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)

Somatostatin receptor subtypes, especially subtype 2 (SSTR2), exert their antitumor (cytostatic and/or cytotoxic) and anti-angiogenic effects. Here we aimed to investigate the anti-angiogenic effect of SSTR2 gene transfer into pancreatic cancer cell line PC-3, and the mechanisms involved in this effect. The full-length human SSTR2 complementary DNA was introduced into pancreatic cancer cell line PC-3 by lipofectamine-mediated transfection, and stable expression of SSTR2 was detected by immunohistochemistry and RT-PCR. Athymic mice were separately xenografted with SSTR2-expressing cells (experimental group), vector control and mock control cells. Intratumoral microvessel density (MVD) was assessed by immunohistochemistry. Immunohistochemistry and RT-PCR were used to determine the expression of angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and matrix metalloproteinase (MMP)-2 in xenograft tumors. MVD was significantly lower in the experimental group (5.16 +/- 1.34) than that in the vector control (16.52 +/- 2.25) and mock control (15.32 +/- 2.53) (P < 0.05). The immunohistochemical assay showed a significant decrease in the expression of VEGF, bFGF and MMP-2 protein in the experimental group compared with the vector control and mock control, considering both the integral optical density and area of staining (P < 0.05). RT-PCR showed a significant reduction of VEGF, bFGF and MMP-2 mRNA expression in the experimental group compared with the vector control and mock control (P < 0.05). Thus, introduction of the SSTR2 gene, the expression of which is frequently lost in human pancreatic adenocarcinoma, exerts its anti-angiogenic effects by down-regulating the expression of the factors, which are involved in tumor angiogenesis and metastasis, suggesting SSTR2 gene transfer as a promising strategy of gene therapy for pancreatic cancer.
Carcinogenesis 2004 Nov
PMID:Anti-angiogenic effects of somatostatin receptor subtype 2 on human pancreatic cancer xenografts. 1520 62

Cyclooxygenase-2 (Cox2) may play a crucial role in lung carcinogenesis. In fact, overexpression of Cox2 is common in non-small cell lung cancer (NSCLC) and seems to be associated with tumor progression, invasion and metastasis. In experimental animal models Cox2 has been shown to be involved in tumor angiogenesis, suggesting that Cox2 is a potential target for NSCLC therapy. Several in vivo studies have already shown that Cox2 specific inhibitors (celecoxib, rofecoxib) have anti-tumor activity and clinical trials using Cox2 inhibitors are currently ongoing in patients with NSCLC.
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PMID:[Cyclooxygenase 2 inhibitors and lung carcinoma]. 1523 38

We identified regulator of G-protein signaling-5 (RGS-5) as an angiogenic pericyte marker at sites of physiologic and pathologic angiogenesis. In a mouse model of pancreatic islet cell carcinogenesis, RGS-5 is specifically induced in the vasculature of premalignant lesions during the "angiogenic switch" and further elevated in tumor vessels. Similarly, RGS-5 is overexpressed in highly angiogenic astrocytomas but not in hypoxia-inducible factor-1alpha (HIF-1alpha)-deficient tumors, which grow along preexisting brain capillaries without inducing neovessels. Elevated levels of RGS-5 in pericytes are also observed during wound healing and ovulation indicating a strong correlation between RGS-5 expression and active vessel remodeling beyond tumor angiogenesis. Moreover, antitumor therapy, which reverses tumor vasculature to an almost normal morphology, results in down-regulation of RGS-5 transcription. Taken together, these data demonstrate for the first time a factor that is specific for "activated" pericytes. This further supports the notion that pericytes, like endothelial cells, undergo molecular changes during neovascularization that makes them a novel target for antiangiogenic therapy.
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PMID:Regulator of G-protein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization. 1545 6

High-level expression of cyclooxygenase (COX)-2 is reported in 80-90% of colorectal adenocarcinomas. Selective inhibition of COX-2 was shown to reduce colorectal tumorigenesis in different models of carcinogenesis and to prevent metastasis in xenograft tumor models, as well as to suppress in vitro induced angiogenesis. Recently, COX-2 was reported to be expressed not only in malignant epithelial cells, but also in the neovasculature that feeds the tumor in a variety of solid human cancers. Thus, one of the possible mechanisms by which selective COX-2 inhibitor reduces tumor growth and metastasis is through inhibition of tumor angiogenesis. Although a report suggested a possible role of endothelial COX-1 in the process of angiogenesis, in a recent study, the selective inhibition of COX-2 was shown to strongly inhibit angiogenesis by inducing endothelial cell (EC) apoptosis. In the present study, using human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the potential antiangiogenic effect of the selective COX-2 inhibitor and its mechanism of action, and clearly demonstrated that selective inhibition of COX-2 caused a dose-dependent decrease in the proliferative activity of ECs, as well as an inhibition of capillary-like tube formation. The inhibitory effect on EC proliferation was dependent on the cell cycle arrest to the G1 phase and not on cell apoptosis.
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PMID:Selective inhibition of cyclooxygenase (COX)-2 inhibits endothelial cell proliferation by induction of cell cycle arrest. 1547 9

