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Growth Factor Expression (growth + factor_expression)
Kinds of Growth Factor Expression Selected AbstractsNerve growth factor expression in parasympathetic neurons: regulation by sympathetic innervationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2000Wohaib Hasan Abstract Interactions between sympathetic and parasympathetic nerves are important in regulating visceral target function. Sympathetic nerves are closely apposed to, and form functional synapses with, parasympathetic axons in many effector organs. The molecular mechanisms responsible for these structural and functional interactions are unknown. We explored the possibility that Nerve Growth Factor (NGF) synthesis by parasympathetic neurons provides a mechanism by which sympathetic,parasympathetic interactions are established. Parasympathetic pterygopalatine ganglia NGF-gene expression was examined by in situ hybridization and protein content assessed by immunohistochemistry. Under control conditions, NGF mRNA was present in ,,60% and NGF protein was in 40% of pterygopalatine parasympathetic neurons. Peripheral parasympathetic axons identified by vesicular acetylcholine transporter-immunoreactivity also displayed NGF immunoreactivity. To determine if sympathetic innervation regulates parasympathetic NGF expression, the ipsilateral superior cervical ganglion was excised. Thirty days postsympathectomy, the numbers of NGF mRNA-positive neurons were decreased to 38% and NGF immunoreactive neurons to 15%. This reduction was due to a loss of sympathetic nerve impulse activity, as similar reductions were achieved when superior cervical ganglia were deprived of preganglionic afferent input for 40 days. These findings provide evidence that normally NGF is synthesized by parasympathetic neurons and transported anterogradely to fibre terminals, where it may be available to sympathetic axons. Parasympathetic NGF expression, in turn, is augmented by impulse activity within (and presumably transmitter release from) sympathetic axons. It is suggested that parasympathetic NGF synthesis and its modulation by sympathetic innervation provides a molecular basis for establishment and maintenance of autonomic axo-axonal synaptic interactions. [source] Effect of 1,,25-dihydroxyvitamin D3 in embryonic hippocampal cellsHIPPOCAMPUS, Issue 6 2010Francesca Marini Abstract Although the role of 1,,25-dihydroxyvitamin D3 in calcium homeostasis of bone tissue is clear, evidence of the involvement of vitamin D3 in the central nervous system functions is increasing. In fact, vitamin D3 regulates vitamin D receptor and nerve growth factor expression, modulates brain development, and reverses experimental autoimmune encephalomyelitis. Only few studies, however, address vitamin D3 effect on embryonic hippocampal cell differentiation. In this investigation, the HN9.10e cell line was used as experimental model; these cells, that are a somatic fusion product of hippocampal cells from embryonic day-18 C57BL/6 mice and N18TG2 neuroblastoma cells, show morphological and cytoskeletal features similar to their neuronal precursors. By this model, we have studied the time course of vitamin D3 localization in the nucleus and its effect on proteins involved in proliferation and/or differentiation. We found that the translocation of vitamin D3 from cytoplasm to the nucleus is transient, as the maximal nuclear concentration is reached after 10 h of incubation with 3H-vitamin D3 and decreases to control values by 12 h. The appearance of differentiation markers such as Bcl2, NGF, STAT3, and the decrease of proliferation markers such as cyclin-1 and PCNA are late events. Moreover, physiological concentrations of vitamin D3 delay cell proliferation and induce cell differentiation of embryonic cells characterized by modification of soma lengthening and formation of axons and dendrites. © 2009 Wiley-Liss, Inc. [source] Long-term treadmill exposure protects against age-related neurodegenerative change in the rat hippocampusHIPPOCAMPUS, Issue 10 2009Rachel M. O'Callaghan Abstract The potential of exercise or environmental enrichment to prevent or reverse age-related cognitive decline in rats has been widely investigated. The data suggest that the efficacy of these interventions as neuroprotectants may depend upon the duration and nature of the protocols and age of onset. Investigations of the mechanisms underlying these neuroprotective strategies indicate a potential role for the neurotrophin family of proteins, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). In this study, we have assessed the effects of 8 months of forced exercise, begun in middle-age, on the expression of long-term potentiation (LTP) and on spatial learning in the Morris water maze in aged Wistar rats. We also assessed these measures in a cage control group and in a group of rats exposed to the stationary treadmill for the same duration as the exercised rats. Our data confirm an age-related decline in expression of LTP and in spatial learning concomitant with decreased expression of NGF and BDNF mRNA in dentate gyrus (DG). The age-related impairments in both plasticity and growth factor expression were prevented in the long-term exercised group and, surprisingly, the treadmill control group. Given the extensive handling that the treadmill control group received and their regular exposure to an environment outside the home cage, this group can be considered to have experienced environmentally enriched conditions when compared with the cage control group. Significant correlations were observed between both learning and LTP and the expression of NGF and BDNF mRNA in the dentate gyrus. We conclude that decreased expression of NGF and BDNF in the dentate gyrus of aged rats is associated with impaired LTP and spatial learning. We suggest that the reversal of these age-related impairments by enrichment and exercise may be linked with prevention of the age-related decline in expression of these growth factors and, furthermore, that enrichment is as efficacious as exercise in preventing this age-related decline. © 2009 Wiley-Liss, Inc. [source] Induction of vascular endothelial growth factor expression in human pulp fibroblasts stimulated with black-pigmented BacteroidesINTERNATIONAL ENDODONTIC JOURNAL, Issue 9 2004L.