Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epidermal growth factor (EGF) and EGF receptor (EGFR) family are often overexpressed in various human cancers including ovarian cancer. While it is generally believed that reactive oxygen species (ROS) are involved in the intracellular signaling events, the role of ROS in EGF-induced angiogenesis and carcinogenesis remains to be elucidated. The present study investigated the role of ROS in the regulation of AKT, p70S6K1, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1 (HIF-1) in ovarian cancer cells. In this study, OVCAR-3 cells were treated with EGF and catalase, an H2O2 scavenger. EGF treatment increases H2O2 production, leading to activation of the AKT/p70S6K1 pathway, resulting in increased VEGF expression at the transcriptional level. The inhibition of H(2)O(2) production by catalase abolished EGF-induced AKT and p70S6K1 activation, and VEGF expression through HIF-1alpha expression. Forced expression of p70S6K1 and HIF-1alpha reversed catalase- and rapamycin-inhibited VEGF transcriptional activation. We also showed that rapamycin, p70S6K1 inhibitor and catalase overexpression inhibited tumor angiogenesis. This study demonstrates a novel mechanism of EGF-induced VEGF and HIF-1alpha expression through production of H2O2 and activation of AKT and p70S6K1 in human ovarian cancer cells. This study also indicates that p70S6K1 and H2O2 are important in tumor angiogenesis. The results of the study could have an important implication in ovarian cancer therapy.
 ...
PMID:Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. 1704 20

Apigenin is a non-toxic dietary flavonoid with anti-tumor properties. We recently showed that apigenin-inhibited hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) expression in human ovarian cancer cells under normoxic condition. However, the effect of apigenin in angiogenesis remains to be elucidated. Angiogenesis is the formation of new blood vessels and is required for tumor growth and metastasis. In this study, we showed that apigenin-inhibited expression of HIF-1 and VEGF in different cancer cells under both normoxic and hypoxic conditions. We demonstrated that apigenin significantly inhibited tumor angiogenesis in vivo, by using both the chicken chorioallantoic membrane and Matrigel plug assays. The inhibition of tumor angiogenesis was associated with the decrease of HIF-1 and VEGF in tumor tissues. Taken together, our results show that apigenin suppresses tumor angiogenesis through HIF-1 and VEGF expression.
Carcinogenesis 2007 Apr
PMID:Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. 1707 32

Angiogenesis is an essential process involved in the development and progression of prostate cancer. Vascular endothelial growth factor (VEGF) is hypothesized to be a critical regulator of angiogenesis during prostate carcinogenesis. We have reported that dietary soy products inhibit prostate tumor progression in animal models, in association with a reduction in tumor microvessel density. The goal of the present study is to investigate potential antiangiogenic mechanisms of genistein, the major soy isoflavone, using in vitro systems. Genistein (5-50 muM) significantly inhibited the growth of human umbilical vein endothelial cells (HUVECs) in control media when stimulated by supplemental VEGF or when cultured in hypoxia-exposed PC-3 prostate adenocarcinoma cell conditioned media. These in vitro studies suggest detectable inhibitory effects by 5-10 muM genistein (P<.05) with an IC(50) of approximately 20 muM or less. Genistein (10-50 muM) caused significant inhibition of basal VEGF expression and hypoxia-stimulated VEGF expression in both human prostate cancer PC-3 cells and HUVECs based on semiquantitative reverse transcription-polymerase chain reaction (P<.05). In parallel, VEGF secretion by PC-3 cells quantitated by enzyme-linked immunosorbent assay was significantly (P<.05) reduced by genistein (10-50 muM). Furthermore, genistein (10-50 muM) significantly (P<.05) reduced PC-3 nuclear accumulation of hypoxia-inducible factor-1alpha, the principle transcription factor that regulates VEGF expression in response to hypoxia. Expression of the VEGF receptor fms-like tyrosine kinase-1, but not kinase insert domain-containing kinase, in HUVECs was also reduced (P<.05) by genistein (10-50 muM). These observations support the hypothesis that genistein may inhibit prostate tumor angiogenesis through the suppression of VEGF-mediated autocrine and paracrine signaling pathways between tumor cells and vascular endothelial cells.
 ...
PMID:Suppression of VEGF-mediated autocrine and paracrine interactions between prostate cancer cells and vascular endothelial cells by soy isoflavones. 1714 33