The cyclooxygenase-2 (COX-2) enzyme has a fundamental role in the carcinogenesis of colorectal cancer. The anticarcinogenic mechanisms of NSAIDs are not completely understood and appear to be only partially dependent on inhibition tumoral COX-2. Moreover, the mechanisms of NSAIDs depend on the concentration. In experimental setting, at low levels NSAIDs downregulate the COX-2 gene in colorectal cancer cells, whereas at clinical relevant concentrations the production of prostaglandin E2 by enzymatic activity of COX-2 is diminished resulting in inhibition of the tumor angiogenesis. At higher levels NSAIDs and especially some selective COX-2 inhibitors are capable of COX-2 independent effects, such as apoptosis induction of tumor cells. In animal models, NSAIDs administration results in inhibition of angiogenesis and proliferation, induction apoptosis and prevention of metastasis. In clinical setting, NSAIDs and selective COX-2 inhibitors have the capacity to prevent the development of colorectal adenomas. We have summarized data regarding the role of COX-2 in CRC and discuss the multiple targets of NSAIDs in their anticarcinogenic action. However, the translation of these anticarcinogenic effects of NSAIDs to its clinical application as adjuvant therapy in CRC is hampered by a lack of randomized clinical trials with long-term follow-up.
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PMID:COX-2 inhibition as a tool to treat and prevent colorectal cancer. 1550 Oct 74

Neoangiogenesis is assumed to play an important role in the progression, metastasis and prognosis of a wide variety of tumors. To get insights into the molecular-genetic pathways and the biological role of angiogenesis in urothelial carcinogenesis, we analyzed comparatively the expression of the mRNA of the vascular endothelial growth factor (VEGF) and of the angiopoietins-1 and -2 (Ang-1 and Ang-2) in 71 transitional cell carcinomas (TCC) of the urinary bladder in relation to the tumor grades and stages, and referring to epidemiological risk factors. Using real-time quantitative reverse transcription-polymerase chain reaction, low-stage superficial TCC expressed VEGF and Ang-2 mRNA at a significantly higher level than high-stage muscle invasive carcinomas, and low-grade TCC at an insignificantly higher level than high-grade tumors. The activity of both angiogenic factors was found to be significantly correlated. Conversely, Ang-1 mRNA was expressed at a 3-fold significantly lower level in low-grade, low-stage compared to high-grade, high-stage TCC. A significantly 3- and 2-fold respectively, drop of the VEGF and Ang-2 mRNA expression in conjunction with a 2-fold significantly higher expression of Ang-1 mRNA in the group of grade 2 TCC when infiltrating the muscle layer may represent a crucial event during urothelial carcinogenesis, and possibly indicates an important step in promoting the conversion of bladder cancer from a low to a high malignancy in this subset of carcinomas. By immunhistochemistry, high-grade, high-stage carcinomas less frequently displayed areas with a strong reactivity for the VEGF protein ('hot spots") than low-grade, low-stage TCC, paralleling the expression of the mRNA. The expression patterns observed are compatible with a reduced vascular destabilization and decreased formation of new blood vessels in advanced TCC, suggesting a balance between vessel regression and vascular growth, with a less pronounced vascular remodeling during late phases of urothelial carcinogenesis. Analyzing the effect of life-style bladder cancer risk factors, habitual smoking and coffee consumption was not observed to substantially alter the expression of the angiogenic mediators, except for weakly elevated levels of VEGF and Ang-2 mRNA in TCC of strong smokers and a borderline significantly decreased VEGF mRNA expression associated with heavy coffee consumption. Certain hazardous occupational exposures (polycyclic hydrocarbons, paints and lacquer, stone dust) may play a role in modulating tumor angiogenesis. The current data indicate that the signaling molecular-genetic pathways underlying vascular remodeling are involved in the progression of urinary bladder cancer to a more malignant and aggressive behaviour.
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PMID:Alteration of the vascular endothelial growth factor and angiopoietins-1 and -2 pathways in transitional cell carcinomas of the urinary bladder associated with tumor progression. 1551 81

Colon cancers often display perturbations in arachidonic acid metabolism, with elevated levels of cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) production frequently observed. Whereas COX-2 and PGE(2) are associated with cancer cell survival and tumor angiogenesis, arachidonic acid itself is a strong apoptotic signal that may facilitate cancer cell death. To further explore how cancer cells exploit the progrowth actions of prostaglandins while suppressing the proapoptotic actions of intracellular arachidonic acid, we determined the cytoplasmic phospholipase A(2) (cPLA(2)) and COX-2 expression levels in a panel of human colon tumors by immunohistochemistry. Although high levels of cPLA(2) and COX-2 expression are predicted to facilitate maximal prostaglandin production, tumors frequently displayed a high-COX-2/low-cPLA(2) phenotype. The least represented phenotype was the high expression of cPLA(2), a characteristic predicted to generate the highest levels of intracellular arachidonic acid. The potential proapoptotic role of cPLA(2) was supported by a higher frequency of terminal deoxynucleotidyl transferase-mediated nick end labeling staining in cPLA(2)-positive tumors. Moreover, analysis of preneoplastic aberrant crypt foci from high-risk patients suggests that acquisition of the high-COX-2/low-cPLA(2) phenotype may arise at an early stage of colon carcinogenesis. We additionally inhibited cPLA(2) in HT-29 cells using antisense oligonucleotides. Our results indicate that cPLA(2) plays an important role in tumor necrosis factor alpha-induced apoptosis in human colon cancer cells. Our data further support the model in which colon cancer growth is favored when intracellular arachidonic acid levels are suppressed by inhibition of cPLA(2) or by a high-COX-2/low-cPLA(2) phenotype.
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PMID:Cytoplasmic phospholipase A2 levels correlate with apoptosis in human colon tumorigenesis. 1578 76

