Platelet-derived Growth factor-AA Expression Research Articles

Zoledronic Acid Abrogates Restraint Stress-Induced Macrophage Infiltration, PDGF-AA Expression, and Ovarian Cancer Growth.

Simple SummaryBiobehavioral disorders can negatively impact patients with ovarian cancer. Growing evidence suggests that chronic stress can promote tumor progression, the release of inflammatory mediators, and macrophage infiltration into the tumor. However, the role of stress hormones in regulating cancer cell/macrophage crosstalk remains unclear. This study aimed to assess the role of stress hormone-stimulated macrophages in modulating inflammatory networks and ovarian cancer biology. Our data show that stress hormones induced secretion of inflammatory proteins in ovarian cancer cell/macrophage co-cultures. Furthermore, we show that restraint stress leads to cancer growth, macrophage infiltration, and PDGF-AA protein expression in animal models of ovarian cancer. Conversely, zoledronic acid was able to prevent the effects of restraint stress on ovarian cancer growth. Overall, our data suggest a role for stress hormone-stimulated macrophages in ovarian cancer progression and suggest the involvement of PDGF-AA as a key mediator of this process.Multiple studies suggest that chronic stress accelerates the growth of existing tumors by activating the sympathetic nervous system. Data suggest that sustained adrenergic signaling can induce tumor growth, secretion of pro-inflammatory cytokines, and macrophage infiltration. Our goal was to study the role of adrenergic-stimulated macrophages in ovarian cancer biology. Cytokine arrays were used to assess the effect of adrenergic stimulation in pro-tumoral cytokine networks. An orthotopic model of ovarian cancer was used to assess the in vivo effect of daily restraint stress on tumor growth and adrenergic-induced macrophages. Cytokine analyses showed that adrenergic stimulation modulated pro-inflammatory cytokine secretion in a SKOV3ip1 ovarian cancer cell/U937 macrophage co-culture system. Among these, platelet-derived growth factor AA (PDGF-AA), epithelial cell-derived neutrophil-activating peptide (ENA-78), Angiogenin, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-5 (IL-5), Lipocalin-2, macrophage migration inhibitory factor (MIF), and transferrin receptor (TfR) were upregulated. Enriched biological processes included cytokine-mediated signaling pathways and positive regulation of cell proliferation. In addition, daily restraint stress increased ovarian cancer growth, infiltration of CD68+ macrophages, and expression of PDGF-AA in orthotopic models of ovarian cancer (SKOV3ip1 and HeyT30), while zoledronic acid, a macrophage-depleting agent, abrogated this effect. Furthermore, in ovarian cancer patients, high PDGFA expression correlated with worse outcomes. Here, it is shown that the adrenergic regulation of macrophages and PDGFA might play a role in ovarian cancer progression.

Reduced PDGF-AA in subchondral bone leads to articular cartilage degeneration after strenuous running.

To identify the effects of running on articular cartilage and subchondral bone remodeling, C57BL/6 mice were randomly divided into three groups: control, moderate-, and strenuous running. Magnetic resonance imaging showed bone marrow lesions in the knee subchondral bone in the strenuous-running group in contrast with the other two groups. The microcomputed tomography analysis showed promoted bone formation in the subchondral bone in mice subjected to strenuous running. Histological and immunohistochemistry results indicated that terminal differentiation of chondrocytes and degeneration of articular cartilage were enhanced but, synthesis of platelet-derived growth factor-AA (PDGF-AA) in the subchondral bone was suppressed after strenuous running. In vitro, excessive mechanical treatments suppressed the expression of PDGF-AA in osteoblasts, and the condition medium from mechanical-treated osteoblasts stimulated maturation and terminal differentiation of chondrocytes. These results indicate that strenuous running suppresses the synthesis of PDGF-AA in subchondral bone, leading to downregulated PDGF/Akt signal in articular cartilage and thus cartilage degeneration.

Platelet-derived growth factor-AA is a substantial factor in the ability of adipose-derived stem cells and endothelial progenitor cells to enhance wound healing.

