Role Of Pregnancy-associated Plasma protein-A Research Articles

The Multi-Faced Role of PAPP-A in Post-Partum Breast Cancer: IGF-Signaling is Only the Beginning.

Insulin-like growth factor (IGF) signaling and control of local bioavailability of free IGF by the IGF binding proteins (IGFBP) are important regulators of both mammary development and breast cancer. A recent genome-wide association study (GWAS) identified small nucleotide polymorphisms that reduce the expression of IGFBP-5 as a risk factor of developing breast cancer. This observation suggests that genetic alterations leading to a decreased level of IGFBP-5 may also contribute to breast cancer. In the current review, we focus on Pregnancy-Associated Plasma Protein A (PAPP-A), a protease involved in the degradation of IGFBP-5. PAPP-A is overexpressed in the majority of breast cancers but its role in cancer has only begun to be explored. More specifically, this review aims at highlighting the role of post-partum involution in the oncogenic function of PAPP-A. Notably, we summarize recent studies indicating that PAPP-A plays a role not only in the degradation of IGFBP-5 but also in the deposition of collagen and activation of the collagen receptor discoidin 2 (DDR2) during post-partum involution. Finally, considering the immunosuppressive microenvironment of post-partum involution, we also discuss the unexpected finding made in Ewing Sarcoma that PAPP-A plays a role in immune evasion. While the immunosuppressive role of PAPP-A in breast cancer remains to be determined, collectively these studies highlight the multifaced role of PAPP-A in cancer that extends well beyond its effect on IGF-signaling.

The relationship between serum pregnancy-associated plasma protein-A level in patients with aortic valve stenosis: a case-control study

Objective Calcific aortic stenosis (AS) is the most common form of calcific aortic valve disease. Many matrix metalloproteinase (MMP) have been shown to be expressed in aortic sclerosis and contribute to valve fibrosis and calcification. We investigated the relationship between Pregnancy-Associated Plasma Protein-A (PAPP-A) and AS. Methods Sixty-one patients who referred to our cardiology clinic having AS diagnosed with transthoracic echocardiography and thirty control subjects were included in this study. The patient group was divided into two groups as mild and moderate-severe AS in terms of echocardiography results. Levels of C-reactive protein (CRP), insulin-like growth factor-1 (IGF-1) and PAPP-A were measured. Results There was statistically significant difference between the patient and control group for PAPP-A (p = 0.009). In addition, the difference between MPV, IGF-1 and PAPP-A levels of control and AS groups was found. We found that serum PAPP-A level was an independent predictor of AS (B = 0.107, p = 0.01) by logistic regression analysis. In linear regression analysis, a significant correlation was found for AS severity with MPV, IGF-1 and PAPP-A levels, respectively (p = 0.025, p = 0.004, p = 0.035). It was revealed that PAPP-A and IGF-1 were negatively correlated (r = −0.327, p = 0.002). Correlation of serum PAPP-A level with echocardiographic parameters was no observed. Conclusion The level of PAPP-A may be a marker used in diagnosis rather than a marker used to determine the severity of AS. Studies with larger patient populations may further explain the role of PAPP-A in the diagnosis and treatment of AS.

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end-stage renal disease (ESRD). The treatment options for ADPKD are limited. We observed an upregulation in several IGF-1 pathway genes in the kidney of Pkd1RC/RC mice, a model of ADPKD. Pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase that cleaves inhibitory IGF binding proteins (IGFBPs), increasing the local bioactivity of IGF-1, was highly induced in the kidney of ADPKD mice. PAPP-A levels were high in cystic fluid and kidneys of humans with ADPKD. Our studies further showed that PAPP-A transcription in ADPKD was mainly regulated through the cAMP/CREB/CBP/p300 pathway. Pappa deficiency effectively inhibited the development of cysts in the Pkd1RC/RC mice. The role of PAPP-A in cystic disease appears to be regulation of the IGF-1 pathway and cellular proliferation in the kidney. Finally, preclinical studies demonstrated that treatment with a monoclonal antibody that blocks the proteolytic activity of PAPP-A against IGFBP4 ameliorated ADPKD cystic disease in vivo in Pkd1RC/RC mice and ex vivo in embryonic kidneys. These data indicated that the PAPP-A/IGF-1 pathway plays an important role in the growth and expansion of cysts in ADPKD. Our findings introduce a therapeutic strategy for ADPKD that involves the inhibition of PAPP-A.

