IGFBP-3 Protease Research Articles

Progress in the Study of the Role and Mechanism of HTRA1 in Diseases Related to Vascular Abnormalities.

High temperature requirement A1 (HTRA1) is a member of the serine protease family, comprising four structural domains: IGFBP domain, Kazal domain, protease domain and PDZ domain. HTRA1 encodes a serine protease, a secreted protein that is widely expressed in the vasculature. HTRA1 regulates a wide range of physiological processes through its proteolytic activity, and is also involved in a variety of vascular abnormalities-related diseases. This article reviews the role of HTRA1 in the development of vascular abnormalities-related hereditary cerebral small vessel disease (CSVD), age-related macular degeneration (AMD), tumors and other diseases. Through relevant research advances to understand the role of HTRA1 in regulating signaling pathways or refolding, translocation, degradation of extracellular matrix (ECM) proteins, thus directly or indirectly regulating angiogenesis, vascular remodeling, and playing an important role in vascular homeostasis, further understanding the mechanism of HTRA1's role in vascular abnormality-related diseases is important for HTRA1 to be used as a therapeutic target in related diseases.

Role of the Insulin-like Growth Factor (IGF) Axis in Diseases

The insulin-like growth factor axis is a multifaceted, complex system that comprises two ligands, IGF-I and IGF-II, receptors (IGF-1R, IGF-IIR, insulin receptor isoforms IR-A and B, and hybrid receptors) six high affinity IGF-binding proteins (IGFBPs 1–6), and IGFBP proteases [...]

Development of a Sensitive Bioassay for the Analysis of IGF-Related Activation of AKT/mTOR Signaling in Biological Matrices

The bioactivity of the IGF system is not a function of isolated hormone concentrations in a given biological matrix. Instead, the biological activities of IGFs are regulated by IGFBPs, IGFBP proteases, and inhibitors of IGFBP proteases. Therefore, assays based on IGF-related bioactivity may describe functions of the complete IGF system in a given biological matrix. Of particular interest are the IGF system effects on the AKT/mTOR pathway, as a dominant system for controlling growth, metabolism, and aging. In order to improve the sensitivity of IGF-dependent bioactivity, we made use of the known short-term and enhancing effects of IGFBP2 on the intracellular PI3K pathway. As a specific readout of this pathway, and further as a marker of the mTOR pathway, we assessed the phosphorylation of AKT-Ser473. Preincubation using IGFBP2 enhanced IGF1-dependent AKT-Ser473 phosphorylation in our experimental system. The assay’s specificity was demonstrated by inhibition of IGF1 receptors outside or inside the cell, using antiserum or small molecule inhibitors, which reduced AKT phosphorylation in response to exogenous IGF1 (p < 0.05). The maximal response of AKT phosphorylation was recorded 15 to 60 min after the addition of IGF1 to cell monolayers (p < 0.001). In our cellular system, insulin induced AKT phosphorylation only at supra-physiological concentrations (µM). Using this novel assay, we identified the differential biological activity of the IGF system in AKT-Ser473 phosphorylation in serum (mouse, naked mole rat, and human), in cerebrospinal fluid (human), and in colostrum or mature milk samples (dairy cow). We have developed a sensitive and robust bioassay to assess the IGF-related activation of the AKT/mTOR pathway. The assay works efficiently and does not require expensive cell culture systems. By using capillary immuno-electrophoresis, the readout of IGF-related bioactivity is substantially accelerated, requiring a minimum of hands-on time. Importantly, the assay system is useful for studying IGF-related activity in the AKT/mTOR pathway in a broad range of biological matrices.