Nonhealing wounds with various forms of complications have been a major challenge for patients with different diseases, and few data are available regarding the clinical significance of platelet-derived growth factor-AA (PDGF-AA) in the enhanced wound healing with stem cells, and the precise molecular mechanism remains unclear. The study aims to investigate the role of PDGF-AA in adipose-derived stem cells (ASCs) and endothelial progenitor cells (EPCs) enhancing wound healing. In this study, ASCs and EPCs were applied to treat wounds in an animal wound model with a wound-healing assay. We knocked down PDGF-AA expression in ASCs using the PDGF-AA short hairpin RNA technique and investigated the related molecular mechanism. The wound model and wound-healing assay of the study showed that transplantation of ASCs could enhance wound healing. The results showed that the PDGF-AA knockdown ASC group had much less improvement of wound healing than other groups treated with wild-type ASCs in wound tissues. The regulation of PDGF-AA in ASCs may contribute to improve wound healing through the PI3K/Akt/eNOS signaling pathway. The data indicated that PDGF-AA might play a vital role in ASCs and EPCs enhancing wound healing, possibly by its effects on angiogenesis. It would be a potential approach using PDGF-AA for clinical treatment of chronic wounds.-Wu, L.-W., Chen, W.-L., Huang, S.-M., Chan, J. Y.-H. Platelet-derived growth factor AA is a substantial factor in the ability of adipose-derived stem cells and endothelial progenitor cells to enhance wound healing.

A static magnetic field inhibits the expression of platelet-derived growth factor-AA in human oral squamous cell carcinoma.

Magnetic attachments are commonly used for overdentures. The deleterious effects of exposure to magnetic flux on human health have not been substantiated so far; nevertheless, there is a need to understand the extent of magnetic field exposure in the oral area resulting from the use of magnetic attachments. The purpose of this study was to investigate the influence of a magnetic field on oral squamous cell carcinoma. Tumor cells cultured on a magnetic plate were compared with those not cultured on a magnetic plate (controls). The cells were seeded at a density of 1 × 105 cells/well and cultured for 6 days. The influence of the magnetic field on cytokine production was examined by cytokine array analysis. Secretion of platelet-derived growth factor-AA (PDGF-AA) was measured by enzyme-linked immunosorbent assay and Western blotting. The expression of PDGF-AA messenger RNA was examined by real-time polymerase chain reaction, whereas nuclear factor-kappa B activity was measured by luciferase assay. The results indicated that the magnetic field inhibited the secretion of PDGF-AA, thereby inhibiting PDGF-AA-induced expression, thus reducing the risk of cancer recurrence.

Expression and prognostic value of platelet‐derived growth factor‐AA and its receptor α in nephroblastoma

To investigate the potential role of platelet-derived growth factor-AA (PDGF-AA) and the PDGF-α receptor as prognostic markers in Wilms' tumour. The expression of PDGF-AA and PDGF-α were investigated using immunohistochemical analysis of 62 Wilms' tumours. Patients were treated with chemotherapeutic agents before surgery and had a mean follow-up of 6.4 years. PDGF-AA and PDGF-α were expressed by the mesenchymal tissue of the normal kidney and mainly detected in the epithelial component of Wilms' tumour. Immunoreactive tumour epithelium cells were found in 50% and 55% for PDGF-AA and PDGF-α, respectively. The epithelial expression of both PDGF-AA and PDGF-α correlated with pathological stage. Univariate analysis showed that epithelial PDGF-AA and PDGF-α receptor expression were indicative of clinical progression. In a multivariate analysis, PDGF-α protein expression by epithelial cells was an independent prognostic marker of a favourable prognosis. Expression of both PDGF-AA and PDGF-α in the epithelial part of Wilms' tumour correlated with tumour stage and clinical progression. Our data suggest that both PDGF-AA and PDGF-α receptor expression are related to prognosis.

Effects of Parenteral Fish‐Oil Emulsion (Omegaven) on Cutaneous Wound Healing in Rats Treated With Dexamethasone

The aim was to assess wound healing when parenteral fish-oil emulsion is given to rats receiving dexamethasone. For 5 days after skin wounding, group S (control; n = 7) received saline 1 mL/kg intraperitoneal (IP); group D (n = 7), dexamethasone 0.2 mg/kg IP; and group DO (n = 9), dexamethasone 0.2 mg/kg IP plus 1 mL/kg Omegaven (Fresenius Kabi, Austria). Wound specimens were assessed for hydroxyproline level, wound depth, histology (epidermal/dermal regeneration, granulation tissue thickness, and angiogenesis), and expression of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-AA (PDGF-AA). Compared with D and DO specimens, controls had higher hydroxyproline (p < .01), deeper wounds (p < .05), and better histologic scores (p < .01 angiogenesis; others p < .05). There were no significant differences between the group D and DO means for hydroxyproline level, wound depth, or histologic scores (p > .05 for all). Controls had higher TGF-beta expression scores than the other groups (p < .01 for both) and a higher PDGF-AA expression score than group DO (p < .01). Groups D and DO had statistically similar TGF-beta scores, but group D had a higher PDGF-AA score (2.71 +/- 0.75 vs 1.55 +/- 0.72, respectively; p < .05). According to the parameters we studied, adding parenteral omega-3 and omega-6 fatty acids to the nutrition regimen of rats treated with dexamethasone does not seem to have adverse effects on wound healing, and effects on wound healing may not need to be considered when determining if these agents should be supplemented in nutrition support regimens.

