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

A semi-synthetic analogue of fumagillin, TNP-470, has been shown to be a potent angiogenesis inhibitor. In this study, we evaluated the anti-tumor efficacy of TNP-470 on rabbits bearing VX2 carcinoma of the tongue, by comparison of topical, intra-tumor (i.t.) injection with systemic, intra-venous (i.v.) administration. The i.t. injection of the angiogenesis inhibitor produced much stronger anti-tumor effects, and almost complete tumor regression was achieved at doses of 10 mg/kg or 20 mg/kg. TNP-470 injected intra-tumorally significantly reduced expression of proliferating cell nuclear antigen (PCNA) and microvessel density in the VX2 carcinoma of the tongue. TNP-470 also halted the tumor-associated neovascularization in the rabbit cornea assay. These data suggest that i.t. injection of TNP-470 effectively inhibits tumor angiogenesis and disrupts microvasculature development, which may suppress tumor growth. In conclusion, the i.t. injection of TNP-470 provided remarkable anti-tumor effects on the VX2 carcinoma of the tongue and is expected to have promising therapeutic uses for oral cancer.
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PMID:Intra-tumor injection of an angiogenesis inhibitor, TNP-470, in rabbits bearing VX2 carcinoma of the tongue. 1010 93

Tumor growth is an angiogenesis-dependent process and therapeutic strategies aimed at inhibiting angiogenesis are theoretically attractive. Angiostatin has been shown to potently inhibit endothelial proliferation in vitro and tumor growth in vivo. We now show that a shift in the balance of tumor angiogenesis by gene transfer of a cDNA coding for mouse angiostatin into mouse squamous cell carcinoma NRS-1 and SCC-VII cells suppresses tumor growth in vivo. The inhibition of an angiostatin-transfected tumor was accompanied by a marked reduction in vascularity and the presence of many apoptotic tumor cells. However, transfected-angiostatin cDNA does not affect the expression of the vascular endothelial growth factor (VEGF) and VEGF-R2 in the vascular endothelium. The inhibition mechanisms of neovascularization may be mediated independent of VEGF:VEGF-R2 complex. Our data may provide a useful approach for human oral cancer therapy by gene therapy with angiostatin.
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PMID:Angiostatin gene therapy inhibits the growth of murine squamous cell carcinoma in vivo. 1133 70

Maspin, which belongs to the serine protease inhibitor (serpin) superfamily, has been proposed as a potent tumor suppressor that inhibits cell motility, invasion, angiogenesis, and metastasis. In the present study, we examined the effects of 5-aza-2(')-deoxycytidine (5-aza-dC), a demethylating agent, and FR901228, a histone deacetylase (HDAC) inhibitor, on maspin expression in oral cancer cell lines. The expression levels of maspin mRNA were divided into two groups, which was the maspin low-expressed and high-expressed cell lines in the 12 oral cancer cell lines. The maspin promoter contained only a few methylated CpG sites in the maspin low-expressed cell lines. Moreover, the methylation status was not altered after 5-aza-dC treatment. However, the transcription of the maspin gene was clearly increased following 5-aza-dC treatment in a number of oral cancer cell lines. These results imply that an action of 5-aza-dC is separate from induction of promoter demethylation. Treatment with FR901228 resulted in a time-dependent stimulation of the re-expression of maspin mRNA as early as 4 h after treatment in the maspin downregulated cells. The re-expression of the maspin gene may contribute to the recuperation of biological functions linked to FR901228 such as an inhibitory effect on tumor angiogenesis and cell invasion. These results indicate that maspin and its target genes may be excellent leads for future studies on the potential benefits of FR901228, a HDAC inhibitor, in cancer therapy.
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PMID:Effects of demethylating agent 5-aza-2(')-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines. 1506 88

Growth-regulated oncogene-1 (GRO-1) is an autocrine growth factor in melanoma and is a member of the CXC family of chemokines which promote chemotaxis of granulocytes and endothelia through binding to CXC receptor 2. A previous article noted that GRO-1 was upregulated in oral cancer using a genome-wide microarray approach. We have examined the expression of GRO-1 in 9 oral squamous cell carcinoma (OSCC) cell lines and 94 OSCC specimens. Using real-time quantitative polymerase chain reaction analyses, GRO-1 expressions were varied in OSCC cell lines. Of the 94 OSCC specimens, 37 (39.4%) showed GRO-1 cytoplasmic immunostaining, and microvessel density revealed a correlation between GRO-1 expression and tumor angiogenesis. GRO-1 expression was also associated with leukocyte infiltration, and lymph node metastasis. These findings suggest a possible relationship between the expression level of GRO-1 and tumor progression.
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PMID:Growth-regulated oncogene-1 expression is associated with angiogenesis and lymph node metastasis in human oral cancer. 1521