SUN-591 PAPP-A Inhibition - a Novel Anti-Obesity Therapeutic Approach

Background: Adipose tissue is a heterogeneous endocrine organ with tremendous capability for expansion. The antithetical pathogenicity of visceral adipose tissue (VAT), compared to subcutaneous adipose tissue (SAT), has been linked to the metabolic stress of enlarging mature adipocytes and a limited ability to recruit new adipocytes. One of the major distinguishing features of VAT preadipocytes is the high expression of Pregnancy Associated Plasma Protein–A (PAPP-A) when compared to SAT. PAPP-A is a zinc metalloprotease that is secreted, and can associate with the cell surface in an autocrine or paracrine fashion. It is the only known physiological IGFBP-4 (Insulin-like Growth Factor Binding Protein) protease. It cleaves the IGF/IGFBP-4 complex, releasing IGF, making it more bio-available for receptor engagement and downstream signaling. The role of IGFs in adipogenic differentiation is well established. While there is quantitative depot-specific variability in PAPP-A expression among preadipocytes, mature adipocytes do not express any PAPP-A. These findings suggest that there may be a relationship between PAPP-A inhibition and adipogenic differentiation and maturation. Similar to human VAT, PAPP-A expression is highest in visceral fat in murine models. The PAPP-A KO mice, when fed a high fat diet, showed restrained visceral adiposity and decreased visceral adipocyte size, suggesting that PAPP-A could regulate adipogenesis locally in tissues that express high PAPP-A. Hypothesis: PAPP-A inhibition is a novel anti-obesity treatment strategy. Methods/Results: We fed 20 male and 20 female wild type mice 42% high fat diet (HFD) starting at 10 weeks of age. Concomitantly, we treated 10 mice in each group with either mAb-PA1/41 (a PAPP-A neutralizing monoclonal antibody) or IgG2a (control isotope), intraperitoneally at a dose of 30 mg/kg weekly for the duration of the HFD. At the end of 15 weeks, the mice were sacrificed and the adipose tissue, serum and solid organs were harvested.Compared to the control (IgG2a) mice, the mAb-PA1/41 treated male and female mice gained 40% less weight (P = 0.03) and had smaller visceral fat depots (mesenteric and pericardial). Also, when we looked at individual adipocyte size, the drug treated mice had 45% smaller mesenteric adipocytes (P = 0.002) and 44% smaller pericardial adipocytes (P= 0.003). Also, the visceral depots in the drug treated mice had 30% more cells (P = 0.006). In both groups, there was decreased liver lipid content (P=0.005). The mAb-PA1/41 treatment had no significant effect on subcutaneous fat depots. Conclusion: Pharmacologic inhibition of PAPP-A decreased weight gain, visceral fat depot weight, visceral adipocyte size, hepatic lipid deposition and increased visceral adipocyte cell number in both male and female mice that were fed a high fat diet.

A characteristic signature of insulin-like growth factor (IGF) axis expression during osteogenic differentiation of human dental pulp cells (hDPCs): Potential co-ordinated regulation of IGF action

The IGF axis is represented by two growth factors (IGF1 and IGF2), two cognate cell surface receptors (IGF1R and IGF2R), six soluble high affinity IGF binding proteins (IGFBP1-6) and several IGFBP proteases. IGF1 and IGF2 are present at high concentrations in bone and play a crucial role in the maintenance and differentiation of both foetal and adult skeleton. In order to understand the role of the IGF axis in bone and other tissues it is necessary to profile the expression and activity of all genes in the axis together with the activity of relevant ancillary proteins (including IGFBP proteases). In the current report we used differentiating human dental pulp cells (hDPC) to examine the expression and activity of the IGF axis during osteogenic differentiation of these cells. We found that, with the exception of IGF1 and IGFBP1, all components of the IGF axis are expressed in hDPCs. IGFBP-4 is the most abundantly expressed IGFBP species at both mRNA and protein levels under both basal and osteogenic conditions. Although we found no difference in IGFBP-4 expression under osteogenic conditions, we report increased expression and activity of pregnancy associated plasma protein-A (PAPP-A - an IGFBP-4 proteinase) leading to increased IGFBP-4 proteolysis in differentiating cell cultures. Further to this we report increased expression of IGF-2 (an activator of PAPP-A), and decreased expression of stanniocalcin-2 (STC2- a recently discovered inhibitor of PAPP-A) under osteogenic conditions. We also demonstrate that STC2 and PAPP-A are able to form complexes in hDPC conditioned medium indicating the potential for regulation of IGFBP-4 proteolysis through this mechanism. We suggest that these changes in the expression and activity of the IGF axis may represent part of an osteogenic signature characteristic of differentiating hDPCs.

