Serum insulin-like growth factor (IGF)-I and IGF-binding proteins in lung cancer patients.

Many studies have shown that insulin-like growth factors (IGF-I & IGF-II) are implicated in the autocrine and paracrine growth of various tumors. Alterations in serum IGFs and IGF-binding proteins (IGFBPs) profiles have been reported in lung cancer. In this study, we measured serum levels of IGF-I and IGFBPs in 41 patients with lung cancer (small cell lung cancer, SCLC, 9; non-small cell lung cancer, NSCLC, 32) by radioimmunoassay and Western ligand blot (WLB). The serum IGF-I level in patients with lung cancer was significantly lower than in controls (207.9+/-62.6 vs 281.3+/-53.9 ng/mL, p<0.01). Patients with NSCLC showed significantly lower serum levels of IGF-I compared with SCLC patients (194.0+/-62.9 vs 258.4+/-27.8 ng/mL, p<0.01). Patients with squamous cell carcinoma tended to show lower serum levels of IGF-I than in those with adenocarcinoma (187.9+/-63.6 vs 215.9+/-59.5 ng/mL, p>0.05). The concentration of IGFBP-3 in lung cancer was 48% of that found in controls by WLB. The serum level of IGFBP-2 was markedly elevated in patients with lung cancer compared with controls (1303.7+/-618.0 vs 696.2+/-300.5, p<0.01). However, there was no significant difference between SCLC and NSCLC groups. This result showed that serum level of IGF-I/IGFBPs may be useful markers for diagnosing and identifying tumor types in lung cancer and further studies are needed.     

Modulation of insulin-like growth factor (IGF)-I and IGF-binding protein interactions enhances skeletal muscle regeneration and ameliorates the dystrophic pathology in mdx mice

Administration of recombinant human insulin-like growth factor-I (rhIGF-I) has beneficial effects in animal models of muscle injury and muscular dystrophy. However, the results of these studies may have been confounded by interactions of rhIGF-I with endogenous IGF-binding proteins (IGFBPs). To date, no study has examined whether inhibiting IGFBP interactions with endogenous IGF-I can improve muscle fiber regeneration or muscular pathologies. We tested the hypothesis that reducing IGFBP interactions with endogenous IGF-I would enhance muscle regeneration after myotoxic injury and improve the dystrophic pathology in mdx mice. We administered an IGF-I aptamer (NBI-31772; 6 mg/kg per day, continuous infusion) to C57BL/10 mice undergoing regeneration after myotoxic injury or to mdx dystrophic mice. NBI-31772 binds all six IGFBPs with high affinity and releases "free" endogenous IGF-I. NBI-31772 treatment increased the rate of functional repair in fast-twitch tibialis anterior muscles after notexin-induced injury as evidenced by an increase in maximum force producing capacity (P(o)) at 10 days after injury. In contrast, NBI-31772 administration for 28 days did not alter P(o) of extensor digitorum longus (EDL) and soleus muscles or normalized force of diaphragm muscle strips from mdx mice. Although IGFBP inhibition reduced the susceptibility of the fast-twitch EDL and the diaphragm muscle to contraction-mediated damage, it increased muscle fatigability during repeated maximal contractions. Although the results in the myotoxic injury model suggest IGF-I signaling is important in this model, the results in the mdx model are mixed.     

Radioimmunoassay for insulin-like growth factor (IGF) II: interference by pure IGF-binding proteins.

A new radioimmunoassay for insulin-like growth factor-II (IGF-II) is described. Compared to recombinant DNA-derived IGF-II standard, the cross-reactivity of natural or recombinant IGF-I was less than 1%. The ED50 for IGF-II standard was 1.0 ng/ml, and the mean IGF-II level in acid-ethanol-extracted serum from healthy adults was 525 +/- 87 ng/ml (SD, n = 30). Addition of the IGF binding protein IGFBP-1 (BP-28, PP12) caused dose-dependent inhibition of IGF-II tracer binding to antiserum, increasing to greater than 90% inhibition at 400 ng/ml IGFBP-1. In contrast, the IGF binding protein IGFBP-3 (BP-53) caused approximately 30% inhibition of tracer binding at 20 ng/ml IGFBP-3, with no further inhibition up to 400 ng/ml IGFBP-3. The influence of added IGF binding proteins on IGF-II displacement curves varied depending on both the type and concentration of binding protein added. It is concluded that interference in IGF radioimmunoassays by IGF binding proteins depends both on the types of binding proteins present, and on the IGF concentration, in the test samples.     

Insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in fluid from human stimulated follicles

Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP- 3) play an important role in regulating follicle growth and maturation. We have evaluated whether responsiveness to gonadotrophins during an in- vitro fertilization (IVF) treatment is related to follicular fluid IGF- I and IGFBP-3 concentrations. We also investigated if a difference is present in IGF-I and IGFBP-3 concentrations between patients treated with human menopausal gonadotrophin (HMG) and patients treated with highly purified follicle stimulating hormone (FSH). We have measured IGF-I and IGFBP-3 in follicular fluid from pre-ovulatory follicles in an IVF programme. All 70 patients were stimulated after being down- regulated with a gonadotrophin-releasing hormone (GnRH) analogue. IGF-I concentrations in follicular fluid were significantly inversely correlated with the number of ampoules FSH administered and number of days of FSH administration, and significantly correlated with the number of follicles aspirated. IGFBP-3 concentrations were not correlated with any other parameter measured nor were IGF-I and IGFBP-3 concentrations correlated. IGFBP-3 concentrations were significantly higher in patients receiving highly purified FSH compared with patients receiving HMG (P < 0.005). These results are new evidence that IGF-I concentration in follicular fluid is higher in women who respond better to follicular stimulation, i.e. women who grow many follicles, women who need a shorter duration of stimulation and women who need fewer ampoules FSH before oocyte retrieval.      

Insulin-like growth factor (IGF)-I affects parasite growth and host cell migration in experimental cutaneous leishmaniasis

While the control or progression of leishmaniasis depends on host immune responses, the initial inflammatory process represents a key event. This process involves the participation of several cytokines and growth factors induced during inflammation as well as factors already present at the site of infection such as insulin-like growth factor (IGF)-I. We have previously demonstrated a potential role for IGF-I in experimental cutaneous leishmaniasis based on the significant increase in lesion size seen in mice injected with Leishmania promastigotes preactivated with IGF-I. In the present study we show that preactivation of Leishmania (Leishmania) amazonensis promastigotes with IGF-I induces an increase in the actual number of parasites at the lesion site from seven days postinfection, in addition to a more intense inflammatory infiltrate. There was a higher numerical density of polymorphonuclear neutrophils from 3 to 24 h, and of mononuclear cells from 48 h of infection onward. A higher density of polymorphonuclear neutrophils and mononuclear cells harboring parasites was also observed. The most important observation, however, was that more parasites per cell were present, revealing that IGF-I appears to favour parasite growth within the macrophages. These results strongly suggest an important role for IGF-I in the development of cutaneous leishmaniasis, where it influences both the inflammatory process and parasite growth.     

Secretion of insulin-like growth factor (IGF)-I and -II and IGF binding proteins (IGFBPs) in fetal stromal-vascular (S-V) cell cultures obtained before and after the onset of adipogenesis in vivo

The present study examined the influence of dexamethasone (DEX) treatment on preadipocyte differentiation and insulin-like growth factor binding protein (IGFBP) secretion in stromal-vascular (S-V) cell cultures established from subcutaneous adipose tissue obtained from nine 75 day and four 50 day pig fetuses. Cultures of S-V cells from four young pigs (5-7 days old) were also studied. Each fetal S-V cell culture represented 1 pool of S-V cells/dam. Cultures were seeded and plated in 10% FBS from day 0-3 and treated with insulin (ITS) + 10 nM DEX from day 3-6 (late DEX treatment). Alternatively, cultures were seeded and plated in 10% FBS + 80 nM DEX from day 0-3 and treated with insulin alone from day 3-6 (early DEX treatment). Conditioned media was collected on day 6 of culture after 3 days of conditioning, and prepared for subsequent 125I-IGF-I ligand blot analysis for IGFBPs and RIA for IGF-I and IGF-II. Early and late DEX increased (P<0.05) preadipocyte (AD-3+) recruitment but only early DEX increased preadipocyte differentiation (lipid + and C/EBP alpha+) by day 6 in S-V cultures from 75 day fetuses. Levels of IGFBP-2, IGFBP-4, IGF-I and IGF-II in media conditioned by 75 day fetal S-V cultures were not influenced by late DEX. However, late DEX reduced levels of 29 kDa IGFBPs and markedly increased (P<0.05) IGFBP-3 levels in 75 day S-V media. Late DEX also markedly increased (P<0.05) IGFBP-3 levels in 50 day S-V media but had little influence on other IGFBPs. Early DEX treatment increased (P<0.05) IGFBP-4 levels in 75 day S-V media but had little to no influence on levels of IGF-I, IGF-II and other IGFBPs. These studies indicate that IGFBP-4 may regulate local metabolism during preadipocyte differentiation, whereas IGFBP-3 may antagonize preadipocyte differentiation by targeting IGF-I away from differentiating cells and towards growing cells.     

