persist.
Conclusions
These cross-sectional data support exploration of the IGF axis as an explanation for some race/ethnic differences in cancer incidence.
doi:10.1016/j.ghir.2008.08.005
PMCID: PMC2702997  PMID: 18812263
Cancer; Insulin-Like Growth Factor; Race/Ethnicity; Age

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