Insulin-like Growth Factor System and Aging

IGF (insulin-like growth factor, IGF) system is composed of three ligands (insulin, IGF-1, IGF-2), three cell surface binding receptors (Ins R, IGF-1R, IGF-2 R), and Insulin-like growth factor binding proteins (IGF binding proteins, IGFBPs) and IGFBP protease. Delaying aging and exploring the molecular mechanism of aging have always been important research topics. IGF system plays an important role in the life processes by binding with the receptor or activating multiple intracellular signaling cascades. The researches have showed IGF system plays an important role in regulating signal pathways about senescence and aging related diseases such as cardiovascular disease, osteoporosis and vertebral aging.

Association between IGF system and PAPP-A in coronary atherosclerosis

Atherosclerosis is a condition that involves multiple pathophysiological mechanisms and whose knowledge has not been fully elucidated. Often, scientific advances on the atherogenic pathophysiology generate that molecules not previously considered in the scene of this disease, were attributed actions on the onset or progression of it. A representative example is the study of a new mechanism involved in the atherogenic process, consisting of the association between the insulin-like growth factor (IGF) system and pregnancy-associated plasma protein-A (PAPP-A). Insulin-like growth factor system is a family of peptides that include 3 peptide hormones, 4 transmembrane receptors and 6 binding proteins. Insulin-like growth factor-1 (IGF-1) is the main ligand of the IGF system involved in coronary atherosclerosis. IGF-1 exerts its effects via activation of the IGF-1R receptor on vascular smooth muscle cells or macrophages. In vascular smooth muscle cells promotes migration and prevents apoptosis which increases plaque stability while in macrophages reduces reverse cholesterol transport leading to the formation of foam cells. Regulation of IGF-1 endothelial bioavailability is carried out by IGFBP proteases, mainly by PAPP-A. In this review, we address the mechanisms between IGF system and PAPP-A in atherosclerosis with emphasis on molecular effects on vascular smooth muscle cells and macrophages.

Pappa2 deletion alters IGFBPs but has little effect on glucose disposal or adiposity

ObjectiveInsulin-like growth factor binding proteins (IGFBPs) are involved in glucose and lipid metabolism, and their actions are modulated by proteases. The aim of this study was to examine the effects of an IGFBP-5 protease, pregnancy associated plasma protein-A2 (PAPP-A2), on glucose metabolism and susceptibility to diet-induced obesity. DesignPostnatal growth, circulating IGF-I, IGFBP-3 and IGFBP-5 levels, and glucose tolerance were measured in Pappa2 deletion mice and littermate controls on a chow diet. Males were subsequently fed a high-fat diet for 8weeks to measure weight gain and adiposity, as well as glucose tolerance in response to a metabolic challenge. ResultsCirculating IGFBP-5 levels were ~2-fold higher in mice with no functional PAPP-A2 than in littermate controls, as expected. In contrast, circulating IGFBP-3 levels were reduced by ~15-fold, and total IGF-I levels were ~60% higher in Pappa2 deletion mice. There was no effect of Pappa2 deletion on fasting blood glucose levels or glucose clearance after intraperitoneal injection of 2g glucose/kg body weight in mice on a chow diet. In males on a high-fat diet, there was no difference between genotypes in weight gain or adiposity, adjusting for differences in initial body weight, or in fasting blood glucose or insulin levels, or in glucose clearance. ConclusionsDespite a dramatic disruption of the balance between circulating IGF-I, IGFBP-3 and -5, we found no effects of Pappa2 deletion on glucose metabolism, weight gain or adiposity on a high-fat diet.