-C. Yang Abstract Aim, To investigate the effect of black-pigmented Bacteroides on the expression of vascular endothelial growth factor (VEGF) gene in human pulp fibroblasts. Methodology, The supernatants of Porphyromonas endodontalis, Porphyromonas gingivalis and Prevotella intermedia were used to evaluate VEGF gene expression in human pulp fibroblasts. The levels of mRNAs were measured by the quantitative reverse-transcriptase polymerase chain reaction analysis. Results, Black-pigmented Bacteroides induced significantly high levels of VEGF mRNA gene expression in human pulp fibroblasts (P < 0.05). In addition, the expression of VEGF depended on the bacteria tested. Conclusions, Black-pigmented Bacteroides may be involved in developing pulpal disease through the stimulation of VEGF production that would lead to the expansion of the vascular network coincident to progression of the inflammation. [source] Tenascin-C regulates angiogenesis in tumor through the regulation of vascular endothelial growth factor expressionINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Keiichiro Tanaka Abstract In order to verify whether tenascin-C (TN-C) is involved in angiogenesis as an extracellular signal molecule during tumorigenesis, cancerous cell transplantation experiments and coculture experiments were carried out, focusing on the regulation of vascular endothelial growth factor (VEGF). The A375 human melanoma cells introduced the GFP gene (A375-GFP), implanted subcutaneously into BALB/cA nude (WT) and TN-C knockout BALB/cA nude (TNKO) congenic mice. Furthermore, coculture experiments between A375-GFP and embryonic mesenchyme, which was prepared from both genotypes, were carried out to investigate the molecular mechanism in the cell-cell interactions. Both the content of TN-C and that of VEGF in the tumor and the conditioned medium were analyzed by the sandwich ELISA method. Seven days after transplantation of the A375-GFP, capillary nets became far more abundant in the tumors grown in WT mice than those in TNKO mice. Interestingly, VEGF and TN-C expressions showed antithetical expression patterns between the tumors in WT mice and those in TNKO mice. This peculiar phenomenon seems to be caused by a time lag prior to the onset of the mesenchymal regulation for the TN-C expression of A375-GFP. The coculture experiments revealed that WT mesenchyme had a much stronger effect than TNKO mesenchyme on both TN-C and VEGF expression. However, the defects of TNKO mesenchyme were restored in all cases by additional TN-C. These results clearly indicated that the expressions of both TN-C and VEGF depend on the surrounding mesenchyme, and that the function of mesenchyme is regulated by its own mesenchymal TN-C. In conclusion, the present data suggest that the matrix microenvironment organized by the host mesenchyme is very important for angiogenesis in tumor development. © 2003 Wiley-Liss, Inc. [source] Effects of sevoflurane on collagen production and growth factor expression in rats with an excision woundACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2010H.-J. LEE Background: Sevoflurane is a widely used inhalation anesthetic, but there are no studies on its effect on the wound-healing process. This study was undertaken to evaluate the effect of exposure time to sevoflurane on wound healing. Method: Male Sprague,Dawley rats were used. Two circular full-thickness skin defects 8 mm in diameter were made on the dorsum of the rats. The animals were divided into six groups according to exposed gas type and time: S1 (sevoflurane, 1 h), S4 (sevoflurane, 4 h), S8 (sevoflurane, 8 h), O1 (oxygen, 1 h), O4 (oxygen, 4 h), and O8 (oxygen, 8 h). The surface area of the wounds was measured 0, 1, 3, and 7 days after surgery. Separately, the mean blood pressures (MBP) and arterial oxygen pressures (PaO2) were monitored during the sevoflurane exposure. Collagen type I production and transforming growth factor-,1 (TGF-,1) and basic fibroblast growth factor (bFGF) expression on the wound surface were analyzed. Routine histological analysis was also performed. Result: Exposure duration to sevoflurane had no influence on MBP and PaO2. The reduction in wound size and collagen type I production was delayed in S8. The expression of TGF-,1 and bFGF on the wound surface in S8 was significantly attenuated in S8. The histology of the S8 demonstrated a delayed healing status. Conclusions: Prolonged exposure to sevoflurane might alter the inflammatory phase of the wound-healing process by attenuation of growth factor expression such as TGF-,1 and bFGF and subsequently by reduced collagen production. [source] Overexpression of c-H-ras p21 is correlated with vascular endothelial growth factor expression and neovascularization in advanced gastric carcinoma ,JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2000Young-Bae Kim Abstract Background and Aims ras Gene and its product (p21) have been reported to be associated with vascular endothelial growth factor (VEGF), which is one of the most important angiogenic factors, and tumor-associated angiogenesis. We tried to evaluate the correlation between the expression of c-H-ras gene product p21 and angiogenesis in advanced gastric carcinoma. Methods Immunohistochemical expression of c-H-ras p21 and VEGF was examined in 49 advanced gastric adenocarcinomas. In addition, double immunohistochemical staining was performed using anti-CD34 and anti-Ki-67 antibodies, and the intratumoral microvessel densities and their endothelial proliferative labeling indices were then counted to evaluate the degree of angiogenesis. Results The expression of c-H-ras p21 was demonstrated in 43 out of 49 gastric adenocarcinomas (87.8%). It did not correlate with histologic type, depth of invasion or metastasis. However, the degree of c-H-ras p21 expression was correlated with VEGF. In addition, the degree of c-H-ras p21 expression was correlated with increased intratumoral microvascular density and endothelial proliferative activity. Conclusions We suggest that c-H-ras oncogene product p21 contributes to the upregulation of tumor-associated angiogenesis by the increased production of VEGF in advanced gastric carcinomas. Therefore, treatment involving the targeting of ras oncogene could inhibit solid tumor growth by suppressing tumor-associated angiogenesis. [source] Cyclic GMP phosphodiesterase inhibition alters the glial inflammatory response, reduces oxidative stress and cell death and increases angiogenesis following focal brain injuryJOURNAL OF NEUROCHEMISTRY, Issue 3 2010Paula Pifarré J. Neurochem. (2010) 112, 807,817. Abstract Recent evidence obtained in cultured glial cells indicates that cGMP-mediated pathways regulate cytoskeleton dynamics, glial fibrillary acidic protein expression and motility in astrocytes, as well as inflammatory gene expression in microglia, suggesting a role in the regulation of the glial reactive phenotype. The aim of this work was to examine if cGMP regulates the glial inflammatory response in vivo following CNS damage caused by a focal cryolesion onto the cortex in