Inorganic arsenic (arsenite and arsenate) in drinking water has been associated with skin cancers and increased incidence of cardiovascular diseases. Additionally, studies have demonstrated the pro-angiogenic effect of arsenite and its potential promotion of tumor angiogenesis and tumor progression. Furthermore, recent reports demonstrated reversal of skin co-carcinogenesis by an organoselenium compound. The present study was undertaken to determine the effect and mechanism on angiogenesis of arsenite at low level and its potential reversal by various selenium-derived compounds. The pro-angiogenesis effects and mechanisms of sodium arsenite were determined using the chick chorioallantoic membrane (CAM) model over 3 days and compared with standard pro-angiogenesis factors, such as basic fibroblast growth factor (b-FGF). Additionally, the potential effect of various selenium-derived compounds--such as dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine--in reversing the pro-angiogenesis effect of arsenite or b-FGF was also determined in the CAM model. The pro-angiogenesis effect of arsenite or b-FGF was significantly (P < 0.01) blocked by dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine. The pro-angiogenesis effect of either sodium arsenite at 33 nM or b-FGF was blocked (P < 0.01) by the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation inhibitor, PD 98059. Additionally, the pro-angiogenic effect of arsenic or b-FGF was blocked as well (P < 0.01) by the alphavbeta3 antagonist, XT199. These data suggest that the pro-angiogenesis effect of arsenic is initiated at the plasma membrane integrin alphavbeta3, involves activation of the ERK1/2 pathway and is effectively reversed by various selenium-derived compounds.
Carcinogenesis 2007 May
PMID:Pro-angiogenesis action of arsenic and its reversal by selenium-derived compounds. 1715 27

Vascular endothelial growth factor (VEGF) is a proangiogenic factor upregulated in many tumors. The alternative splicing of VEGF mRNA renders 3 major isoforms of 121, 165 and 189 amino-acids in humans (1 less amino-acid for each mouse VEGF isoform). We have designed isoform specific real time QRT-PCR assays to quantitate VEGF transcripts in mouse and human normal and malignant prostates. In the human normal prostate, VEGF(165) was the predominant isoform (62.8% +/- 5.2%), followed by VEGF(121) (22.5% +/- 6.3%) and VEGF(189) (p < 0.001) (14.6% +/- 2.1%). Prostate tumors showed a significant increase in the percentage of VEGF(121) and decreases in VEGF(165) (p < 0.01) and VEGF(189) (p < 0.05). However, the amount of total VEGF mRNA was similar between normal and malignant prostates. VEGF(164) was the transcript with the highest expression in the mouse normal prostate. Unlike human prostate cancer, tumors from TRAMP mice demonstrated a significant increase in total VEGF mRNA levels and in each of the VEGF isoforms, without changes in the relative isoform ratios. Morpholino phosphorodiamide antisense oligonucleotide technology was used to increase the relative amount of VEGF(121) while proportionally decreasing VEGF(165) and VEGF(189) levels in human prostate cell lines, through the modification of alternative splicing, without changing transcription levels and total amount of VEGF. The increase in the VEGF(121)/VEGF(165-189) ratio in PC3 cells resulted in a dramatic increase in prostate tumor angiogenesis in vivo. Our results underscore the importance of VEGF(121) in human prostate carcinoma and demonstrate that the relative expression of the different VEGF isoforms has an impact on prostate carcinogenesis.
 ...
PMID:Increased expression of VEGF121/VEGF165-189 ratio results in a significant enhancement of human prostate tumor angiogenesis. 1727 99