Modeling the Insulin-Like Growth Factor System in Articular Cartilage

IGF signaling is involved in cell proliferation, differentiation and apoptosis in a wide range of tissues, both normal and diseased, and so IGF-IR has been the focus of intense interest as a promising drug target. In this computational study on cartilage, we focus on two questions: (i) what are the key factors influencing IGF-IR complex formation, and (ii) how might cells regulate IGF-IR complex formation? We develop a reaction-diffusion computational model of the IGF system involving twenty three parameters. A series of parametric and sensitivity studies are used to identify the key factors influencing IGF signaling. From the model we predict the free IGF and IGF-IR complex concentrations throughout the tissue. We estimate the degradation half-lives of free IGF-I and IGFBPs in normal cartilage to be 20 and 100 mins respectively, and conclude that regulation of the IGF half-life, either directly or indirectly via extracellular matrix IGF-BP protease concentrations, are two critical factors governing the IGF-IR complex formation in the cartilage. Further we find that cellular regulation of IGF-II production, the IGF-IIR concentration and its clearance rate, all significantly influence IGF signaling. It is likely that negative feedback processes via regulation of these factors tune IGF signaling within a tissue, which may help explain the recent failures of single target drug therapies aimed at modifying IGF signaling.

Transgenic overexpression of pregnancy-associated plasma protein-A in skeletal muscle of mice increases myofiber size and central nucleation in sedentary muscle and promotes muscle regeneration in the injured muscle

ObjectiveWhile there is compelling evidence for an anabolic role of PAPP-A, an IGFBP protease, in muscle development, its effect on dynamic regulation of muscle regeneration has not been investigated. In this study, we evaluated the effect of transgenic PAPP-A overexpression in skeletal muscle of mice on myofiber formation in intact and crush-injured tibialus anterior muscle. DesignSkeletal muscle in transgenic mice overexpressing human PAPP-A in skeletal muscle was subjected to crush-injury. Myofiber formation and myogenic gene expression were then evaluated in injured or intact muscle of PAPP-A transgenic mice and wild-type mice. ResultsIn the intact muscle, aging PAPP-A transgenic (Tg.) mice (age of 12months) showed more than a 2-fold increase in both myofiber size and number of nuclei per myofiber compared with their wild-type (Wt.) littermates. Myofibers with centered nuclei, a hallmark of muscle regeneration, were increased from <1% in Wt. mice to 65% in Tg. muscle. In the injured muscle, reduced inflammatory cell infiltration and increased new myofiber size and the area occupied by new myofibers were observed in PAPP-A transgenic mice compared to wild-type littermates. MyoD and creatine kinase in the injured muscle was also significantly increased in the Tg. mice. Although TNF-α induced PAPP-A expression in skeletal myoblast culture and its expression increased upon injury, abrogation of TNF-α signaling in TNF-α receptor knockout mice had no impact on the extent of injury induction of PAPP-A. We also found that TGF-β expression was significantly increased following muscle injury in vivo and treatment with recombinant TGF-β in vitro significantly enhanced PAPP-A expression in skeletal myoblasts. ConclusionOur findings demonstrate that exogenous PAPP-A can promote recovery of muscle injury in aging mice albeit the expression of endogenous PAPP-A had already been increased dramatically upon muscle injury.

