Insulin-like Growth Factor Components Research Articles

Transcription profile of the insulin-like growth factor signaling pathway during human ovarian follicular development.

The IGF signaling cascade exerts important regulatory functions in human ovarian folliculogenesis. The scope of this study was to evaluate the transcription profile of insulin-like growth factor (IGF) genes during human ovarian follicle development and to analyze follicle fluid levels of key IGF proteins. Gene expression profiling was performed with microarray gene analysis. The analysis was assessed from ovarian follicles and granulosa cells (GCs) obtained from isolated stage-specific human ovarian follicles, including preantral follicles, small antral follicles, and preovulatory follicles. Numerous genes involved in the IGF signaling pathway was evaluated and key genes were validated by qPCR from GCs. Protein levels of various IGF components of human follicular fluid (FF) were measured by ELISA and time-resolved immunofluorometric assays (TRIFMA). The gene expression levels of PAPPA, IGF2, IGF receptors and intracellular IGF-activated genes increased with increasing follicle size. This was especially prominent in the late preovulatory stage where IGF2 expression peaked. Protein levels of intact IGF binding protein-4 decreased significantly in FF from large preovulatory follicles compared with small antral follicles concomitant with higher protein levels of PAPP-A. The IGF modulators IGF-2 receptor, IGFBPs, stanniocalcins, and IGF-2 mRNA binding proteins were all observed to be expressed in the different follicle stages. This study confirms and highlights the importance of PAPP-A regulating bioactive IGF levels throughout folliculogenesis and especially for the high rate of granulosa cell proliferation and expression of key ovarian hormones important in the last part of the follicular phase of the menstrual cycle.

The IGF pathway is activated in insulinomas but downregulated in metastatic disease.

Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n=48) and immunohistochemistry (n=86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2-4 folds higher than in islets. High protein expression of IGF2, IGF1R and INSR (in 51-92% of the tumors) and low to moderate expression of mTORC1 pathway proteins p-PS6k and p-4EBP1 (7-28% of the tumors) were observed. Correlations were found between 1) ERK1 mRNA expression and that of numerous IGF pathway genes, 2) p-ERK and IGF1R protein expression and 3) decrease of IGF pathway components and both metastatic disease and shorter 10 years disease free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas.

Changes in Acid Labile Subunit (ALS) and Insulin-Like Growth Factor 1 (IGF-1) Concentration in Hyperthyroidism before and After Medical Treatment: A Prospective Controlled Study

Background:The relationship of altered thyroid status with GH and components of insulin-like Growth factor (IGF-1) axis is complex and not fully understood. We aimed to evaluate changes in Acid labile subunit (ALS) and IGF-1 in hyperthyroidism, before and after normalization of thyroid status. Methods:Thirty-four hyperthyroid patients matched with 36 normal controls were studied. The patients and controls were assessed at baseline and the patients were followed up prospectively and re-assessed after 6 months of treatment with antithyroid drug (ATD) (carbimazole). On each occasion, blood was collected for measurement of ALS, IGF-1, glucose, insulin, intact proinsulin and thyroid function. Results: Pre-treatment levels of ALS (p=0.012) and IGF-1 (p=0.007) were significantly lower in patients than controls. Five to 10 weeks post-treatment with ATD, all patients were restored to euthyroidism. ALS and IGF-1 levels increased significantly to similar levels of controls after 6 months of ATD. Within the patients, ALS (p=0.049) and IGF-1 (p=0.001) correlated inversely with free T3, whereas, only IGF-1 (p=0.005) correlated inversely with free T4. Conclusion:These results demonstrate that untreated hyperthyroidism is associated with reduction in ALS and IGF-1. Due to the fact that ALS and IGF-1 were related inversely with thyroid status and their concentrations were normalized with euthyroidism, it would be possible to consider their reductions as helpful markers of altered thyroid status, namely hyperthyroidism.