Role of Pregnancy-Associated Plasma Protein-A and Uterine Artery Doppler in Early Detection of Preeclampsia

The purpose of this study was to evaluate the role of pregnancy-associated plasma protein-A and uterine artery Doppler in early detection of preeclampsia. Subjects of this prospective cohort study included (120) pregnant women with viable singleton pregnancies in the first trimester between (11- 13+6 ) weeks of gestation, were recruited during the period from March 2018 to January 2020 and who came for ante natal clinic, in the Department of Obstetrics and Gynecology at Benha University Hospital. Consideration criteria were Pregnant ladies going to antenatal forethought toward Benha outpatient facility for singleton feasible pregnancy In 11-13+6 weeks gestation (Fetal crown-rump length (CRL) might have been 45-84 mm for typical fetal morphology). For each tolerant we measure uterine corridor doppler and pregnancy cohorted plasma protein and the outcomes were Pregnancy copartnered plasma protein (PAPP-A) indicated profoundly noteworthy Contrast between instances for preeclampsia What's more instances that don’t create preeclampsia (p quality 0. 004) same time both uterine corridor pulstality list (UTPI) Furthermore uterine corridor imperviousness list (UTRI ) are stastically critical. We closed that mix for uterine corridor stream indices Also pregnancy connected plasma protein from the beginning trimester needed progressed early identification about preeclampsia.

Abstract 1597: Inhibition of the novel therapeutic target pregnancy associated plasma protein A (PAPP-A) in Ewing sarcoma enhances efficacy of IGF1R targeting in vivo

Abstract Background: Despite intensive treatment regimens, Ewing sarcoma (EWS) patients with metastatic or relapsed disease still face a 5-year overall survival of less than 20%, indicating a clear need for novel targeted therapies. Utilizing ribosomal depleted RNA sequencing of 122 EWS samples (49 cell lines and 73 tumor samples) and 96 normal samples of variable tissues, we previously reported PAPP-A as one of the top 5 genes overexpressed in EWS (> than 4-fold) compared to normal tissue. Notably, PAPP-A showed substantial expression in tumors (median log2FPKM = 3.933, n=122) and minimal expression in normal tissue (median log2FPKM = -1.564, n=96). Pregnancy Associated Plasma Protein A (PAPP-A) is a secreted zinc metalloproteinase, that anchors to cell surface of heparan sulfate proteoglycans and enhances local IGF signaling. Through the release of IGFs from IGFBP-4, IGFBP-2 and IGFBP-5, free, bioactive IGF is being increased in close proximity to its receptors. In pregnancy PAPP-A is highly expressed by placental trophoblasts and represents a key regulator of fetal growth. The impact of IGF signaling in EWS is illustrated by the modest activity of IGF-1R inhibition as a single agent treatment in clinical trials, an approach that is limited by the rapid development of resistance. Methods: In an attempt to investigate the role of PAPP-A in Ewing sarcoma, we used CRISPR/Cas9 technology to target the PAPP-A locus in EWS cell lines and generated PAPP-A knockout clones (EW8, TC32) for further investigation in vitro and in vivo. Additionally, we tested inhibition of PAPP-A proteolytic function in a xenograft NSG mouse model, as a single agent treatment as well as in conjunction with IGF1R inhibition. Results: Knockout of PAPP-A in EWS cell lines utilizing CRISPR/Cas9 technology completely abrogated PAPP-A secretion and metalloproteinase activity in single cell clones, resulting in significantly increased complexed IGFBP-4 and diminished bioactive IGF-1, together with decreased cell growth in vitro. This phenotype could be rescued by recombinant, soluble PAPP-A. In vivo experiments showed that treatment with a monoclonal PAPP-A neutralizing antibody that inhibits the IGFBP-4 proteolytic activity of PAPP-A delays tumor growth of xenografted EWS tumor cells (EW8) in NSG mice. Furthermore, in conjunction with IGF1R inhibition (mAB h7C10), PAPP-A neutralization significantly decreased tumor growth and resulted in prolonged survival of mice (p=0.021).Conclusions: PAPP-A is a novel biologically relevant and highly tumor specific cell surface target in Ewing sarcoma. Our data suggest that neutralization of PAPP-A is a new therapeutic option that merits further evaluation for the treatment of Ewing's Sarcoma. Citation Format: Sabine Heitzeneder, John F. Shern, Lee J. Helman, Javed Khan, Crystal L. Mackall. Inhibition of the novel therapeutic target pregnancy associated plasma protein A (PAPP-A) in Ewing sarcoma enhances efficacy of IGF1R targeting in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1597. doi:10.1158/1538-7445.AM2017-1597