Regulation of insulin-like growth factors and their binding proteins by thyroid stimulating hormone in human osteoblast-like (SaOS2) cells

Thyroid stimulating hormone (TSH) is shown to have definite anabolic effects on skeletal metabolism. Previous studies have demonstrated that Insulin-like growth factors (IGF-I and IGF-II) and their six high affinity binding proteins (IGFBPs 1-6) regulate proliferation and differentiation of bone-forming osteoblasts. The current study was intended to determine whether the anabolic effects of TSH on human osteoblastic (SaOS2) cells are mediated through insulin-like growth factor system components. TSH given at 0.01 ng to 10 ng/ml dose levels for 24 and 48 h significantly increased human osteoblastic (SaOS2) cell proliferation and alkaline phosphatase activity, the differentiation marker. TSH significantly increased IGFs (IGF-I and IGF-II) mRNA expression after 6 and 24 h and their protein levels after 24 and 48 h of treatment, respectively. Unlike the IGFs, the IGFBPs responded differently to TSH treatment. Though there were some inconsistencies in the regulation of stimulatory IGF binding protein-3 and -5 by TSH treatment, there was an overall increase at the mRNA abundance and protein levels. Again, the inconsistency persisted at the regulation of the inhibitory IGFBPs 2, 4, and 6 especially at the level of mRNA expression due to TSH treatment, there is an overall decrease in the levels of IGFBP-2, 4, and 6 in the conditioned media (CM) of SaOS2 cell cultures. The IGFBP proteases which control the availability of IGFs are also regulated by hormones. Pregnancy-Associated Plasma Protein-A (PAPP-A) is responsible for the proteolysis of IGFBP-4. TSH treatment significantly unregulated the expression of PAPP-A both at mRNA and protein levels. In conclusion, TSH promotes human osteoblastic (SaOS2) cell proliferation and differentiation by upregulating IGFs and their stimulatory IGF binding proteins and down regulating the inhibitory IGF binding proteins.

Evaluation of the insulin-like growth factors (IGF) IGF-I and IGF binding protein 3 in patients at high risk for breast cancer

Our data suggest that serum concentrations of insulin-like growth factor I and insulin-like growth factor binding protein 3 do not correlate with breast cancer development.

IGF system in cancer

Insulin-like growth factors (IGFs) are important mediators of growth, development, and survival, and have been implicated in the pathogenesis of malignancies. The IGF system is a complex system comprising two growth factors (IGF-I and IGF-II), cell surface receptors (IGF-IR and IGF-IIR), six specific high-affinity binding proteins (IGFBP-1 to IGFBP-6), IGFBP proteases, and several other IGFBP-interacting molecules that regulate and propagate IGF actions in several tissues. IGFs are produced by almost any cell in the body; circulate in more than 1000-fold higher concentrations than most other peptide hormones, such as insulin, and their action is modulated by several binding proteins. Studies have revealed that IGFs may promote cell cycle progression and inhibition of apoptosis either by directly associating with other growth factors or indirectly by interacting with other molecular systems that have an established role in carcinogenesis and cancer promotion, such as steroid hormones and integrins. In addition, studies also suggest that increased serum levels of IGFs and/or altered levels of their binding proteins are associated with increased risk of developing cancers. These data underline the significance of IGFs system in the development of cancer risk, and a potential target for novel anticancer treatments and/or preventative strategies in high-risk groups. The researchers review the IGFs pathway and its implications in cancer development and treatment.

Acute regulation of IGF-I by alterations in post-exercise macronutrients

This investigation sought to examine the contributions of exercise and nutrient replenishment on in vivo regulation of the insulin-like growth factor-I (IGF-I) axis components. Eight college-aged males completed three high-intensity interval training (HIIT) protocols followed by three post-exercise nutritional protocols: (1) placebo (EX); (2) carbohydrate only (CHO); and (3) essential amino acid/carbohydrate (EAA/CHO). Samples were analyzed for growth hormone (GH), free IGF-I, IGFBP-1, IGFBP-2, insulin, hematocrit, hemoglobin, serum leucine, matrix metalloproteinase-9 (MMP-9) proteolytic activity, and presence of IGFBP-3 protease activity. No evidence for IGFBP-3 proteolysis was observed. Significant increases in [free IGF-I] and [leucine] were observed in the EAA/CHO group only. Significant differences were noted in [IGFBP-1] and [IGFBP-2] across conditions. Significant increases in [GH] and MMP-9 activity were observed in all groups. These results indicate that post-exercise macronutrient ratio is a determinant of [free IGF-I], [IGFBP-1 and -2] and may play a role in modulating the IGF-I axis in vivo.