Platelet-Derived Growth Factor-AA Is an Essential and Autocrine Regulator of Vascular Endothelial Growth Factor Expression in Non–Small Cell Lung Carcinomas

It is widely accepted that angiogenesis is required for tumor progression. Vascular endothelial growth factor (VEGF) is a key molecule for tumor angiogenesis; however, its expressional regulation is not well understood during all stages of tumorigenesis. Using cell lines and surgical specimens of human non-small cell lung cancers (NSCLCs), we here show that platelet-derived growth factor-AA (PDGF-AA) is an essential autocrine regulator for VEGF expression. To directly assess the expression of PDGF-AA-dependent VEGF and its roles in tumorigenesis, we stably transfected established cell lines with their antisense genes. In addition, the levels of PDGF-AA and VEGF expression in surgical sections were measured and compared with clinicopathologic findings such as tumor size and patient prognosis. PDGF-AA tightly regulated VEGF expression and had a greater effect on tumor size and patient prognosis than did VEGF in both cell lines and surgical sections. PDGF-AA expression was not seen in the atypical adenomatous hyperplasia at all, whereas VEGF was occasionally seen. Furthermore, the frequency of VEGF expression was higher in advanced NSCLCs than in precancerous lesions, which was tightly correspondent to the results for PDGF-AA. These results indicate that PDGF-AA is an important regulator of the frequency and level of VEGF expression during the transition from a precancerous lesion to advanced cancer. The PDGF-AA/VEGF axis, therefore, may be a ubiquitous autocrine system for enhancing angiogenic signals, and PDGF-AA, and its related pathways could be a more efficient target of antiangiogenic therapy for cancers than VEGF and its pathways.

The role of platelet derived growth factor in endomyocardial biopsies shortly after heart transplantation in relation to postoperative course.

Platelet-derived growth factor (PDGF) plays an important role in structural alterations of blood vessels after heart transplantation (HTx). The aim of this study was to clarify the effect of peritransplant injury and postoperative complications on the expression of PDGF ligand and receptor. Right ventricular endomyocardial biopsies were collected from 46 patients before implantation, and then 1 and 2 weeks after HTx. According to the clinical course in the first postoperative year and to histopathological evaluation (based on the standardised 'International Society for Heart and Lung Transplantation' grading system) three groups were formed: (a) clinical uneventful course; (b) histologically and/or serologically proven cardiac or systemic infections; and (c) acute rejection episodes > or =grade 3A. Both, infections and rejections were detectable after the second postoperative week. The expression of PDGF AA/BB and PDGF receptors alpha/beta was examined immunohistochemically. The infiltrating cells were characterised by using monoclonal antibodies against CD3, CD4, CD8, CD57 and CD68. Only endothelial cells revealed a relevant expression of PDGF ligand and receptor. Prior to implantation there was no or only weak reactivity of single cells for all PDGF factors. One week after HTx a significantly increased immunoreactivity of all PDGF factors was observed in all groups. Two weeks after HTx the expression of PDGF AA in the infection group and the expression of all four PDGF factors in the rejection group remained significantly elevated. In contrast, in the group with an uneventful course there was no statistical difference in the expression of all the four PDGF factors. Compared with the uneventful group, there were significantly more CD3+ cells in the infection and rejection group at all three time points. Two weeks after HTx, the rejection group showed a significantly elevated number of CD3+ cells compared to the values before implantation. Two weeks after HTx there were significant more CD68+ cells in the infection and rejection group compared with before implantation. One week after HTx the peritransplant injury predominantly influences the endothelial expression of PDGF ligand and receptor. In the first postoperative week, expression of PDGF could be detected. The persistence of evaluated PDGF expression might be of prognostic value in terms of a risk for either infection or rejection. These patients should be carefully monitored.