rats. Results show that treatment with the cGMP phosphodiesterase inhibitor zaprinast (10 mg/kg i.p.) 2 h before and 24 and 48 h after the lesion results 3 days post-lesion in notably enhanced astrogliosis manifested by increased glial fibrillary acidic protein immunoreactivity and protein levels around the lesion. In contrast, zaprinast decreased the number of round/ameboid lectin-positive cells and the expression of the activated microglia/macrophage markers Iba-1 and CD11b indicating decreased recruitment and activation of these cells. This altered inflammatory response is accompanied by a decrease in protein oxidative stress, apoptotic cell death and neuronal degeneration. In addition, zaprinast enhanced angiogenesis in the lesioned cortex probably as a result of vascular endothelial growth factor expression in reactive astrocytes. These results suggest that regulation of the glial inflammatory response may contribute to the reported neuroprotective effects of cGMP-phosphodiesterase inhibitors in brain injury. [source] A novel inducible tyrosine kinase receptor to regulate signal transduction and neurite outgrowthJOURNAL OF NEUROSCIENCE RESEARCH, Issue 12 2009Ronald W. Alfa Abstract Nervous system growth factor gene delivery can promote axonal growth and prevent cell death in animal models of CNS trauma and neurodegenerative diseases. The ability to regulate growth factor expression or signaling pathways downstream from growth factor receptors remains a desirable goal for in vivo gene transfer. To achieve precise pharmacological modulation of neurotrophin activity, we have generated a chimeric trkA receptor (ItrkA) by fusing the entire intracellular domain of the trkA high-affinity NGF receptor to two intracellular, modified FK506 binding domains for the synthetic small molecule dimerization ligand AP20187. Rat PC12 cells were transduced with lentiviral vectors containing ItrkA and green fluorescent protein (GFP; via an internal ribosome entry site). Treatment of ItrkA-expressing PC12 cells with AP20187 induced neurite outgrowth and differentiation in a time- and dose-dependent fashion, with a half-maximal response at a concentration of 1 nM AP20187. Seventy percent of cells responded to AP20187 by day 3. Western blots demonstrated that AP20187 treatment resulted in phosphorylation of Erk1/2 and Akt in ItrkA-transduced PC12 cells but not in nontransduced, naïve cells. Phosphorylation levels were comparable to levels obtained with 50 ng/ml nerve growth factor (NGF). In addition, ItrkA lentiviral transduction of primary E15 dorsal root ganglion neurons significantly increased neurite growth three- to fourfold in the presence of AP20187 compared with control GFP transduced and naïve neurons. These results demonstrate that small ligand-induced dimerization of the intracellular domain of trkA can efficiently simulate the biological activity of NGF and provide a means to regulate intracellular neurotrophin receptor signaling. © 2009 Wiley-Liss, Inc. [source] Correlation of basic fibroblast growth factor expression with the invasion and the prognosis of oral squamous cell carcinomaJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 3 2006Takashi Hase Background:, The aim of this study was to evaluate the relationship between the expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) in cancer cells and fibroblasts at the invasive front of oral squamous cell carcinoma (OSCC), and the pathologic and clinical characteristics. Methods:, Sections of 61 biopsy specimens of primary OSCC were immunostained to assess the expression of bFGF and FGFR-1 in cancer cells and fibroblasts at the invasive front. Results:, The bFGF and FGFR-1 expressions in the cancer cells were evident in all specimens, whilst, in fibroblasts, they were detected in 41 (67%) of 61 specimens. These expressions in the fibroblasts occurred notably more often in high-invasive OSCC specimens than low-invasive OSCC specimens. The prevalence of bFGF and FGFR-1 expressions in cases with lymph node metastasis was significantly higher (P < 0.05) than in cases without metastasis. Moreover, these expressions were well correlated with patient prognosis. Conclusion:, This study concludes that bFGF and FGFR-1 expressions in fibroblasts at the invasive front are linked to the mode of invasion and the prognosis in OSCC. [source] Effect of ketoprofen in topical formulation on vascular endothelial growth factor expression and tumor growth in nude mice with osteosarcomaJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2004Kenshi Sakayama Abstract OST cells, a low metastatic cell line established from human osteosarcoma, were inoculated under the periosteum of the ossa cranii of nude mice. Four weeks later, tumors were percutaneously treated for an additional 4 weeks with a patch containing either placebo or ketoprofen (KP). In the placebo group, OST cells formed osteoid and invaded the cranial bone. Tumor mass weighed 3.54 g. Approximately 85% of cells within the tumor expressed proliferating cell nuclear antigen (PCNA), indicating that they were proliferating with a high mitotic activity. Many feeder vessels were located within the tumor. The majority of tumor cells expressed intensely vascular endothelial growth factor (VEGF). In the KP group, invasion of OST cells into the cranial bone was suppressed and the tumor mass was 47% of that of the placebo group. Approximately 65% of cells within the tumor were PCNA-negative, indicating that their growth was arrested. There were considerably fewer feeder vessels within the tumor in the KP group than in the placebo group. Only a small number of cells expressed VEGF. Based on these findings, we concluded that topical administration of KP to nude mice with osteosarcoma inhibited VEGF expression, reduced the development of feeder vessels for supply of nutrients and oxygen, and suppressed tumor growth. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source] Expression of cyclooxygenase-2 in primary and remnant gastric carcinoma: Comparing it with p53 accumulation, Helicobacter pylori infection, and vascular endothelial growth factor expressionJOURNAL OF SURGICAL ONCOLOGY, Issue 2 2002Atsushi Kawabe MD Abstract Background and Objectives Cyclooxygenase-2 (COX-2) expression may contribute to the synthesis of prostanoids, which have been related to carcinogenesis and tumor progression. It is well known that the gastric remnant is at greater risk of the development of gastric cancer than is the whole stomach; incidence rates for gastric cardia adenocarcinoma are rising in the United States and Europe. Our objective was to determine the involvement of COX-2 in primary and remnant gastric cancer tissues as well as in adjacent noncancerous mucosa. Methods We investigated the expression of COX-2 in 91 human gastric cancer tissue and adjacent noncancerous mucosa samples (40 remnant gastric cancer, 37 gastric cardia cancer, and 14 gastric corpus and antrum cancer), using immunohistochemistry. In addition, p53 expression, Helicobacter pylori infection, and vascular endothelial growth factor in the tissues were evaluated by immunohistochemical staining and compared with COX-2 expression. Results There were no significant differences in clinicopathological data in the gastric cancer tissues. There was a significant relation between the expression of COX-2 and p53 in gastric cancer tissues (P,=,0.0048). However, vascular endothelial growth factor expression and Helicobacter pylori infection showed no correlation with the expression of COX-2. In the case of adjacent noncancerous mucosa, the positive rate of COX-2 expression was significantly higher in the remnant gastric cancers (75.0%) than in the primary gastric cancers (25.5%) (P,<,0.0001). Conclusions This information may help in the analysis of the carcinogenesis of gastric cancer; there is also a possibility that the COX-2 selective inhibitor to the remnant gastric cancer has a chemopreventive effect. J. Surg. Oncol. 2002;80:79,88. © 2002 Wiley-Liss, Inc. [source] Cyclic acetal hydroxyapatite composites and endogenous osteogenic gene expression of rat marrow stromal cellsJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 6 2010Minal Patel Abstract In this study, bone marrow stromal cells (BMSCs) were differentiated on cyclic acetal composites containing hydroxyapatite (HA) particles (110 or 550 nm). These composites were evaluated for their role in influencing osteogenic signalling by encapsulated BMSCs. While a number of factors exert influence on osteogenic signalling during the production of an osteogenic matrix, we hypothesize that HA particles may upregulate bone growth factor expression due to enhanced BMSC adhesion. To this end, fluorescence-activated cell sorting (FACS) analysis was performed for the evaluation of BMSC surface marker expression after culture on two-dimensional (2D) cyclic acetal/HA composites. Three-dimensional (3D) composites were then fabricated by incorporating 110 or 550 nm HA particles at 5, 10 and 50 ng/ml concentrations. Bone growth factor molecules (TGF,1, FGF-2 and PDGFa), bone biomarker molecules (ALP, OC, OPN and OCN) and extracellular matrix-related molecules (FN, MMP-13, Dmp1 and aggrecan) were selected for evaluation of osteogenic signalling mechanisms when in presence of these composites. FACS results at day 0 demonstrated that BMSCs were a heterogeneous population with a small percentage of cells staining positive for CD29, CD90 and CD51/61, while staining negative for CD34 and CD45. At day 3, a significant enrichment of cells staining strongly for CD29, CD90 and CD51/61 was achieved. Gene expression patterns for bone growth factors and extracellular matrix molecules were found to be largely dependent upon the size of HA particles. Bone marker molecules, except OCN, had unaltered expression patterns in response to the varied size of HA particles. Overall, the results indicate that larger-sized HA particles upregulate PDGF and these groups were also associated with the most significant increase in osteodifferentiation markers, particularly ALP. Our results suggest that endogenous signalling is dependent upon material properties. Furthermore, we propose that studying gene expression patterns induced by the surrounding biomaterials environment is a fundamental step in the creation of engineered tissues. Copyright © 2010 John Wiley & Sons, Ltd. [source] Age-dependent vascular endothelial growth factor expression and angiogenic capability of bladder smooth muscle cells: implications for cell-seeded technology in bladder tissue engineeringJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 8 2009Joseph Azzarello Abstract Cell seeding technology is commonly used in the field of tissue engineering to enhance the performance of bioscaffolds and promote tissue regeneration. The age of cells used for ex vivo seeding to achieve maximal tissue regeneration has not been defined. Since rapid angiogenesis is the most critical step for tissue graft survival and success, we evaluated passage-dependent vascular endothelial growth factor (VEGF) expression in cultured smooth muscle cells (SMCs) obtained from urinary bladder and endothelial cell response to bladder SMCs. Levels of various VEGF isoforms mRNA expression and total VEGF secretion were determined by a semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA) analysis, respectively. In vitro endothelial cell migration in Transwell® and capillary-like tube formation in MatrigelÔ were used to predict the ability of bladder SMCs to promote angiogenesis. VEGF produced by cultured bladder SMCs increased from passages 4 to 7, and decreased from passages 7 to 12 at both mRNA and protein levels. Endothelial cell migration as well as capillary-like tube formation correlated with levels of VEGF expression by bladder SMCs. Pre-incubation of endothelial cells with a VEGF receptor 1/2 inhibitor, SU5416, significantly reduced the number of capillary-like tubes in SMC-endothelial cell MatrigelÔ co-culture, and confirmed the involvement of VEGF in endothelial cell tube formation. Our results demonstrate that cell passage number is related to levels of VEGF production, which may translate to angiogenesis in engineered tissues. Copyright © 2009 John Wiley & Sons, Ltd. [source] Hypoxia-inducible factor-1 alpha and vascular endothelial growth factor expression in ischaemic colitis and ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2006T. OKUDA Summary Background Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcriptional factor induced by ischaemic crisis in many tissues. Vascular endothelial growth factor (VEGF) is an important growth factor that plays a major role in angiogenesis. Aim We examined the aetiology and pathophysiology of human ischaemic colitis and ulcerative colitis from the viewpoint of the expression of these two ischaemic factors. Methods Thirty-two patients with ischaemic colitis, 16 with ulcerative colitis and 25 normal controls underwent colonoscopy. Biopsy samples were taken from a colitis lesion and a normal region in the same patient. In the normal controls, four biopsy samples were obtained from each subject. Biopsy samples were subjected to real-time polymerase chain reaction. Results Hypoxia-inducible factor and VEGF were overexpressed in ischaemic colitis lesions and quickly decreased to normal levels in the healing phase. In contrast, HIF but not VEGF was overexpressed in active ulcerative