Does Endometriosis Affect PAPP-A Concentration in First Trimester Fetal Screening Test?

Objective Pregnancy-associated plasma protein A (PAPP-A) is a macromolecular glycoprotein. The peritoneal fluid of women affected by endometriosis shows a significant increase of PAPP-A levels. Given the important role of PAPP-A in first trimester screening test, we wondered if its presence in the peritoneal fluid of women with endometriosis could affect biochemical parameters of the test performed during pregnancy. Methods A prospective study enrolled 78 women with singleton pregnancy who performed combined test between 11 + 0 and 13 + 6 weeks of gestation: 25 women with previous histological diagnosis of endometriosis and 53 women without. All patients were sampled to determine PAPP-A concentrations. Serum levels of PAPP-A were expressed in UI/L and in MoM (multiples of median). The two groups – endometriosis women and non-endometriosis women – were compared in order to find a possible different concentration of serum PAPP-A. Results We found an increased concentration of both PAPP-A UI/L and PAPP-A MoM in deep endometriosis patients versus ovarian endometriosis with significant difference in PAPP-A MoM (p = 0.018). We also found a significant association between the stage of the disease and PAPP-A UI/L and MoM levels (PAPP-A UI/L p = 0.05, PAPP-A MoM p = 0.01). Conclusions Women with deep endometriosis show increased serum PAPP-A concentrations compared to women with ovarian endometriosis. Likewise, women with moderate or severe stage of the disease show increased serum PAPP-A concentrations compared to women with minimum or mild disease. This increase could affect first trimester aneuploidy screening test and endometriosis could represent a confounding factor in the calculation of aneuploidy risk.

The role of PAPP-A in the IGF system: location, location, location.

Although discovered as a placental protein present abundantly in the circulation of pregnant women, pregnancy-associated plasma protein-A (PAPP-A) is widely expressed in multiple tissues. PAPP-A is a highly specific metalloproteinase binding tightly to glycosaminoglycans present on the surface of cells. By cleaving a subset of insulin-like growth factor binding proteins (IGFBPs), PAPP-A thus functions within tissues as a growth-promoting enzyme, releasing bioactive IGF in close proximity to the IGF receptor. IGFBP-4 is believed to be the principal PAPP-A substrate, and the focus in this review is on PAPP-A enzymatic activity and its role in the PAPP-A-IGFBP-4-IGF axis, which is subject to regulation at several different levels. These include e.g., transcriptional control, competing reactions potentially sequestering IGF from IGFBP-4 and hence antagonizing PAPP-A-mediated IGF activation, and proteolytic inhibition of PAPP-A. The latter may involve the protein stanniocalcin-2 (STC2), recently found to potently inhibit PAPP-A activity by forming a covalent complex with PAPP-A. PAPP-A or complex-bound variants may escape from pathological tissues into the circulation. It is emphasized that the potential use of PAPP-A as a diagnostic or predictive biomarker in nonpregnant individuals requires precise knowledge of analyte identity and assay specificity in addition to an appropriate material for standardization. Finally, PAPP-A may serve as a therapeutic target to indirectly inhibit IGF signaling in tissues where this is driven by increased PAPP-A activity. By taking advantage of the intricate interaction between PAPP-A and IGFBP-4, highly specific and selective inhibition of PAPP-A is possible.