Expression of Platelet-Derived Growth Factor-AA is Associated with Tumor Progression in Osteosarcoma

Platelet-derived growth factors are secreted by mesenchymal cells. The homodimer platelet-derived growth factor-AA especially stimulates bone cells through interaction with the platelet-derived growth factor-α receptor homodimer. In this study we wanted to determine the expression of the receptor and its ligand in human osteosarcomas and to correlate the expression of platelet-derived growth factor-AA and -α receptor with clinicopathological parameters. Fifty-seven osteosarcomas were immunohistochemically analyzed for expression of platelet-derived growth factor-AA and platelet-derived growth factor-α receptor. Spearman's correlation coefficient revealed a strong correlation between the expression of platelet-derived growth factor-AA and platelet-derived growth factor-α receptor (r = 0.867). No differences were observed relative to gender, age, tumor stage, tumor location, and response to neoadjuvant chemotherapy between high or low platelet-derived growth factor-AA and platelet-derived growth factor-α receptor expression. High platelet-derived growth factor-AA expression correlated with tumor progression in univariate analysis (P = .0415; log-rank test), whereas platelet-derived growth factor-α receptor expression showed a trend toward a shorter disease-free survival, which failed to reach significance (P = .0627, log-rank test). In multivariate analysis, platelet-derived growth factor-AA expression remained a significant independent predictor of tumor progression (P = .021, Cox regression). Immunohistochemical analysis of platelet-derived growth factor-AA expression in osteosarcoma may be a useful marker of prognosis and may be considered as a possible target for novel therapeutic strategies.

Induction of rat aortic smooth muscle cell growth by the lipid peroxidation product 4-hydroxy-2-nonenal.

Atherosclerotic lesion formation is a complex process, in part mediated by inflammatory and oxidative mechanisms including lipid peroxidation. To further characterize the potential role of lipid peroxidation products in atherogenesis, we studied the effects of 4-hydroxy-2-nonenal (HNE) on rat aortic smooth muscle cell growth. HNE, at concentrations of 1.0 and 2.5 micromol/L, significantly stimulated rat aortic smooth muscle cell growth as determined by cell counts, [3H]-thymidine uptake, and incorporation of bromo-deoxyuridine. To characterize the mechanism of HNE-induced mitogenesis, its effect on activation of intracellular growth signaling pathways was examined. Treatment with HNE resulted in activation of extracellular signal-regulated protein kinases ERK1 and ERK2, induction of c-fos and c-jun protein expression, and an increase in transcription factor AP-1 DNA binding activity. In addition, HNE induced expression of platelet-derived growth factor-AA (PDGF-AA) protein, and an anti-PDGF-AA antibody specifically inhibited HNE-mediated DNA synthesis, suggesting that growth factor induction may play a role in HNE-induced vascular smooth muscle cell growth. The role of redox-sensitive mechanisms in this process was further supported by the observation that HNE-induced DNA synthesis and AP-1 activation were inhibited by the antioxidants N-acetylcysteine and pyrrolidine dithiocarbamate. These data demonstrate that HNE, one of several important lipid peroxidation products, induces rat aortic smooth muscle cell growth through redox-sensitive mechanisms and growth factor expression. These observations are consistent with a role for lipid peroxidation products in vascular smooth muscle cell growth in atherogenesis.

Determination and expression of platelet-derived growth factor-AA in bone cell cultures

Determination and expression of platelet-derived growth factor-AA in bone cell cultures

Determination and expression of platelet-derived growth factor-AA in bone cell cultures.

We describe a sensitive technique for the extraction and quantitation of platelet-derived growth factor (PDGF)-AA in serum-free culture medium conditioned by fetal rat osteoblast-enriched (Ob) cells and demonstrate the expression of PDGF-A mRNA in Ob cells. Using C18 Sep-Pak chromatography with a methanol step gradient, we extracted immunoreactive PDGF-AA from the culture medium. A RIA protocol employing a recombinant human PDGF-AA standard enabled us to measure picomolar equivalents of PDGF-AA in Ob cell culture medium. The recovery of recombinant human PDGF-AA was 50 +/- 4%, and the coefficient of variation, including chromatographic extraction, was 15% for intraassay and 8.3% for interassay variability. The polyclonal antibody to recombinant human PDGF-AA displayed approximately 20-30% cross-reactivity with PDGF-AB, but did not bind PDGF-BB or other growth factors and cytokines known to be secreted by bone cells. Medium from Ob cells cultured for 24 h contained 0.9-1.3 pM human PDGF-AA equivalents, and exposure to cycloheximide (3.6 microM) decreased those levels by 65%. Treatment of cells with recombinant human transforming growth factor-beta 1 at 0.04-4 nM for 24 h increased PDGF-AA levels by up to 3.5-fold. Northern blot analysis of RNA from Ob cells revealed the expression of PDGF-A, but not PDGF-B, transcripts, and transforming growth factor-beta 1 at 0.04 and 0.2 nM increased steady state PDGF-A mRNA by 3- to 6-fold. Our studies describe a sensitive and reproducible technique for monitoring PDGF-AA levels in cell-conditioned medium and demonstrate that Ob cells synthesize PDGF-AA.