colitis lesions. In the remission phase of ulcerative colitis, VEGF decreased to low levels, although HIF was continuously overexpressed. Conclusions Overexpression of HIF and VEGF contribute to the tolerance of ischaemia in patients with active ischaemic colitis. The inconsistency in their expression might be associated with the chronic intestinal damage characteristic of ulcerative colitis. [source] Selective cyclooxygenase-2 inhibition suppresses basic fibroblast growth factor expression in human esophageal adenocarcinomaMOLECULAR CARCINOGENESIS, Issue 12 2007Mark Baguma-Nibasheka Abstract Inhibition of cyclooxygenase (COX)-2 is reported to suppress growth and induce apoptosis in human esophageal adenocarcinoma (EADC) cells, although the precise biologic mechanism is unclear. In this study we tested the hypothesis that the antitumor activity of COX-2 inhibitors may involve modulation of basic fibroblast growth factor (FGF-2), which is overexpressed in EADC. We evaluated the effects of NS-398, a selective COX-2 inhibitor, on FGF-2 expression and proliferation of EADC cell lines that express COX-2 and those that do not. We also correlated COX-2 and FGF-2 expression with clinico-pathologic findings and outcome in a well-characterized series of surgically resected EADC tissues. Seg-1 cells robustly expressed COX-2 and FGF-2, whereas Bic-1 cells expressed neither transcript. FGF-2 was reduced to undetectable levels in Seg-1 cells following NS-398 treatment, but increased within 4 h of drug removal. NS-398 significantly inhibited the growth of Seg-1 cells, and this effect was ameliorated by addition of exogenous FGF-2. In contrast, NS-398 had no effect on Bic-1 cell proliferation and FGF-2 alone had no effect on proliferation of either cell line. NS-398, or a neutralizing anti-FGF-2 antibody, induced apoptosis in Seg-1 cells, and these effects were inhibited by addition of exogenous FGF-2. COX-2 protein was strongly expressed in 46% (10/22) of EADCs, and was associated with a trend towards reduced disease-free survival. These findings indicate that the antitumor effects of COX-2 inhibition in EADC cells may be mediated via suppression of FGF-2, and that COX-2 may be a clinically relevant molecular marker in the management of human EADC. © 2007 Wiley-Liss, Inc. [source] Tumor cell-associated neuropilin-1 and vascular endothelial growth factor expression as determinants of tumor growth in neuroblastomaNEUROPATHOLOGY, Issue 3 2005Karen Marcus We sought to characterize the expression of vascular endothelial growth factor (VEGF) and its receptors in neuroblastoma (NBL) and to correlate the results with N-myc (MYCN) expression and in vivo growth of these tumors. Two representative human-derived NBL cell lines, SK-N-AS (AS) with low and SK-N-DZ (DZ) with a high MYCN copy number, were used for the study. We examined their proliferation, VEGF and VEGF receptor expression in vitro and xenograft tumor growth in vivo. In parallel, human NBL specimens were analyzed for expression of VEGF and neuropilin-1 (NRP-1). DZ cells exhibited a 4-fold higher proliferation rate than AS. In contrast, VEGF protein expression was significantly higher in AS cells. NRP-1 was the only VEGF receptor produced in AS and DZ cells in vitro and in vivo. Both AS and DZ cells formed tumors in athymic mice but AS tumors grew 3.5 times larger than DZ tumors and had larger diameter tumor vessels. VEGF and NRP-1 expression was also demonstrated in human NBL specimens. Our studies indicate that VEGF and VEGF receptor expression in NBL tumor cells are associated with tumor growth and that angiogenic factors may serve as a biological marker together with already established MYCN amplification. [source] Vascular endothelial growth factor expression in oligodendrogliomas: a correlative study withSainte-Anne malignancy grade, growth fractionand patient survivalNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2000P. Varlet Microangiogenesis is a delayed but crucial event in the malignant progression of oligodendrogliomas. Accord-ingly, in the new Sainte-Anne grading system of oligodendrogliomas, endothelial hyperplasia and contrast enhancement, both being indicators of microangiogenesis, are key criteria for the distinction of grade A from grade B tumours. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor: a strong correlation between VEGF expression, Sainte-Anne malignancy grade and patient outcome might thus be expected. In order to assess this hypothesis, VEGF immunostaining was performed in a series of 34 oligodendrogliomas that included 11 grade B and 23 grade A, of which nine became grade B during the study period (mean clinical and imaging follow-up: 41 months). VEGF expression correlated strongly with Sainte-Anne tumour grade (P < 0.001), and inversely with patient survival (P < 0.001) and recurrence-free survival (P = 0.002). One hundred per cent of grade B but only 17% of grade A were VEGF-positive. By contrast, the MIB-1 labelling index did not correlate with VEGF expression, total survival or recurrence-free survival. In accordance with the grading system, this study showed that, in oligodendrogliomas, VEGF expression and microangiogenesis are progression-related phenomena that confer on these tumours a growth advantage by presumably reducing hypoxia-induced apoptotic cell death. These findings might have important implications in the future for the indication and timing of anti-angiogenic therapies. [source] Association of hepatocyte growth factor expression with salivary gland tumor differentiationPATHOLOGY INTERNATIONAL, Issue 12 2003Keiichi Tsukinoki To clarify the significance of hepatocyte growth factor (HGF) expression in salivary gland tumors, HGF distribution in tissue sections and HGF concentrations in saliva and serum were examined. Sixty salivary gland adenomas, 61 salivary gland carcinomas and three autopsy fetuses were studied. Hepatocyte growth factor expression was observed in the duct-type luminal cells by immunohistochemical staining and in situ hybridization. However, HGF failed to be expressed in acinar cells and myoepithelium of normal salivary gland tissue. Hepatocyte growth factor tended to be expressed more intensely in benign salivary gland tumors than in malignant salivary gland tumors (P < 0.0001). In highly malignant tumors, the expression was limited in some cases. Salivary and serological HGF concentrations of 18 patients, comprised of 12 benign cases and six malignant cases, were analyzed before and after operation by an ELISA system. The concentrations were distinctly elevated after operation, in both saliva and serum, compared to before operation (P < 0.0005). However, there were no significant relationships