Role of PAPP-A in aging and age-related disease

As suggested by its name, pregnancy-associated plasma protein-A (PAPP-A) plays an important role in pregnancy and fetal development (Brizot et al., 1996; Lin et al., 1974; Smith et al., 2002). On the opposite end of life's spectrum, recent studies using genetically-engineered mice indicate a newly recognized role for PAPP-A in aging and in the development of age-related disease. These latter studies will be reviewed in this article.

Is Serum Pregnancy-Associated Plasma Protein A Really a Potential Marker of Atherosclerotic Carotid Plaque Stability?

Objectives The search for markers predicting risk of plaque rupture in carotid atherosclerosis is still ongoing. Previous findings showed that pregnancy-associated plasma protein-A (PAPP-A) levels correlate with an adverse plaque morphology. However, the role of PAPP-A in plaque destabilisation is still uncertain. Material and methods Patients with carotid artery stenosis involved in the study were asymptomatic ( n = 29) and symptomatic ( n = 37). Carotid plaques were characterised by histology ( n = 33). Immunohistochemistry ( n = 17) was used to determine expression of PAPP-A and CD68 within the plaques. Serum levels of PAPP-A were measured by the enzyme-linked immunosorbent assay (ELISA). Results Circulating PAPP-A levels were significantly higher in patients with unstable versus stable plaques (0.10 ± 0.06 vs. 0.07 ± 0.04 μg ml −1, p = 0.047) and interestingly, in asymptomatic versus symptomatic patients (0.11 ± 0.05 vs. 0.069 ± 0.09 μg ml −1, p = 0.025). These differences remained statistically significant after adjustment for age, gender and degree of stenosis ( p = 0.050). PAPP-A expression in plaques correlated significantly with CD68 positive macrophages, cap-thickness and its serological values ( r = +0.291, p < 0.001, r = −0.639, p < 0.001 and r = 0.618, p < 0.008, respectively). Furthermore, PAPP-A serum values demonstrated a significant positive predictive value of 68.8% for unstable plaques. Conclusion Our present data confirmed the close relationship between expression of PAPP-A and plaque instability and furthermore correlated significantly with cap thickness. However, the question whether PAPP-A is a useful predictive marker of plaque instability remains unresolved.

Pregnancy-associated plasma protein a: Has this biomarker crossed the boundary from research to clinical practice?

There is already a substantial body of evidence suggesting that pregnancy-associated plasma protein A (PAPP-A) participates in the atherosclerotic process. In several studies, PAPP-A has been associated with the development of vascular injury. PAPP-A has been proposed as a marker of the presence and extent of atherosclerotic disease and high-risk vulnerable plaques. It has been suggested that PAPP-A could have a role in the risk stratification of subjects in different clinical settings. Controversy exists, however, regarding the ability of commercially available assays to measure total versus free PAPP-A. The determination of PAPP-A, particularly in the very early phases of an acute myocardial infarction, may have a complementary role to that of cardiac troponins. This article focuses on the role of PAPP-A as both a marker of risk and a pathogenic factor in atherosclerotic disease.

Role of PAPP-A in atherothrombosis: Messages to take home

Pregnancy-associated plasma protein-A (PAPP-A), first characterised in pregnancy in the 1970s, is a potentially useful prognostic and diagnostic marker for patients with coronary artery disease [1]. Even among stable and troponin-negative patients, plasma PAPP-A concentrations are directly associated with the risk of an acute coronary syndrome (ACS) [2] and with the number of unstable (and total) coronary plaques [3]. In ACS, raised PAPP-A levels are more sensitive for early diagnosis than CK-MB or troponin T [2,4] and a stronger predictor of adverse events than C-reactive protein [5].