The role of IGFs in the regulation of ovarian follicular growth in the brushtail possum (Trichosurus vulpecula)

IGFs are known to be key regulators of ovarian follicular growth in eutherian mammals, but little is known regarding their role in marsupials. To better understand the potential role of IGFs in the regulation of follicular growth in marsupials, expression of mRNAs encoding IGF1, IGF2, IGF1R, IGF-binding protein 2 (IGFBP2), IGFBP4 and IGFBP5 was localized by in situ hybridization in developing ovarian follicles of the brushtail possum. In addition, the effects of IGF1 and IGF2 on granulosa cell function were tested in vitro. Both granulosa and theca cells synthesize IGF mRNAs, with the theca expressing IGF1 mRNA and granulosa cell expressing IGF2 mRNA. Oocytes and granulosa cells express IGF1R. Granulosa and theca cells expressed IGFBP mRNAs, although the pattern of expression differed between the BPs. IGFBP5 mRNA was differentially expressed as the follicles developed with granulosa cells of antral follicles no longer expressing IGFBP5 mRNA, suggesting an increased IGF bioavailability in the antral follicle. The IGFBP protease, PAPPA mRNA, was also expressed in granulosa cells of growing follicles. Both IGF1 and IGF2 stimulated thymidine incorporation but had no effect on progesterone production. Thus, IGF may be an important regulator of ovarian follicular development in marsupials as has been shown in eutherian mammals.

Transgenic overexpression of pregnancy-associated plasma protein-A in murine arterial smooth muscle accelerates atherosclerotic lesion development

Pregnancy-associated plasma protein-A (PAPP-A) increases local IGF-I bioavailability through cleavage of inhibitory IGF binding protein (IGFBP)-4 in a variety of systems, including the cardiovascular system. To test the hypothesis that expression of PAPP-A promotes the development of atherosclerotic lesions, we generated transgenic mice that express human PAPP-A in arterial smooth muscle. Four founder lines were characterized for transgenic human PAPP-A mRNA and protein expression, IGFBP-4 protease activity, and tissue specificity. In study I, apolipoprotein E knockout (ApoE KO) mice, a well-characterized mouse model of atherosclerosis, and ApoE KO mice expressing the human PAPP-A transgene at relatively high levels (ApoE KO/Tg) were fed a high-fat diet. At harvest, aortas were dissected and opened longitudinally for en face staining of lipid-rich lesions. Lesion area was increased 3.5-fold in aortas from ApoE KO/Tg compared with ApoE KO mice (P < 0.001), but no significant difference was seen in lesion number. In study II, replacement of PAPP-A expression in arterial smooth muscle of double ApoE KO/PAPP-A KO mice resulted in a 2.5-fold increase in lesion area (P = 0.002), without an effect on lesion number. PAPP-A transgene expression was associated with a significant increase in an IGF-responsive gene (P < 0.001), suggesting increased local IGF-I action. We therefore conclude that expression of human PAPP-A localized to arterial smooth muscle accelerates lesion progression in a mouse model of atherosclerosis. These data provide further evidence for the importance of PAPP-A in the cardiovascular system and suggest PAPP-A as a potential therapeutic target in the control of atherosclerosis.