between HGF concentration and histology, age, gender, size or location. Our findings suggest that HGF may play an important role in the development of salivary ducts of normal salivary tissues and differentiation of ductal structures of their neoplasms, while HGF kinetics in saliva and serum would be less likely to reflect the neoplastic character, benign or malignant. [source] Placental Anomalies in Children with Infantile HemangiomaPEDIATRIC DERMATOLOGY, Issue 4 2007Juan Carlos López Gutiérrez M.D., Ph.D. We investigated the pathogenic significance of placental features and their relationship to the development of infantile hemangioma in order to obtain a better understanding of its cause. Placental specimens were reviewed from 26 singleton pregnancies of women whose offspring weighed less than 1500 g. A group of 13 neonates who developed infantile hemangioma in the immediate neonate period were compared with 13 healthy preterm infants of comparable postconception age who had no infantile hemangioma. Pathologic placental changes were analyzed in both groups. Gross lesions with disturbance of the utero-placental circulation were found in all placentas from children who developed infantile hemangioma, including massive retroplacental hematoma in two infants, extensive ischemic infarction in seven, and large dilatated vascular communications, severe vasculitis, chorioamnionitis and funiculitis in four. Placental features included percentages greater than 25% of avascular villi, platelet and fibrin aggregates, and multifocal disease involving more than one histologic section. Examination of 13 placentas of low-birth-weight infants without infantile hemangioma only showed abnormal placentation in one and isolated villous dismaturity in two. The higher ratio of placental pathologic findings in patients with infantile hemangioma suggests that reduced placental oxygen diffusive conductance contributes to fetal hypoxic stress and that hypoxic/ischemic changes in the placenta could be related to infantile hemangioma development via vascular endothelial growth factor and placental growth factor expression, among others, within the villious vessels and throphoblasts. [source] Epithelial,mesenchymal interactions in keloid pathogenesis modulate vascular endothelial growth factor expression and secretion,THE JOURNAL OF PATHOLOGY, Issue 1 2007CT Ong Abstract Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis during the wound healing process. As epithelial,mesenchymal interactions have been shown to regulate a plethora of genes in wound healing, we hypothesized that these interactions might have a role in modulating VEGF expression and angiogenesis. A two chamber co-culture model was used, wherein normal and keloid keratinocytes and fibroblasts were physically separated by membrane inserts while allowing cytokine diffusion. Cell lysates obtained from keratinocytes co-cultured with fibroblasts demonstrated increased expression of VEGF. An enzyme-linked immunosorbent assay (ELISA) showed significant increase in VEGF expression in co-culture conditioned media compared with controls. Additionally, the conditioned medium from keloid keratinocyte and fibroblast co-cultures increased proliferation and formation of complex three-dimensional capillary-like structures in human umbilical vein endothelial cells, emphasising the importance of epithelial,mesenchymal interactions in the angiogenic process. Immunostaining of keloid tissue localized VEGF in the basal layer of the epidermis and also demonstrated higher blood vessel density than normal skin. Keloid tissue extract also demonstrated increased expression of VEGF compared with normal skin. It is likely that epidermal VEGF exerts significant paracrine control over the dynamics and expression profile of underlying dermal fibroblasts. Addition of the inhibitors WP631, mitoxantrone, and Rapamycin to keloid keratinocyte and fibroblast co-cultures, downregulated secreted VEGF expression in a dose-dependent manner, suggesting therapeutic potential for these compounds in the treatment of keloid scars. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Rhinovirus upregulates matrix metalloproteinase-2, matrix metalloproteinase-9, and vascular endothelial growth factor expression in nasal polyp fibroblastsTHE LARYNGOSCOPE, Issue 9 2009Jong Hwan Wang MD Abstract Objectives/Hypothesis: Upregulation of matrix metalloproteinase (MMP) and vascular endothelial growth factor (VEGF) has been suggested to have an important role in the pathogenesis of nasal polyps (NPs). The aim of this study was to investigate the effect of rhinovirus (RV) infection on the expression of MMPs, tissue inhibitor of metalloproteinase (TIMP)-1, and VEGF in NP fibroblasts. Methods: NP fibroblasts (5 × 105 cells/mL) obtained from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) were infected with RV serotype 16 (RV-16) for 4 hours. The RV-16 infection was confirmed by seminested reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization. After 48 hours, MMP-2, MMP-9, TIMP-1, and VEGF protein levels were measured from culture supernatants by enzyme-linked immunosorbent assay. The changes in the expression of MMP-2, MMP-9, TIMP-1, and VEGF mRNA were assayed by RT-PCR. Results: RV-16 infection significantly enhanced the gene and protein expressions of MMP-2, MMP-9, and VEGF in NP fibroblasts, whereas TIMP-1 expression was not significantly affected by RV-16. MMP-2, MMP-9, and VEGF protein expression increased by 2.39-, 2.99-, and 3.02-fold, respectively, in RV-infected NP fibroblasts compared to noninfected controls. RV-16 infection also significantly upregulated the expression of MMP-2, MMP-9, and VEGF mRNA by 1.27-, 1.70-, and 1.53-fold, respectively, compared to control levels. Conclusions: These in vitro findings suggest that RV infection may contribute to the pathogenesis of NP formation in patients with CRSwNP. Laryngoscope, 2009 [source] Effect of Antibodies on EndotheliumAMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2009X. Zhang Patients developing posttransplant antibodies against HLA and non-HLA antigens expressed by the endothelium of the graft undergo more frequent episodes of rejection and have decreased long-term graft survival. Antibodies against the endothelium can alter/damage the cells of the graft through several mechanisms. Historically, antibodies were thought to elicit endothelial cell injury via complement-dependent mechanisms. New research has shown that antibodies can also contribute to the process of transplant rejection by stimulating proinflammatory and proproliferation signals. Antibody ligation leads to several functional alterations in EC including Weibel Palade body exocytosis, leukocyte