Elevated concentrations of hyaluronan are often associated with human breast cancer malignancy. Here, we investigated the roles of hyaluronan in carcinogenesis and cancer progression using the mouse mammary tumor virus (MMTV)-Neu transgenic model of spontaneous breast cancer. Conditional transgenic mice that express murine hyaluronan synthase 2 (Has2) by Cre-mediated recombination were generated and crossed with the MMTV-Neu mice. In expressing Cre recombinase under the control of the MMTV promoter, the bigenic mice bearing Has2 and neu transgenes exhibited a deposition of hyaluronan matrix and aggressive growth of Neu-initiated mammary tumors. Notably, forced expression of Has2 impaired intercellular adhesion machinery and elicited cell survival signals in tumor cells. Concurrent with these alterations of tumor cells, intratumoral stroma and microvessels were markedly induced. To reveal the molecular basis of hyaluronan-mediated neovascularization, various hyaluronan samples were examined for their ability to potentiate in vivo angiogenesis. In Matrigel plug assays, basic fibroblast growth factor-induced neovascularization was elevated in the presence of either hyaluronan oligosaccharides or a hyaluronan aggregate containing versican. Administration of hyaluronan-versican aggregates, but not native hyaluronan alone, promoted stromal cell recruitment concurrently with the infiltration of endothelial cells. Taken together, these results suggest that hyaluronan overproduction accelerates tumor angiogenesis through stromal reaction, notably in the presence of versican.
 ...
PMID:Hyperproduction of hyaluronan in neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment: possible involvement of versican/PG-M. 1732 91

Previous studies by our laboratory indicated that zinc ribbon domain-containing 1 (ZNRD1) suppressed the growth of gastric cancer cells with a G(1) cell cycle arrest. However, the precise molecular mechanism underlying the growth-inhibitory effect of ZNRD1 remained fragmentary. In the present study, we have demonstrated that ZNRD1 could significantly inhibit the in vitro and in vivo growth of gastric cell line MKN28. Human cDNA microarray, reverse transcription-polymerase chain reaction and western blot analyses were used to identify differentially expressed cell cycle-related genes in MKN28 cells over-expressing ZNRD1. ZNRD1-induced growth suppression was found at least partially to regulate various proteins and signaling pathways controlling G(1) to S progression, including inhibition of cyclin D1 and CDK4, up-regulation of p21(CIP1/WAF1) and p27(Kip1) and acceleration of pRb dephosphorylation. Furthermore, ZNRD1 significantly inhibited the transcriptional activity of cyclin D1. p27(Kip1) might play a pivotal role in ZNRD1-induced cell cycle arrest because the p27(Kip1) anti-sense could block the cytostatic effects of ZNRD1. Moreover, ZNRD1 suppressed Skp2 expression via an increase in the protein instability, and induced significant decrease in cyclin E-CDK2 kinase activity. In addition, ZNRD1 could reduce tumor microvessel densities through inhibition of VEGF. Taken together, these results suggested that ZNRD1 might inhibit cell growth by targeting cell cycle-related genes and reducing tumor angiogenesis.
Carcinogenesis 2007 Aug
PMID:Mechanisms of growth arrest by zinc ribbon domain-containing 1 in gastric cancer cells. 1738 17

Tumor angiogenesis is required for tumor development and is stimulated by angiogenic inducers like VEGF (vascular endothelial growth factor). Our previous study demonstrated that STAT3 (signal transducer and activator of transcription 3) up-regulates HIF-1alpha (hypoxia inducible factor-1alpha) protein stability and enhances HIF-1-mediated VEGF expression in hypoxic solid tumor cells, thus suggesting that the inhibition of STAT3 signaling may have clinical applications. In this study, we examined in vitro and in vivo, whether caffeic acid (CA) or its derivative CADPE [3-(3,4-dihydroxy-phenyl)-acrylic acid 2-(3,4-dihydroxy-phenyl)-ethyl ester] exert anticancer activity by targeting STAT3. It was found that CA or CADPE significantly inhibit STAT3 activity, and that this in turn down-regulates HIF-1alpha activity. Consequently, sequential blockade of STAT3 and HIF-1alpha resulted in the down-regulation of VEGF by inhibiting their recruitment to the VEGF promoter. In mice bearing a Caki-I carcinoma, both CA and CADPE retarded tumor growth and suppressed STAT3 phosphorylation, HIF-1alpha expression, vascularization and STAT3-inducible VEGF gene expression in tumors. Taken together, our results demonstrate that CA and CADPE are potential inhibitors of STAT3 and that they suppress tumor angiogenesis by inhibiting the activity of STAT3, the expression of HIF-1alpha and VEGF.
Carcinogenesis 2007 Aug
PMID:Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells. 1755 5