Cross-Sectional Associations between Body Size, Circulating Sex-Steroid Hormones and IGF Components among Healthy Chinese Women

The incidence of breast cancer has increased in Asian countries and rates of hormone receptor (HR) negative breast cancer exceed those of Western countries. Epidemiologic data suggest that the association between body size and BC risk may vary by HR status, and could differ geographically. While body size may influence BC risk by moderating the synthesis and metabolism of circulating sex-steroid hormones, insulin-like growth factor (IGF)-1 and related binding proteins, there is a dearth of literature among Asian women. We aimed to examine these specific associations in a sample of Chinese women. In Sichuan Province 143 women aged ≥40 years were recruited through outpatient services (2011–2012). Questionnaires, anthropometric measurements, and blood samples were utilized for data collection and linear regression was applied in data analyses. Among women <50 years we observed a non-monotonic positive association between body mass index (BMI) and 17β-estradiol, and a reversed J-shaped association between BMI and IGF-1 (p ≤0.05). We observed similar associations between waist-to-hip ratio and these markers. Our finding of augmented IGF-1 among women with low body mass may have implications for understanding breast tumor heterogeneity in diverse populations and should be evaluated in larger prospective studies with cancer outcomes.

Telomerase activity promotes osteoblast differentiation by modulating IGF-signaling pathway.

The contribution of deficient telomerase activity to age-related decline in osteoblast functions and bone formation is poorly studied. We have previously demonstrated that telomerase over-expression led to enhanced osteoblast differentiation of human bone marrow skeletal (stromal) stem cells (hMSC) in vitro and in vivo. Here, we investigated the signaling pathways underlying the regulatory functions of telomerase in osteoblastic cells. Comparative microarray analysis and Western blot analysis of telomerase-over expressing hMSC (hMSC-TERT) versus primary hMSC revealed significant up-regulation of several components of insulin-like growth factor (IGF) signaling. Specifically, a significant increase in IGF-induced AKT phosphorylation and alkaline phosphatase (ALP) activity were observed in hMSC-TERT. Enhanced ALP activity was reduced in presence of IGF1 receptor inhibitor: picropodophyllin. In addition, telomerase deficiency caused significant reduction in IGF signaling proteins in osteoblastic cells cultured from telomerase deficient mice (Terc−/−). The low bone mass exhibited by Terc−/− mice was associated with significant reduction in serum levels of IGF1 and IGFBP3 as well as reduced skeletal mRNA expression of Igf1, Igf2, Igf2r,Igfbp5 and Igfbp6. IGF1-induced osteoblast differentiation was also impaired in Terc−/− MSC. In conclusion, our data demonstrate that impaired IGF/AKT signaling contributes to the observed decreased bone mass and bone formation exhibited by telomerase deficient osteoblastic cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s10522-015-9596-6) contains supplementary material, which is available to authorized users.

Association of in vitro fertilization outcome with circulating insulin-like growth factor components prior to cycle initiation

Components of the insulin-like growth factor (IGF) system enhance in vitro embryo quality and implantation rates in both animal models and human in vitro fertilization (IVF). We evaluated whether differences in serum levels of these components in women prior to initiation of an IVF cycle would be predictive of subsequent outcome. In this retrospective study sera from women obtained at day 2 of their IVF cycle (at baseline before stimulation) were assayed for IGF-I, IGF-II, and IGF binding protein (BP)-1 by enzyme-linked immunosorbent assay. Samples from 54 women with a live birth, 38 with a transient biochemical pregnancy, 45 with a spontaneous abortion, 54 who did not become pregnant, and 35 who had an ectopic pregnancy were available for analysis. Associations between the assays and outcome were evaluated by the Kruskal-Wallis test and receiver operating characteristic analysis. There were no differences in the number of oocytes retrieved, oocyte quality, fertilization rates, or embryo grade between groups. Median concentrations of IGF-I were elevated in women with a live birth (29.1 ng/mL) as compared to women with a biochemical pregnancy (25.6 ng/mL), with spontaneous abortion (21.2 ng/mL), who were not pregnant (18.7 pg/mL), or who had an ectopic pregnancy (4.2 pg/mL) (P < .001). Conversely, median levels of IGF-II were reduced in women with a live birth (294.5 ng/mL) as opposed to 357.5, 393.6, 407.2, and 426.9 ng/mL in women with a biochemical pregnancy, with ectopic pregnancy, with spontaneous abortion, or who were not pregnant, respectively (P < .001). Median IGFBP-1 concentrations were markedly elevated in women with a live birth (23.6 ng/mL) compared to 18.3, 14.1, 13.8, and 9.5 ng/mL in women with a biochemical pregnancy, with spontaneous abortion, who were not pregnant, or with an ectopic pregnancy (P < .001). The combination of IGF-I and IGFBP-1 best predicted the occurrence of a live birth with an area under the curve of 0.892. Maternal serum levels of IGF-I, IGF-II, and IGFBP-1 prior to initiation of an IVF cycle are correlated with the likelihood of a live birth. Alterations in maternal IGF system components may influence oocyte quality or the success of early postfertilization events and embryo implantation.