recruitment, growth factor expression and cell proliferation. In contrast, under certain circumstances, antibodies may induce prosurvival signals and graft accommodation. The signaling events regulating accommodation vs. rejection appear to be influenced by the specificity and concentration of the anti-HLA antibody and the degree of molecular aggregation. Knowledge of the HLA and non-HLA antibody-mediated signaling pathways has the potential to identify new therapeutic targets to promote accommodation and prevent acute and chronic antibody-mediated rejection. [source] Experimental ischaemia-reperfusion injury induces vascular endothelial growth factor expression in the rat testisANDROLOGIA, Issue 4 2009H. Hashimoto Summary Testicular torsion causes ischaemia-reperfusion (I-R) injury of testis and might lead to male infertility. Its injury initiates a pathophysiological cascade, including an activation of inflammatory cytokines and generation of nitric oxide and other reactive oxygen species. Vascular endothelial growth factor (VEGF) mediates angiogenesis and promotes endothelial cell survival. The aim of our study was to investigate the time course expression of VEGF, VEGF-receptor (R)1, VEGF-R2, nitric oxide synthases (NOS) in experimental I-R injury of rat testis. In torsion side testis, the expression of VEGF protein and mRNA significantly increased in a time-dependent manner (P < 0.001 and P < 0.001, respectively). Although the expression of VEGF-R1 mRNA was increased in a similar way (P < 0.001), VEGF-R2 mRNA expression was not detected. In immunohistochemistry, the increase in VEGF protein staining was observed in testicular vascular endothelial cells and germ cells at 24 h after reperfusion. Significant activation of inducible NOS and endothelial NOS was investigated at 12 and 24 h after reperfusion (P < 0.01 and P < 0.001, respectively). This is the first report to show the time course expression of VEGF in experimental I-R rat testis. [source] Hypoxia-inducible factor-1, expression in experimental cirrhosis: correlation with vascular endothelial growth factor expression and angiogenesis,APMIS, Issue 7 2007SEVGI BOZOVA Angiogenesis progresses together with fibrogenesis during chronic liver injury. Hypoxia-inducible factor-1, (HIF-1,), a master regulator of homeostasis, plays a pivotal role in hypoxia-induced angiogenesis through its regulation of vascular endothelial growth factor (VEGF). The association between hypoxia, angiogenesis and VEGF expression has been demonstrated in experimental cirrhosis. However, expression of HIF-1, has yet to be reported. The aim of this study was to investigate the significance of HIF-1, expression during experimental liver fibrosis and the relationships between HIF-1, expression, VEGF expression and angiogenesis. Cirrhosis was induced in male Wistar rats by intraperitoneal administration of diethyl nitrosamine (DEN) (100 mg/kg, once a week). The serial sections from liver tissues were stained with anti-HIF-1,, anti-VEGF and anti-CD34 antibodies before being measured by light microscopy. Our results showed that HIF-1, expression gradually increases according to the severity of fibrosis (p<0.01). Moreover, its expression was found to be correlated with angiogenesis (r=0.916) and VEGF expression (r=0.969). The present study demonstrates that HIF-1, might have a role in the development of angiogenesis via regulation of VEGF during experimental liver fibrogenesis and suggests that this factor could be a potential target in the manipulation of angiogenesis in chronic inflammatory diseases of the liver. [source] Regulation of CCN2/Connective tissue growth factor expression in the nucleus pulposus of the intervertebral disc: Role of Smad and activator protein 1 signalingARTHRITIS & RHEUMATISM, Issue 7 2010Cassie M. Tran Objective To investigate transforming growth factor , (TGF,) regulation of connective tissue growth factor (CTGF) expression in cells of the nucleus pulposus of rats, mice, and humans. Methods Real-time reverse transcription,polymerase chain reaction and Western blot analyses were used to measure CTGF expression in the nucleus pulposus. Transfections were used to measure the effects of Smads 2, 3, and 7 and activator protein 1 (AP-1) on TGF,-mediated CTGF promoter activity. Results CTGF expression was lower in neonatal rat discs than in skeletally mature rat discs. An increase in CTGF expression and promoter activity was observed in rat nucleus pulposus cells after TGF, treatment. Deletion analysis indicated that promoter constructs lacking Smad and AP-1 motifs were unresponsive to treatment. Analysis showed that full-length Smad3 and the Smad3 MH-2 domain alone increased CTGF activity. Further evidence of Smad3 and AP-1 involvement was seen when DN-Smad3, SiRNA-Smad3, Smad7, and DN-AP-1 suppressed TGF,-mediated activation of the CTGF promoter. When either Smad3 or AP-1 sites were mutated, CTGF promoter induction by TGF, was suppressed. We also observed a decrease in the expression of CTGF in discs from Smad3-null mice as compared with those from wild-type mice. Analysis of human nucleus pulposus samples indicated a trend toward increasing CTGF and TGF, expression in the degenerated state. Conclusion TGF,, through Smad3 and AP-1, serves as a positive regulator of CTGF expression in the nucleus pulposus. We propose that CTGF is a part of the limited reparative response of the degenerated disc. [source] Tumour growth following portal branch ligation in an experimental model of liver metastases,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 6 2010O. Kollmar Background: Portal branch ligation (PBL) is being used increasingly before hepatectomy for colorectal metastases. This study evaluated the effect of PBL on angiogenesis, growth factor expression and tumour growth in a mouse model of hepatic colorectal metastases. Methods: CT26.WT cells were implanted into the left liver lobe of BALB/c mice. Animals underwent PBL of the left liver lobe or sham treatment. Angiogenesis, microcirculation, growth factor expression, cell proliferation and tumour growth were studied over 14 and 21 days by intravital multifluorescence microscopy, laser Doppler flowmetry, immunohistochemistry and western blotting. Results: Left hilar blood flow and tumour microcirculation were significantly diminished during the first 7 days after PBL. This resulted in tumour volume being 20 per cent less than in sham controls by day 14. Subsequently, PBL-treated animals demonstrated recovery of left hilar blood flow and increased expression of hepatocyte growth factor and transforming growth factor ,, associated with increased cell proliferation and acceleration of growth by day 21. Conclusion: PBL initially reduced vascular perfusion and tumour growth, but this was followed by increased growth factor expression and cell proliferation. This resulted in delayed acceleration of tumour growth, which might explain the stimulated tumour growth observed occasionally after PBL. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Increased vascular endothelial growth factor expression, CD3-positive cell infiltration, and oxidative stress in premalignant lesions of the cervixCANCER, Issue 16 2009Yenddy Carrero MSc Abstract BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in cervical intraepithelial neoplasia (CIN) progression. The occurrence of leukocytes has been documented in CIN; however, their role in VEGF production remains unknown. Oxidative stress has been involved in the progression of malignant neoplasias, but to the authors' knowledge tissue oxidative stress in CIN has not been documented. The objective of the current study was to investigate the expression of VEGF, leukocyte infiltration, leukocyte VEGF expression, and nitrogen/oxygen metabolism in cervical tissues from patients with CIN. METHODS: Indirect immunofluorescence was used to study the expression of VEGF and leukocyte infiltration in cervical samples from 55 patients with CIN and 7 normal controls. Superoxide anion (O2,) expression was determined by a cytochemical method, and tissue and serum nitric oxide by the Griess reaction. Human papillomavirus (HPV) DNA and HPV types were identified by the hybrid capture 2 HPV DNA test. RESULTS: Increased expression of VEGF was observed related to the progression of CIN. A significant increment of CD3 lymphocytes was found in CIN type 3 (CIN 3) and coexpression of CD3/VEGF and monocyte-macrophage/VEGF in CIN 2 and 3. Increased O2, -positive cells were found in CIN 2 and 3; however, tissue nitrate-nitrite content remained similar to controls. The incidence of HPV infection was 16% in patients with CIN. No significant differences were observed in the values of HPV-positive or HPV-negative patients. CONCLUSIONS: Different factors leading to cervical neoplasia progression may be involved in the evolution of CIN, and the presence of these factors is most likely not related to the HPV infection status. Cancer 2009. © 2009 American Cancer Society. [source] RhoC is essential for angiogenesis induced by hepatocellular carcinoma cells via regulation of endothelial cell organizationCANCER SCIENCE, Issue 10 2008Wei Wang The angiogenesis induced by tumor cells is essential for metastasis of hepatocellular carcinoma. Available information suggests that RhoC participates in angiogenesis through regulation of vascular endothelial growth factor expression in tumor cells. For its broad functions in cell migration and cytoskeletal organization, we hypothesized that RhoC regulating angiogenesis does not exclusively depend on regulation of vascular endothelial growth factor expression. To address this question, in the present study, we used a retroviral small interfering RNA approach to selectively knockdown the expression of RhoC in a neovascularization model in vivo and in vitro. Our present results indicate that RhoC is the downstream regulator of vascular endothelial growth factor in endothelial cells and is essential for angiogenesis induced by vascular endothelial growth factor, notwithstanding that RhoC regulates the expression of vascular endothelial growth factor in tumor cells. Furthermore, we show that knockdown of RhoC is associated with the inhibition of invasion and migration but not apoptosis of endothelial cells. Knockdown of RhoC results in inhibition of endothelial cell organization through restraining the reorganization of F-actin filaments, which represses endothelial cell network and sprout formation. In conclusion, our results demonstrate that knockdown of RhoC inhibits angiogenesis induced by tumor cells not only through effecting the release of vascular endothelial growth factor, but also through inhibiting endothelial cell migration and organization, which implies that it blocks tumor metastasis by specifically inhibiting RhoC in endothelial cells. (Cancer Sci 2008; 99: 2012,2018) [source] Clinical and histological findings after intravitreal injection of bevacizumab (Avastin®) in a porcine model of choroidal neovascularizationACTA OPHTHALMOLOGICA, Issue 3 2010Nathan Lassota Abstract. Purpose:, To examine the effect of intravitreally injected bevacizumab (Avastin®) on the histological and angiographic morphology of choroidal neovascularization (CNV) in a masked and placebo-controlled animal study. Methods:, Choroidal neovascularization was induced surgically in 11 porcine eyes by perforating Bruch's membrane with a retinal perforator. After closure of the ports used for the vitrectomy, which was performed to facilitate the Bruch's membrane rupture, 0.05 ml of either bevacizumab or Ringer-Lactat (placebo) was injected into the vitreous cavity. Eyes were enucleated after 14 days. Fundus photographs and fluorescein angiograms (FAs) were obtained immediately prior to enucleation. Sections of formalin- and paraffin-embedded eyes were examined by light microscopy and by immunohistochemical staining. Results:, Placebo-injected eyes exhibited the highest propensity to leak, with five of six eyes leaking on FA, whereas only one of five bevacizumab-injected eyes exhibited leakage. On histological examination, all 11 eyes contained CNV membranes of similar size, regardless of treatment. The number of vascular endothelial cells was significantly reduced (p = 0.03) in CNV membranes from eyes that had been injected with bevacizumab when compared with CNV membranes from placebo-injected eyes. There was a trend towards more retinal pigment epithelium cells (p = 0.16) and fewer glial fibres (p = 0.08) in membranes from bevacizumab-treated eyes compared with placebo-treated eyes. Bevacizumab was identified immunohistochemically in the inner limiting membrane (ILM) and to a lesser degree in the remaining retina. Strong staining was also detected in both retinal blood vessels and entire CNV membranes with no cellular predisposition. Vascular endothelial growth factor expression was found in the CNV membranes, in the ILM, in the ganglion cell layer, in Müller cells throughout the neuroretina and in retinal blood vessels. Conclusions:, Bevacizumab significantly reduced the proliferation of vascular endothelial cells in CNV membranes and showed a strong trend towards a reduction of leakage from these membranes. After a single injection, bevacizumab did not exhibit a size reducing effect on CNV, but it was still present in the membranes 14 days after intravitreal injection. [source] | |||||||||||||||||||||||||||||||