For more than a century, inhibition of prostaglandin biosynthesis via inhibition of the fatty acid cyclooxygenase (COX) has been achieved by non-steroidal anti-inflammatory drugs (NSAIDs), which targets both COX-1 and COX-2 and as such could be responsible for causing gastrointestinal (GI) toxicity. COX-2 is an inducible enzyme produced by many cell types in response to multiple stimuli. Recently, COX-2 over-expression has been found in several types of human cancers such as colon, breast, prostate and pancreas and appears to control many cellular processes. Because of its role in carcinogenesis, apoptosis, and angiogenesis, it is an excellent target for developing new drugs with selectivity for prevention and/or treatment of human cancers. Development of selective COX-2 inhibitors has been successfully documented and as such showed less toxicity to GI tract as compared to conventional NSAIDs. However, the long term use of COX-2 selective inhibitors showed cardiovascular toxicity, and thus their utilization for cancer prevention and therapy is currently questionable, suggesting that further development of novel COX-2 selective agents are needed. Among many solid tumors, pancreatic cancer has the worst prognosis, and inflammation has been identified as a significant factor in the development of pancreatic malignancy. Several cytokines, reactive oxygen species (ROS) and mediators of inflammatory pathway such as activation of nuclear factor-kappaB (NF-kappaB) and COX-2 leads to an increase in cell proliferation, survival, and inhibition of pro-apoptotic pathway, ultimately resulting in tumor angiogenesis, invasion and metastasis. In this brief review, we summarize the role of COX-2 and discuss some of the experimental data linking inflammation with the development of pancreatic cancer. In addition, we provide further evidence regarding the state of our knowledge toward the development of novel COX-2 targeting agents for the prevention and/or treatment of human cancers especially pancreatic cancer.
 ...
PMID:Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. 1758 58

Members of the vascular endothelial growth factor (VEGF) family are critical players in angiogenesis and lymphangiogenesis. Although VEGF-A has been shown to exert fundamental functions in physiologic and pathologic angiogenesis, the exact role of the VEGF family member placental growth factor (PlGF) in tumor angiogenesis has remained controversial. To gain insight into PlGF function during tumor angiogenesis, we have generated transgenic mouse lines expressing human PlGF-1 in the beta cells of the pancreatic islets of Langerhans (Rip1PlGF-1). In single-transgenic Rip1PlGF-1 mice, intra-insular blood vessels are found highly dilated, whereas islet physiology is unaffected. Upon crossing of these mice with the Rip1Tag2 transgenic mouse model of pancreatic beta cell carcinogenesis, tumors of double-transgenic Rip1Tag2;Rip1PlGF-1 mice display reduced growth due to attenuated tumor angiogenesis. The coexpression of transgenic PlGF-1 and endogenous VEGF-A in the beta tumor cells of double-transgenic animals causes the formation of low-angiogenic hPlGF-1/mVEGF-A heterodimers at the expense of highly angiogenic mVEGF-A homodimers resulting in diminished tumor angiogenesis and reduced tumor infiltration by neutrophils, known to contribute to the angiogenic switch in Rip1Tag2 mice. The results indicate that the ratio between the expression levels of two members of the VEGF family of angiogenic factors, PlGF-1 and VEGF-A, determines the overall angiogenic activity and, thus, the extent of tumor angiogenesis and tumor growth.
 ...
PMID:Placental growth factor-1 attenuates vascular endothelial growth factor-A-dependent tumor angiogenesis during beta cell carcinogenesis. 1800 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>