胰岛素样生长因子(IGF)与子宫内膜异位症关系的研究进展

本文对IGF家族的组成、结构、在多种肿瘤中的作用机制及其在内异症中的研究进展作一综述,旨在为内异症的诊治提供新的依据。其中研究较明确的是IGF-I和IGFBP-3。IGF-I促进甾体激素的生成、促进细胞增殖、抑制细胞凋亡,与多种肿瘤的发生有关。IGF-I促进异位子宫内膜生长,与内异症形成有关。IGFBP-3作用与IGF-I相反,可能是通过与IGF-I的结合而实现。     

Concentrations of insulin-like growth factor (IGF)-I, -II, and IGF binding protein-4, and -5 in human bone cell conditioned medium do not change with age

We examined the effects of age on the secretion of insulin-like growth factor (IGF)-I, -II, and IGF binding protein-4, and -5 in long-term bone cell cultures from 71 female donors, aged 28-79 years. Our results suggest that under basal conditions, the intrinsic capacity of human bone cells to produce these IGF components is largely preserved with age.     

Immunohistochemical pattern of insulin-like growth factor (IGF) I, IGF II and IGF binding proteins 1 to 6 in carcinoma in situ of the testis.

AIM: To study the immunohistochemical localisation of insulin-like growth factor (IGF) I, IGF II, and IGF binding proteins 1-6 in intratubular germ cell neoplasia in the vicinity of solid germ cell tumours of the testis. METHODS: Testes were obtained from 13 patients (20-35 years old) who had undergone orchidectomy for treatment of a solid germ cell tumour. Tumour cells were verified histologically by their distinctive morphology and by visualisation of placental alkaline phosphatase immunoreactivity. RESULTS: The majority of carcinoma in situ (CIS) cells were immunopositive for IGF I, whereas no CIS cells stained for IGF II. Of all the IGF binding proteins investigated, CIS cells showed intense immunoreactivity for IGF binding protein 5 and lower expression of all other IGF binding proteins. CONCLUSIONS: These results suggest that the action of IGF binding protein 5 in CIS cells may modulate the activity of IGF I. This may be related to a proliferative advantage that could facilitate tumour development.     

Mining the acute respiratory distress syndrome proteome: identification of the insulin-like growth factor (IGF)/IGF-binding protein-3 pathway in acute lung injury

To obtain a more complete protein profile of the airspace milieu in acute respiratory distress syndrome (ARDS) and to identify new mediators, we analyzed bronchoalveolar lavage fluid (BALF) by shotgun proteomics. Using BALF from three patients, we identified a total of 870 different proteins, a nearly 10-fold increase from previous reports. Among the proteins identified were known markers of lung injury, such as surfactant, proteases, and serum proteins. We also identified several biologically interesting proteins not previously identified in patients with ARDS, including insulin-like growth factor-binding protein-3 (IGFBP-3). Because of the known role of IGFBP-3 in regulating cell survival, we measured IGFBP-3 levels by enzyme-linked immunosorbent assay in ARDS BALF. Normal controls had low levels of IGFBP-3, whereas patients with early ARDS had a significant increase in IGFBP-3. The IGF pathway, acting through the type 1 IGF-receptor, repressed apoptosis of lung fibroblasts but not lung epithelial cells. Furthermore, depletion of IGF in ARDS BALF led to enhanced fibroblast apoptosis. Our data suggest that the IGFBP-3/IGF pathway is involved in the pathogenesis of lung injury, illustrating the power of shotgun proteomics to catalog proteins present in complex biological fluids, such as BALF, from which hypotheses can be developed and tested.     