Autoregulation of insulin-like growth factor 2 and insulin-like growth factor-binding protein 6 in periodontal ligament cells in vitro

The insulin-like growth factor (IGF) system plays an important role in tissue development and presumably also governs pathophysiology of the periodontal ligament (PDL). It has been the aim of this study to elucidate the specific expression pattern of IGF2 and IGFBP6 in PDL cells and to determine whether PDL cells feature autoregulatory mechanisms upon exposure to these IGF components. Human PDL cells (n=6) were exposed to IGF2 (100 ng/ml), IGFBP6 (450 ng/ml, 675 ng/ml, 1125 ng/ml) or a combination of 100 ng/ml IGF2 and 675 ng/ml IGFBP6 for 1, 3 or 5d. qRT-PCR was run for IGF2, IGFBP6, Ki67, ALP, osteocalcin. Immunocytochemical quantification was performed for IGF2 and IGFBP6. Results showed a time-dependent increase in IGF2 and IGFBP6 gene expression, as opposed to a general decrease at the protein level. At the transcriptional and protein level, challenge with IGF2 and IGFBP6 dampened the expression of both molecules at all time points investigated. Only in the case of IGF2 did combined treatment with IGF2 and IGFBP6 contrarily increased protein expression in both nuclear and cytoplasmatic structures compared to the vehicle treated controls. Analyses of PDL cell proliferation and differentiation revealed Ki67 downregulation by IGF2 and IGFBP6 alone or in combination. Beyond this, the osteogenic differentiation potential of PDL cells was suppressed as ALP and osteocalcin expression was reduced. Our results indicate that IGF2 and IGFBP6 appear to govern various regulatory feedback mechanisms in PDL cells. Thus, the functional properties of these molecules in oral structures are presumably self-controlled under impact of different biological processes such as expression levels of these IGF components, cell proliferation and differentiation.

Changes in Mouse Placental Weight Resulting from Inhaled Cadmium Oxide Nanoparticle Exposure Is Associated with Altered mRNA Expression of Growth Hormone and Insulin-Like Growth Factor Components.

Changes in Mouse Placental Weight Resulting from Inhaled Cadmium Oxide Nanoparticle Exposure Is Associated with Altered mRNA Expression of Growth Hormone and Insulin-Like Growth Factor Components.

MRNA expression pattern of insulin-like growth factor components of granulosa cells and cumulus cells in women with and without polycystic ovary syndrome according to oocyte maturity

The mRNA expression of insulin-like growth factor (IGF) components was investigated in granulosa cells (GCs) and cumulus cells (CCs) sampled from immature and mature follicles in women with and without polycystic ovary syndrome (PCOS). Gene expression for IGF-binding protein (IGFBP) 3 in GCs definitely differed between normal women and women with PCOS, whereas increase in IGF-I and IGF receptor (IGFR) 2 mRNA in mature-follicle GCs, increase in IGF-II, IGFR-1, and IGFBP-4 mRNA in immature-follicle GCs, increase in IGFR-2 and IGFBP-2 mRNA in mature-follicle CCs, and increase IGFBP-6 mRNA in immature-follicle CCs were observed in both normal women and women with PCOS.