Pregnancy-associated plasma protein-A and cardiovascular risk

Coronary artery disease (CAD) progression leading to acute coronary syndrome (ACS) is a rather unpredictable phenomenon. Clinicians currently depend on relatively crude risk scores to identify individuals at risk of developing serious cardiovascular events. Conventional risk factors are able to single out only a proportion of those individuals at a high risk of developing fatal cardiac events. The fact that both atherogenesis and atherosclerotic cardiovascular disease progression are directly linked to inflammatory mechanisms has generated interest among scientists as to the potential role of inflammatory molecules as markers of cardiovascular risk. C-reactive protein, a marker of inflammation, has been shown to add value to the predictive ability of conventional risk factors. However, given the complexity of the mechanisms responsible for both disease progression and acute events, it is unlikely that a single molecule can provide clinicians with an accurate prediction of cardiovascular risk. Current markers, including C-reactive protein, are non-specific and the search should continue for better markers of both atheromatous plaque activity and patient vulnerability. New markers of CAD progression have been identified in recent years, among which, pregnancy-associated plasma protein-A (PAPP-A) appears to offer an interesting profile. Studies have shown that increased plasma PAPP-A levels correlate with the presence of vulnerable coronary artery stenoses and the extent of angiographic CAD1–3 and predict clinical outcome in patients with ACS.4,5 Elesber et al .6 report that in patients with chronic stable CAD, increased plasma PAPP-A levels predict the occurrence of serious cardiovascular events. Findings in this study are of interest as they confirm and expand previous observations, suggesting a role for PAPP-A in atherogenesis and the prediction of cardiovascular risk. PAPP-A is a zinc-binding proteinase produced by different cell types, which circulates as an active homodimer covalenty bound to the proform of oeosinophil major … *Corresponding author. Tel: +44 20 8725 5901; fax: +44 20 8725 3328. E-mail address : jkaski{at}sgul.ac.uk

Insulin-like growth factor binding protein-4 protease produced by smooth muscle cells increases in the coronary artery after angioplasty.

Insulin-like growth factor (IGF)-I stimulates vascular smooth muscle cell (VSMC) migration and proliferation, which are fundamental to neointimal hyperplasia in postangioplasty restenosis. IGF-I action is modulated by several high-affinity IGF binding proteins (IGFBPs). IGFBP-4 is the predominant IGFBP produced by VSMCs and is a potent inhibitor of IGF-I action. However, specific IGFBP-4 proteases can cleave IGFBP-4 and liberate active IGF-I. In this study, we document IGFBP-4 protease produced by human and porcine coronary artery VSMCs in culture as pregnancy-associated plasma protein-A (PAPP-A). This was shown by a distinctive IGFBP-4 cleavage pattern, specific inhibition of IGFBP-4 protease activity with PAPP-A polyclonal antibodies, and immunorecognition of PAPP-A by monoclonal antibodies. Furthermore, we found a 2-fold increase in IGFBP-4 protease activity in injured porcine VSMC cultures in vitro (P<0.05). We also evaluated IGFBP-4 protease/PAPP-A expression in vivo after coronary artery balloon injury. Twenty-five immature female pigs underwent coronary overstretch balloon injury, and vessels were examined at defined time points after the procedure. Abundant PAPP-A expression was observed in the cytoplasm of medial and neointimal cells 7, 14, and 28 days after angioplasty (P<0.01 vs control). The highest PAPP-A labeling indices were located in the neointima (36.1+/-2.1%) and the media (31.7+/-1.2%) 28 days after injury. Western blot analysis confirmed increased PAPP-A in injured vessels. PAPP-A, a regulator of IGF-I bioavailability through proteolysis of IGFBP-4, is thus expressed by VSMCs in vitro and in restenotic lesions in vivo. These results suggest a possible role for PAPP-A in neointimal hyperplasia.