Insulin-like growth factor (IGF) and bone

Bone is not only a rich source of a diverse group of growth factors, but is also a very responsive tissue to such growth promoting agents. IGF-I and IGF-II are reported to be synthesized and retained in bone. While both IGF-I and IGF-II stimulate DNA, collagen, and noncollagenous protein synthesis in cultured calvariae, these explant cultures have quantitative differential sensitivities to these IGF's. In addition to the observed increase in collagen synthesis, collagen degradation decreased in calvariae treated with IGF-I or IGF-II.     

Insulin growth factor (IGF) 1, IGF-binding proteins and ovarian cancer risk: A systematic review and meta-analysis

BackgroundInsulin resistance (IR) has been implicated in carcinogenesis, but there is no consensus regarding its involvement in ovarian cancer. We performed a systematic review and meta-analysis to evaluate the association between IR and ovarian cancer.MethodsSearches were conducted in five databases for studies evaluating IR markers (levels of serum insulin, C peptide, insulin growth factor [IGF] 1 and IGF-binding proteins [IGFBPs], homeostatic model assessment insulin resistance, and quantitative insulin-sensitivity check index) and ovarian cancer risk. Study selection, data extraction and an assessment of risk of bias were performed independently by three researchers. The associations between IR markers and ovarian cancer were quantified as mean differences (MDs) or standardized MDs (SMDs) and their 95% CIs using random-effects models.ResultsFourteen case-control studies satisfied our inclusion criteria (n = 8130). There was little information on IR markers with the exception of the IGF system. Ovarian cancer was associated with lower IGF-1 levels (SMD −0.43 ng/mL, 95% CI −0.67 to −0.18; p = 0.0006), and lower IGFBP-3 levels (SMD −0.11 ng/mL, 95% CI −0.21 to −0.00; p = 0.04). However, ovarian cancer was associated with higher levels of IGFBP-2 and IGFBP-1 (MD 527.3 ng/mL, 95%CI 473.6, 581.0; p < 0.00001, and MD 3.47 ng/mL, 95%CI 1.42, 5.52; p = 0.0009 respectively). Subgroup analyses by menopausal status and age (≤55 vs >55y) for IGF-1 and IGFBP-3 showed the subgroups were similar, although heterogeneity remained high.ConclusionThe evidence suggests that levels of IGF-1 and IGFBP-3 are lower in patients with ovarian cancer. In contrast, higher levels of IGBP-2 and IGBP-1 are found in patients with ovarian cancer.     

Effects of exercise and alkalosis on serum insulin-like growth factor I and IGF-binding protein-3.

This investigation examines the effects of orally induced alkalosis on serum IGF-I and IGFBP3 concentrations in response to an acute 90-s bout of high intensity cycle exercise. Ten healthy, active men, ages 24.60 +/- 4.90 years, participated in a randomized, double-blind, counterbalanced trial order with a cross-over design. Subjects ingested an experimental bicarbonate solution or a placebo solution. Blood was sampled at baseline; pre-exercise; and 0, 5, 10, and 30 min postexercise. The pH between groups for pre-exercise and postexercise time points differed significantly (p < or = .05) in the experimental condition (from 7.42 +/- 0.01 to 7.35 +/- 0.02) versus the placebo condition (from 7.36 +/- 0.01 to 7.25 +/- 0.03). Increases in IGF-I over resting conditions occurred with placebo conditions at 5 and 10 min postexercise and in the experimental condition at 5 min postexercise. Concentrations of IGFBP3 were elevated above baseline at IP in both experimental and placebo conditions.     

Gastric cancer: the role of insulin-like growth factor 2 (IGF 2) and its receptors (IGF 1R and M6-P/IGF 2R)