C-myb stimulates cell growth by regulation of insulin-like growth factor (IGF) and IGF-binding protein-3 in K562 leukemia cells

c-myb plays an important role in the regulation of cell growth and differentiation, and is highly expressed in immature hematopoietic cells. The human chronic myelogenous leukemia cell K562, highly expresses IGF-I, IGF-II, IGF-IR, and IGF-induced cellular proliferation is mediated by IGF-IR. To characterize the impact of c-myb on the IGF–IGFBP-3 axis in leukemia cells, we overexpressed c-myb using an adenovirus gene transfer system in K562 cells. The overexpression of c-myb induced cell proliferation, compared to control, and c-myb induced cell growth was inhibited by anti-IGF-IR antibodies. c-myb overexpression resulted in a significant increase in the expression of IGF-I, IGF-II, and IGF-IR, and a decrease in IGFBP-3 expression. By contrast, disruption of c-myb function by DN-myb overexpression resulted in significant reduction of IGF-I, IGF-II, IGF-IR, and elevation of IGFBP-3 expression. In addition, exogenous IGFBP-3 inhibited the proliferation of K562 cells, and c-myb induced cell growth was blocked by IGFBP-3 overexpression in a dose-dependent manner. The growth-promoting effects of c-myb were mediated through two major intracellular signaling pathways, Akt and Erk. Activation of Akt and Erk by c-myb was completely blocked by IGF-IR and IGFBP-3 antibodies. These findings suggest that c-myb stimulates cell growth, in part, by regulating expression of the components of IGF–IGFBP axis in K562 cells. In addition, disruption of c-myb function by DN-myb may provide a useful strategy for treatment of leukemia.

Insulin-Like Growth Factor-II Is Increased in Systemic Sclerosis-Associated Pulmonary Fibrosis and Contributes to the Fibrotic Process via Jun N-Terminal Kinase- and Phosphatidylinositol-3 Kinase-Dependent Pathways

Systemic sclerosis (SSc)-related pulmonary fibrosis, for which there are few effective therapies, is the most common cause of SSc-related mortality. We examined insulin-like growth factor (IGF)-II expression in explanted lung tissues from control and SSc patients to determine its role in the pathogenesis of fibrosis. IGF-II levels in vivo were detected using immunohistochemistry. Primary lung fibroblasts were cultured from lung tissues, and IGF-II mRNA was measured using reverse transcriptase-polymerase chain reaction. Western blot analysis measured extracellular matrix (ECM) production and phosphorylated signaling molecules. Immunostaining revealed increased IGF-II expression in fibroblastic foci of SSc lungs. Furthermore, primary SSc lung fibroblasts had a fourfold increase in IGF-II mRNA and a twofold increase in IGF-II protein compared with normal lung fibroblasts. IGF-II mRNA in SSc lung fibroblasts was expressed primarily from the P3 promoter of the IGF-II gene, and IGF-II induced both a dose- and time-dependent increase in collagen type I and fibronectin production. IGF-II triggered the activation of both phosphatidylinositol-3 kinase and Jun N-terminal kinase signaling cascades, the inhibition of which diminished IGF-II-induced ECM production. Our study demonstrates increased local IGF-II expression in SSc-associated pulmonary fibrosis both in vitro and in vivo as well as IGF-II-induced ECM production through both phosphatidylinositol-3 kinase- and Jun N-terminal kinase-dependent pathways. Our results provide novel insights into the role of IGF-II in the pathogenesis of SSc-associated pulmonary fibrosis.