Relationship Between Pregnancy-Associated Plasma Protein-A and Lung Cancer

BackgroundPregnancy-associated plasma protein-A (PAPP-A) has insulin-like growth factor (IGF)-dependent IGFBP-4 protease activity and plays an important role in amplifying local IGF-1 activity in wound healing, vascular repair, and bone remodeling. We postulated that PAPP-A may contribute to the availability and activity of IGFs, which affect lung cancer. Therefore, we determined the levels of PAPP-A in patients with lung cancer and their possible clinical significance. MethodsThe study population consisted of 83 patients with lung cancer and 33 healthy subjects as a control group. Serum PAPP-A levels were determined using an ultrasensitive enzyme-linked immunosorbent assay. ResultsThe serum PAPP-A levels were higher in patients with lung cancer [median (interquartile range) 10.7 (7.6–14.2) ng/mL] than in the control group [6.2 (5.2–9.8) ng/mL, P < 0.001]. There was a significant negative correlation between the serum PAPP-A levels and Karnofsky performance status (r=−0.330; P < 0.001) and a positive correlation with patient age (r=0.358; P < 0.001). ConclusionPAPP-A is a proatherosclerotic metalloproteinase that is also thought to be an inflammatory marker. We found that the serum PAPP-A levels increased in patients with lung cancer and postulated that PAPP-A levels may be a prognostic factor in such cases.

Complement 1s is the serine protease that cleaves IGFBP-5 in human osteoarthritic joint fluid

Insulin-like growth factor-I (IGF-I) and IGF binding proteins (IGFBPs) are trophic factors for cartilage and have been shown to be chondroprotective in animal models of osteoarthritis (OA). IGFBP-5 is degraded in joint fluid and inhibition of IGFBP-5 degradation has been shown to enhance the trophic effects of IGF-I. To determine the identity of IGFBP-5 protease activity in human OA joint fluid. OA joint fluid was purified and the purified material was analyzed by IGFBP-5 zymography. Both crude joint fluid and purified material contained a single band of proteolytic activity that cleaved IGFBP-5. Immunoblotting of joint fluid for complement 1s (C1s) showed a band that had the same Mr estimate, e.g., 88 kDa. In gel tryptic digestion and subsequent peptide analysis by LC-MS/MS showed that the band contained human C1s. A panel of protease inhibitors was tested for their ability to inhibit IGFBP-5 cleavage by the purified protease. Three serine protease inhibitors, FUT175 and CP-143217 and CB-349547 had IC50's between 1 and 6 microM. Two other serine protease inhibitors had intermediate activity (e.g., IC50's 20-40 microM) and MMP inhibitors had no detectible activity at concentrations up to 300 microM. Human OA fluid contains a serine protease that cleaves IGFBP-5. Zymography, immunoblotting and LC-MS/MS analysis indicate that C1s is the protease that accounts for this activity.

Elevated free IGF2 levels in localized, early-stage breast cancer in women

Epidemiological studies imply an association between circulating IGF1 and breast cancer, whereas the role of IGF2, which also acts on the IGF1 receptor, is less settled. This study investigates the association between IGF2 and breast cancer in patients with localized disease. The participants were women with well-characterized, early stage, localized breast cancer (n=43) and matched healthy women (n=38), from whom fasting serum levels of IGF-related peptides were measured. In patients, mean free IGF2 was increased (+57%, P<0.001), in spite of reduced total IGF2 levels (-12%, P=0.003) when compared with controls. Similar changes were seen in free IGF1 (+28%, P=0.004) and total IGF1 (-16% P=NS). Pro-IGF2 and IGF-binding protein 1 (IGFBP1) were unchanged. IGFBP2 was reduced by 22% in the patients (P=0.004). The patients showed reduced IGFBP3 protease activity and accordingly increased levels of intact IGFBP3, whereas total IGFBP3 was unchanged. Women with localized, early-stage breast cancer show elevated circulating free IGF1 and IGF2, reduced total IGF2 and alterations in IGFBPs. The changes observed despite minimal cancer disease suggest a role for the circulating IGF system in the progression of breast cancer in women.

Maintaining the integrity of trophoblast during growth of the placenta. Focus on “Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placenta”

maternal-fetal exchange of nutrients and respiratory gases occurs across the brush border of the trophoblast lining the intervillous space of the placenta. The trophoblast is syncytial in nature and has a high rate of turnover. Therefore syncytiotrophoblast is continually replenished from an