Insulin-like growth factor 2 (IGF 2) appears to be involved in the progression of many tumours. It binds to at least two different types of receptor: IGF type 1 (IGF 1R) and mannose 6-phosphate/IGF type 2 (M6-P/IGF 2R). Ligand binding to IGF 1R provokes mitogenic and anti-apoptotic effects. M6-P/IGF 2R has a tumour suppressor function--it mediates IGF 2 degradation. Mutation of M6-P/IGF 2R causes both diminished growth suppression and augmented growth stimulation. The aim of this study was to investigate the role of IGF 2 and its receptors (IGF 1R and IGF 2R) in human gastric cancer. The expression of IGF 2 and its receptors was measured in order to analyse the possible correlation between the activity of these genes and cell proliferation in two different gastric tumour types: diffuse and intestinal. The effect of IGF 1 receptor blockage on cell proliferation and anchorage-independent cell growth was also examined. Increased expression of IGF 2 and IGF 1R genes (at the mRNA and protein level) was found in gastric cancer when compared with non-tumour tissue. Furthermore, there was a significant difference between IGF 2 expression in the more aggressive diffuse type and that in the intestinal type of gastric cancer. Moreover, the IGF 2 peptide level in the culture media obtained from the diffuse type of cancer cells was significantly higher when compared with the intestinal type. The level of IGF 2 peptide in the conditioned media strongly correlated with [3H]thymidine incorporation and cell proliferation. On the contrary, IGF 2R mRNA expression was much higher in the intestinal type of cancer than in the diffuse type. In addition, IGF 2R protein expression was substantially lower with progression of the diffuse cancer type to a higher stage. The alphaIR3 monoclonal antibody strongly inhibited [3H]thymidine incorporation and decreased the number of colonies in soft agar of cells overexpressing IGF 2. These findings suggest that members of the IGF family are involved in the pathogenesis of gastric cancer, probably by autocrine/paracrine stimulation of cell growth. Such tumours might be excellent candidates for therapeutic strategies aimed at interference with this pathway.     

The emerging role of insulin-like growth factor 1 receptor (IGF1r) in gastrointestinal stromal tumors (GISTs)

Recent years have seen a growing interest in insulin-like growth factor 1 receptor (IGF1R) in medical oncology. Interesting data have been reported also on IGF1r in gastrointestinal stromal tumors (GISTs) especially in children and in young adult patients whose disease does not harbour mutations on KIT and PDGFRA and are poorly responsive to conventional therapies. However, it is too early to reach conclusions on IGF1R as a novel therapeutic target in GIST because the receptor's biological role is still to be defined and the clinical significance in patients needs to be studied in larger studies. We update and comment the current literature on IGF1R in GISTs and discuss the future perspectives in this promising field.     

Decidualization and insulin-like growth factor (IGF) binding protein: implications for its role in stromal cell differentiation and the decidual cell in haemochorial placentation

The somatomedins or insulin-like growth factors (IGFs) are polypeptides which are involved in proliferation of a number of cell types and have been implicated in fetal growth and development. Cellular responses to IGFs are mediated via binding to two classes of trans-membrane receptors. However, IGFs also bind with high affinity to binding proteins (IGF-BP) in plasma and other body fluids. In plasma the majority of IGF is associated with a GH-dependent 150 kd IGF-BP whereas a second small mol. wt (29-35 kd) IGF-BP is relatively unsaturated. It is this latter class of IGF-BP which has been demonstrated to be synthesized or secreted by a number of cell types and is detected in body fluids and secretions such as amniotic fluid, cerebrospinal fluid and milk. Although the exact relationship between these binding proteins and their role in IGF action has not been clarified, evidence suggests that the 29-35 kd form may function as an inhibitor and promoter of IGF action. During the menstrual cycle IGF-BP synthesis of this latter class appears associated with stromal fibroblast populations and it is proposed that this is involved in specifying proliferation of this cell type which differentiates into decidual cells. This IGF-BP also represents the major soluble secretory protein of the decidualized endometrium and its component decidual cell, during pregnancy and probably is the major source of the protein in pregnancy, contributing to the amniotic fluid and peripheral serum levels. In this article the implications of local decidual production of IGF-BP is discussed with reference to the thesis that decidualization, which is associated with species exhibiting haemochorial placentation, is involved in regulatory mechanisms of feto-placental development and growth.     

Signalling pathways of insulin-like growth factors (IGFs) and IGF binding protein-3

Although the insulin-like growth factor (IGF) system is essential for normal growth and development, its dysregulation has been implicated in a range of pathological states. The peptide growth factors IGF-I and IGF-II exert their effects by binding to cell-surface heterotetrameric tyrosine kinase receptors and activating multiple intracellular signalling cascades, leading to changes in the expression of proteins essential for cell proliferation, survival and differentiation. The IGF system comprises multiple ligands, receptors and high-affinity IGF binding proteins (IGFBPs), with added complexity arising from crosstalk between its receptors and other key growth-regulatory pathways such as those activated by steroid hormones, integrins and other receptor tyrosine kinases. The IGFBPs are also increasingly recognised for their intrinsic growth-regulatory activity, and the ability of IGFBP-3 to modulate signalling pathways of nuclear hormone and growth factor receptors, as well as novel receptors, is believed to play a role both in normal physiology and in disease.