Expression of components of the IGF axis in childhood acute myelogenous leukemia

Insulin-like growth factor (IGF) system as regulator for cellular proliferation is of particular interest in search for new prognostic approaches in cancer treatment. We analyzed the mRNA expression profile of IGF-I, -II, and IGFBP-2, -3 in 50 children with previously untreated AML (mean age 10.8 +/- 4.8 years; patients in CCR n = 20, patients with relapse during later course of disease n = 15). MNC samples from peripheral blood as well as bone marrow of healthy donors were used as controls. IGFBP-2 expression was significantly higher in AML cells than in healthy cells of peripheral MNC (P < 0.001) and of bone marrow cells (P < 0.01). Conversely, AML cells showed significantly lower IGFBP-3 and IGF-I gene expression compared to controls (P = 0.02; P < 0.001). Patients with relapse (median +/- range: 0.0929 +/- 0.049) during later course of disease demonstrated higher IGFBP-2 expression compared to patients in CCR (0.0121 +/- 0.047; P = 0.06) at time of diagnosis. A multivariate analysis identified the IGFBP-2 mRNA expression as an independent factor for the prediction of relapse. Furthermore, the probability of relapse-free survival (RFS) in patients with IGFBP-2 mRNA level >0.1000 was 28%; whereas, the probability of RFS in patients with IGFBP-2 mRNA level <0.1000 was 62% (P = 0.04, log-rank test). No prognostic influence could be found for the other investigated genes. Results identified different expressions of IGF components between normal and AML cells. Patients with IGFBP-2 mRNA levels up to 0.1000 (relative to KG1 cell line) more likely developed a relapse. Identification of these patients at diagnosis may allow more individualized treatment.

Modulating peripheral gonadotrophin levels affects follicular expression of mRNAs encoding insulin-like growth factors and receptors in sheep

Evidence suggests that the insulin-like growth factor (IGF) system is involved in follicular growth and development in sheep. However, little information exists as to the role that key peripheral factors play in regulating the expression of IGF components within the follicle. The present study investigated the regulatory effects of FSH and LH on gene expression for IGF ligands and receptors in ovine follicles, using bovine follicular fluid (bFF) and gonadotrophin-releasing hormone antagonist (GnRHa) model systems to perturb endogenous gonadotrophin secretion. Gene expression studies were carried out using in-situ hybridisation with sheep-specific ribonucleotide probes. Treatment of ewes with bFF had no effect on IGF-I mRNA levels. However, IGF-II mRNA levels, particularly in small follicles, and follicular type II IGF-R gene expression significantly increased following bFF administration ( P < 0.001). Conversely, there was a significant ( P < 0.001) decrease in type I IGF-R mRNA levels after only 12 h of bFF treatment, especially in healthy follicles, although this was transient and was followed by a significant ( P < 0.01) increase in gene expression levels by 60 h of bFF treatment. Treatment of ewes with GnRHa resulted in a significant increase in mRNA levels encoding IGF-I ( P < 0.001), IGF-II in early atretic and large follicles ( P < 0.05), and type II IGF-R in healthy and early atretic follicles ( P < 0.001). In contrast, GnRHa administration decreased type I IGF-R gene expression levels after 60 h of treatment ( P < 0.001). These data highlight the roles that endogenous FSH and LH play in regulating IGF ligand and receptor gene expression in the sheep follicle.

Characterization of the insulin-like growth factor axis and Wilms' tumour suppressor gene in hyperparathyroidism

Genetic mutations and upregulation of growth factors are implicated in the pathogenesis of hyperparathyroidism. The aim of this study was to evaluate the role of Wilms' tumour suppressor gene (WT-1) and the insulin-like growth factor (IGF) axis in hyperparathyroidism. The expression of WT-1 and IGF components was examined by immunohistochemistry, reverse transcriptase-polymerase chain reaction and western immunoblotting in a panel of parathyroid specimens from both primary and secondary hyperparathyroidism. A human parathyroid cell culture model was established to examine the parathyroid response to IGF stimulation. There was a significantly lower level of WT-1 expression in parathyroid tumours than in normal parathyroid glands. Most tumours expressed IGF-I and IGF-II receptors and responded to IGF stimulation. Only IGF-I was present in normal parathyroid glands, whereas IGF-II was expressed exclusively in parathyroid tumours. Abnormal expression of WT-1 and the IGF axis may play a role in the pathogenesis of hyperparathyroidism.