Heparan sulfate proteoglycans are integral components of the extracellular matrix that surrounds all mammalian cells. In addition to providing structural integrity, they act as a storage depot for a variety of heparan sulfate (HS)-binding proteins, including growth factors and chemokines. Heparanase is a matrix-degrading enzyme that cleaves heparan sulfate side chains from the core proteoglycans, thus liberating such HS-binding proteins, as well as potentially contributing to extracellular matrix degradation. Here, we report that heparanase mRNA and protein expression are increased in the neoplastic stages progressively unfolding in a mouse model of multistage pancreatic islet carcinogenesis. Notably, heparanase is delivered to the neoplastic lesions in large part by infiltrating Gr1+/Mac1+ innate immune cells. A sulfated oligosaccharide mimetic of heparan sulfate, PI-88, was used to inhibit simultaneously both heparanase activity and HS effector functions. PI-88 had significant effects at distinct stages of tumorigenesis, producing a reduction in the number of early progenitor lesions and an impairment of tumor growth at later stages. These responses were associated with decreased cell proliferation, increased apoptosis, impaired angiogenesis, and a substantive reduction in the number of invasive carcinomas. In addition, we show that the reduction in tumor angiogenesis is correlated with a reduced association of VEGF-A with its receptor VEGF-R2 on the tumor endothelium, implicating heparanase in the mobilization of matrix-associated VEGF. These data encourage clinical applications of inhibitors such as PI-88 for the many human cancers where heparanase expression is elevated or mobilization of HS-binding regulatory factors is implicated.
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PMID:A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. 1580 57

Recent studies have revealed that 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG) has anti-tumorigenic activity in vitro. In the present work, we evaluated the in vitro and in vivo antiangiogenic and antitumor activities of PGG and examined its molecular mechanisms. PGG significantly inhibited the proliferation and tube formation in basic fibroblast growth factor (bFGF)-treated human umbilical vein endothelial cells (HUVECs) at non-cytotoxic concentrations. PGG effectively disrupted the bFGF-induced neo-vascularization in chick chorioallantoic membrane (CAM) and in Matrigel plugs in the mice. When mice were intraperitoneally injected, PGG also significantly inhibited tumor angiogenesis induced by Lewis lung carcinoma (LLC) and the growth of LLC by 57 and 91% of control tumor weight at 4 and 20 mg/kg, respectively. Immunohistochemical analysis revealed decreased microvessel density, decreased expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), reduced tumor cell proliferation and increased tumor cell apoptosis. Similarly, PGG significantly attenuated the expression of COX-2 and VEGF and reduced the secretion of VEGF and prostaglandin E2 in bFGF-treated HUVECs. Furthermore, the COX-2 inhibitor NS398 significantly inhibited tube formation and neo-vascularization in CAM, supporting the role of COX-2 in PGG inhibition of angiogenesis. PGG diminished the phosphorylation of extracellular signal regulated kinase 1/2, Jun NH2-terminal kinase and activated phospho-p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner in bFGF-treated HUVECs. In addition, p38 inhibitor SB203580 abolished the downregulation of COX-2, VEGF and the antiproliferative activity by PGG. Taken together, our data demonstrate that PGG exerts antitumor activity primarily via inhibition of angiogenesis through COX-2 and MAPK- dependent pathways.
Carcinogenesis 2005 Aug
PMID:Penta-O-galloyl-beta-D-glucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis: roles of cyclooxygenase-2 and mitogen-activated protein kinase pathways. 1584 50

Cyclooxygenase-2 (Cox2) may play a crucial role in lung carcinogenesis. In fact, overexpression of Cox2 is common in non-small cell lung cancer (NSCLC) and seems to be associated with tumor progression, invasion and metastasis. In experimental animal models Cox2 has been shown to be involved in tumor angiogenesis, suggesting that Cox2 is a potential target for NSCLC therapy. Several in vivo studies have already shown that Cox2 specific inhibitors (celecoxib, rofecoxib) have anti-tumor activity and clinical trials using Cox2 inhibitors are currently ongoing in patients with NSCLC.
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PMID:[Cyclooxygenase 2 inhibitors and lung carcinoma]. 1589 34


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