Pregnancy-Associated Plasma Protein-A Gene Expression in Human Ovaries Is Restricted to Healthy Follicles and Corpora Lutea

Recently, Pregnancy-Associated Plasma Protein-A (PAPP-A) in human follicular fluid was identified as an insulin-like growth factor binding protein-4 protease (IGFBP-4ase). The ability of IGFBP-4ase to inactivate the FSH antagonist, IGFBP-4, has suggested a possible role for PAPP-A in regulating FSH action. Despite growing interest in this protease, the question of whether the PAPP-A gene is expressed in ovaries of normal cycling women is unknown. To fill this basic gap in our knowledge, we have identified the cellular sites of PAPP-A gene expression in normal human ovaries by in situ hybridization. PAPP-A mRNA was low or undetectable in preantral follicles, small (1–2 mm) healthy and atretic antral follicles, larger atretic antral follicles, surface epithelium, tunica albuginea and connective tissue cells. In contrast, an intense PAPP-A hybridization signal was evident in the healthy antral follicles examined from 5 mm to the preovulatory stage. In these follicles, the signal was restricted to the granulosa cells (GC). An intense signal for PAPP-A mRNA was also present in healthy corpora lutea (CL), being localized to a subset of large luteal cells. Collectively, these results provide the first evidence that the gene encoding PAPP-A is expressed in ovaries of normal cycling women and show that the gene is expressed almost exclusively in healthy GC and CL cells. The restricted pattern of PAPP-A expression in normal human ovaries suggests that PAPP-A may be a functional marker of the dominant follicle and its product, the CL. Although the physiological function of ovarian PAPP-A remains to be identified, we hypothesize it might play a role in controlling survival, growth, and/or differentiation of the dominant follicle and CL by inactivating the gonadotropin antagonist, IGFBP-4.

Pregnancy-associated plasma protein-A gene expression in human ovaries is restricted to healthy follicles and corpora lutea.

Recently, Pregnancy-Associated Plasma Protein-A (PAPP-A) in human follicular fluid was identified as an insulin-like growth factor binding protein-4 protease (IGFBP-4ase). The ability of IGFBP-4ase to inactivate the FSH antagonist, IGFBP-4, has suggested a possible role for PAPP-A in regulating FSH action. Despite growing interest in this protease, the question of whether the PAPP-A gene is expressed in ovaries of normal cycling women is unknown. To fill this basic gap in our knowledge, we have identified the cellular sites of PAPP-A gene expression in normal human ovaries by in situ hybridization. PAPP-A mRNA was low or undetectable in preantral follicles, small (1-2 mm) healthy and atretic antral follicles, larger atretic antral follicles, surface epithelium, tunica albuginea and connective tissue cells. In contrast, an intense PAPP-A hybridization signal was evident in the healthy antral follicles examined from 5 mm to the preovulatory stage. In these follicles, the signal was restricted to the granulosa cells (GC). An intense signal for PAPP-A mRNA was also present in healthy corpora lutea (CL), being localized to a subset of large luteal cells. Collectively, these results provide the first evidence that the gene encoding PAPP-A is expressed in ovaries of normal cycling women and show that the gene is expressed almost exclusively in healthy GC and CL cells. The restricted pattern of PAPP-A expression in normal human ovaries suggests that PAPP-A may be a functional marker of the dominant follicle and its product, the CL. Although the physiological function of ovarian PAPP-A remains to be identified, we hypothesize it might play a role in controlling survival, growth, and/or differentiation of the dominant follicle and CL by inactivating the gonadotropin antagonist, IGFBP-4.

Potential role of pregnancy-associated plasma protein-A in human reproduction

By radioimmunoassay, pregnancy-associated plasma protein-A (PAPP-A) was undetectable in matched follicular and luteal phase serum samples ( n = 17) or in the peripheral circulation of normal males ( n = 17). However, seminal plasma (91.5%), cervical mucus (100%) and pre-ovulatory follicular fluid (99.6%) were consistenly PaPP-A positive. In addition to PAPP-A, four circulating protease inhibitors (PIs) were detected in pooled seminal plasma whereas pooled follicular fluid contained an additional six. Follicular concentrations of serum PIs were inversely related to molecular size. By contrast, PAPP-A formed a positive concentration gradient across the blood-reproductive tract barrier suggesting PAPP-A production within the reproductive tract. A minor proportion (1.7%) of ejaculated spermatozoa were coated with PAPP-A, as demonstrated by direct immunofluorescence. Since PAPP-A specifically inhibits leucocyte elastase, it is suggested that PAPP-A coated spermatozoa were “selected” to overcome localized phagocytic-proteolytic degradation. The physiological significance of these findings are discussed in relation to human reproduction.