Immunohistochemical localization of components of the insulin-like growth factor system in human permanent teeth

There is growing evidence that the insulin-like growth factor (IGF) system plays an important role in the biology of oro-dento-facial tissues and organs, including the development, homeostasis and regeneration of the periodontium. To obtain basic data on the occurrence and distribution of IGF components in human permanent teeth we immunohistochemically investigated 25 extracted, decalcified and paraffin-embedded teeth using mono and polyclonal antibodies against the ligands IGF-I and -II, the IGF1 receptor (IGF1R) and all six IGF binding proteins (IGFBP-1 to -6). In the extracellular matrix (ECM) of the adhering periodontal ligament (PDL), immunoreactivity for IGF-I, -II and IGFBP-1 and -6 was observed. PDL fibroblasts showed immunostaining for the IGF1R. For the cementum, in the acellular cementum only IGF-II could be detected, while outer cementum layers with inserting Sharpey's fibers reacted with all antibodies applied except for IGFBP-4 and -6. In the pulp, mainly fibrotic areas and areas around denticles were immunoreactive for IGF-I, IGFBP-1, -3, -5 and -6. Predentin and odontoblastic processes were stained for IGF-I and IGFBP-3. The spatially oriented occurrence of components of the IGF system in human permanent teeth indicates that specific functions of the IGFs may be localized in particular tissue compartments. In the cementum, several IGF components were found indicating roles in tissue homeostasis or attachment. The PDL may function as a reservoir for IGFs probably bound to ECM components. PDL fibroblasts could then respond in a paracrine manner. In the pulp, the IGF system may be involved in odontoblast biology, fibrosis and denticle formation.

Expression of mRNAs encoding insulin-like growth factor (IGF) ligands, IGF receptors and IGF binding proteins during follicular growth and atresia in the ovine ovary throughout the oestrous cycle

The components of the insulin-like growth factor (IGF) system appear to be involved in the regulation of ovarian follicular growth and atresia in sheep. However, previous studies have only investigated a select few components of the system. The aim of the present study was to investigate the expression of mRNA encoding all of the components of the sheep IGF system among follicles of varying size and health status throughout the oestrous cycle using sheep-specific ribonucleotide probes and in situ hybridisation. For all IGF components, gene expression was unaffected by stage of oestrous cycle. IGF-I mRNA expression in all classes of follicle was generally low throughout the oestrous cycle, while IGFBP-1 mRNA expression could not be demonstrated at all. In contrast, there was relatively intense follicular expression of mRNAs encoding all remaining IGF system components. For IGF-II, both IGF receptors and IGFBP-2, -3, -4, -5, and -6, gene expression decreased as follicles increased in diameter ( P < 0.01). IGF-II, type I IGF-R and IGFBP-2, -3, -4, and -6 mRNA expression significantly decreased as follicles progressed from healthy to atretic status ( P < 0.01), whereas gene expression for type II IGF-R and IGFBP-5 was greater in atretic follicles ( P < 0.01). This study demonstrates the spatial patterns of follicular gene expression for all of the IGF system components in cycling sheep for the first time. These results further highlight the potential functional role of IGF-II, in contrast to IGF-I, in the autocrine and/or paracrine regulation of follicle growth in sheep.

Ethinylestradiol and testosterone have divergent effects on circulating IGF system components in adolescents with constitutional tall stature

Pharmacological doses of estrogens or testosterone are used to limit the final height of girls or boys with constitutional tall stature but the mechanism behind this growth inhibition is still debated. We therefore studied the changes in the circulating components of the insulin-like growth factor (IGF) system during high dose sex steroid therapy. Twenty three girls and twenty boys with constitutional tall stature were treated with 100 microg ethinylestradiol per day or 250 mg testosterone ester every 14 days respectively. In 19 girls and 18 boys, the levels of IGF-I, free IGF-I, IGF-II, acid-labile subunit (ALS) and IGF binding proteins (IGFBP)-2 to -6 were measured before and 3-6 months after the start of therapy (group 1). In 18 girls and 11 boys, samples were collected at the end of therapy and 3 to 6 months afterwards (group 2). Fourteen girls and nine boys belonged to both groups. All parameters were measured by radioimmunoassay or ELISA. Levels of IGF-I were decreased significantly by estrogen treatment but remained unchanged during testosterone treatment. Free IGF-I decreased during estrogen treatment but increased during testosterone therapy. Estrogens increased IGF-II and testosterone reduced it. The important reduction of IGFBP-2 during estrogen therapy is not reproduced by androgen therapy, neither is the stimulation by estrogens of IGFBP-4. IGFBP-3 is not modulated by either sex steroid. We found that IGFBP-6 is up-regulated by testosterone but not by estrogens; the reverse is true for ALS, which increased during estrogen treatment but remained unchanged during testosterone treatment. Our findings demonstrate that androgens and estrogens exert differential effects on the circulating levels of several IGF components.

Association between Components of the Insulin-Like Growth Factor System and Epithelial Ovarian Cancer Risk

Background: Components of the insulin-like growth factor (IGF) system have been associated with several cancers, but very few studies are available for ovarian cancer. Methods: A case-control study conducted between 1999 and 2003 in Italy, including a total of 59 women with incident, histologically confirmed ovarian cancer and 108 controls admitted to the same hospital network as cases, for acute non-neoplastic diseases. All subjects were interviewed using a validated questionnaire. Results: After adjustment for potential confounders, the multivariate odds ratios for the highest versus the lowest tertile of various IGF components were 0.6 (95% confidence interval, CI: 0.2–1.4) for free IGF-I, 0.4 (CI: 0.1–1.5) for total IGF-I, 2.6 (CI: 0.9–6.9) for IGF-binding protein (IGFBP)-1, and 0.2 (CI: 0.0–0.6) for IGFBP-3. Conclusions: This study suggests a protective role of IGFBP-3 and a positive association of IGFBP-1 with ovarian cancer. The complex role of the IGF system in ovarian carcinogenesis deserves further clarification.

Selective Activation of Insulin Receptor Substrate-1 and -2 in Pleural Mesothelioma Cells

Molecular mechanisms active in transforming human pleural cells remain incompletely understood. Our previous microarray analysis of malignant pleural mesothelioma revealed alterations in components of the insulin-like growth factor (IGF) system, implicating this signaling axis in tumorigenesis. Therefore, in this current study, we characterized the molecular phenotype and investigated the key signaling pathways of the IGF system in malignant pleural mesothelioma specimens. For the major IGF components, we assessed mRNA abundance and total protein levels. We measured IGF-I ligand-dependent activation of signaling pathways downstream of the type I IGF receptor in a subset of malignant pleural mesothelioma cell lines and determined the corresponding biological consequences. At the transcriptional level, we observed consistent changes in IGF components that may contribute to a malignant phenotype. IGF-I stimulation of cells resulted in enhanced activation of type I IGF receptor and IRS adaptor proteins. Differential activation of IRS-1 signaling was associated with cell growth, whereas IRS-2 signaling was associated with cell motility. Thus, these data suggest that multiple mechanisms likely contribute to malignant pleural mesothelioma tumorigenesis. Therefore, IGF system components represent novel malignant pleural mesothelioma therapeutic targets for investigation.

Association between Components of the Insulin-Like Growth Factor System and Endometrial Cancer Risk

Objective: The insulin-like growth factor (IGF) system has been related to cell proliferation, obesity, diabetes, hyperinsulinemia and endometrial cancer risk. We used data from a case-control study conducted in Italy to provide additional information on the relation between the IGF system and endometrial cancer. Methods: A case-control study was conducted between 1999 and 2002 in Italy, including a total of 73 women with incident, histologically confirmed endometrial cancer and 108 controls admitted to the same hospital network for acute, nonneoplastic diseases. All subjects were interviewed using a validated questionnaire. Results: The odds ratios for endometrial cancer comparing the highest versus the lowest tertile of various IGF components were as follows: 0.5 [95% confidence interval (CI) 0.2–1.2] for free IGF-I, 1.1 (95% CI 0.5–2.6) for total IGF-I, 1.2 (95% CI 0.6–2.6) for total IGF-II, 2.4 (95% CI 1.0–5.9) for IGF binding protein (IGFBP)-1 and 0.8 (95% CI 0.4–2.0) for IGFBP-3. Further allowance for all IGF components in the model did not modify the results. The direct relation with IGFBP-1 was stronger and limited to heavier and older women. Conclusions: The present findings suggest a limited effect of the IGF system on endometrial cancer risk. Increasing IGFBP-1 levels seem to be associated with endometrial cancer risk in older women and in women with a higher body mass index.