The present study was aimed to speculate whether the up-regulation of VEGF in oral squamous cell carcinoma (OSCC) is associated with oxygen levels, tumor angiogenesis and severity of disease. Under different oxygen levels, VEGF protein production in two oral cancer cell lines was quantitatively documented by using ELISA kit. Correlations between expression of VEGF, microvessel density, and various clinico-pathologic factors were studied in forty patients with OSCC. VEGF production was continuously elevated in supernatants from both cell lines in respond to the drop of oxygen levels. When oxygen level decreased to 1%, there was a 2.1-fold and nearly a 2.9-fold elevation of VEGF production in TSCCa and GNM cell line, respectively. On hypoxia VEGF production also presented a time-dependent up-regulation in both oral cancer cell lines. VEGF positivity was correlated with regional lymph nodal involvement and clinical stage. Microvessel density was significantly higher in VEGF-positive tumors than in VEGF-negative tumors. The presence of hypoxia in oral cancers is partly responsible for the up-regulation of VEGF. The elevation of VEGF expression in OSCC tissues correlates with the increased microvessel density and severity of the disease.
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PMID:VEGF is up-regulated by hypoxic stimulation and related to tumour angiogenesis and severity of disease in oral squamous cell carcinoma: in vitro and in vivo studies. 1638 29

Slit is a secreted protein known to function through the Roundabout (Robo) receptor as a repellent for axon guidance and neuronal migration, and as an inhibitor in leukocyte chemotaxis. We have previously shown that Slit2 is also secreted by a variety of human cancer cells whereby it acts as a chemoattractant to vascular endothelial cells for tumor angiogenesis. We used a blocking antibody to investigate the role of Slit-Robo signaling in tumor angiogenesis during oral carcinogenesis. In this report we undertook a multistage model of 7,12-dimethyl-1,2-benzanthracene-induced squamous cell carcinoma in the hamster buccal pouch. R5, a monoclonal antibody against the first immunoglobulin domain of Robo1, was used to study whether R5 blocks the Slit-Robo interaction and furthermore inhibits tumor angiogenesis and growth in our model. In addition, the expression of Slit2, von Willebrand factor, and vascular endothelial growth factor were examined using human tissue of oral cheek mucosa with oral squamous cell carcinoma. Our data showed that Slit2 was expressed minimally in normal and hyperplastic mucosa, moderately in dysplastic mucosa, and highly in neoplastic mucosa obtained from hamster buccal pouch. We also found that increased Slit2 expression was associated with higher tumor angiogenesis, as reflected by increased vascular endothelial growth factor expression and microvessel density. A similar Slit2 expression profile was found in human tissue. Importantly, interruption of the Slit2-Robo interaction using R5 inhibited tumor angiogenesis and growth in our in vivo model, which indicates that Slit2-mediated tumor angiogenesis is a critical process underlying the carcinogenesis of chemical-induced squamous cell carcinoma. Therefore, targeting Slit-Robo signaling may offer a novel antiangiogenesis approach for oral cancer therapy.
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PMID:Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis. 1820 Dec 75

The RECK gene is a novel tumor suppressor gene that regulates matrix metalloproteinases (MMPs) to inhibit tumor angiogenesis, invasion and metastasis. We investigated the methylation status of the RECK gene in 40 primary oral squamous cell carcinomas (OSCC) and 20 paired adjacent normal mucosa by methylation-specific PCR. Furthermore, we determined the prognostic importance of RECK hypermethylation in OSCC patients. Our findings showed that the RECK gene was methylated in 52.5% (21 of 40) of the primary OSCC. Among the 20 cases with corresponding normal tissues, RECK hypermethylation was detected in both primary tumor (55%, 11 of 20) and adjacent normal mucosa (30%, 6 of 20). Methylation of the RECK gene was not detected in all normal oral mucosa samples of the 12 healthy controls. In univariate analysis, RECK hypermethylation was inversely correlated with recurrence-free survival (p=0.027) and overall survival (p=0.023) of the OSCC patients. Multivariate analysis showed that the methylation status of the RECK gene was the only independent prognostic factor affecting overall survival (p=0.037). The result indicates that hypermethylation of RECK promoter is a common event in human OSCC, occurs concurrently in tumor-adjacent normal mucosa and is correlated with poor prognosis in OSCC patients. Although additional work is needed, hypermethylation of the RECK gene is a promising biomarker in early detection and prognosis for oral cancer patients.
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PMID:Hypermethylation of the RECK gene predicts poor prognosis in oral squamous cell carcinomas. 1848 91

Tumstatin - non-collagenous (NC1) domain of the alpha 3 chain of type IV collagen - is a potent inhibitor of tumor angiogenesis. Successful tumor inhibition has been reported in glioma, bronchopulmonary cancer and melanoma experimental model. In this study, the effects of tumstatin, in vitro and in vivo, were investigated in an oral cancer model. Recombinant human tumstatin proteins were obtained by the transformation of Tn 5B1-4 cells, transfected with a plasmid containing tumstatin cDNA using the lipofection method, as previously described. Tumstatin inhibited the proliferation of human umbilical vascular endothelial cells in a dose dependent manner in a proliferation assay. For the in vivo analysis, we established an orthotopic oral squamous cell carcinoma (AT-84 cells) animal (C3H/He) model. In this animal model, the in vivo inhibitory effects of tumstatin on the tumor growth and on the metastasis of tumors were demonstrated. However, the tumors did not show complete remission. Immunostaining of the tumor microvessels (CD-31/PECAM) revealed that the density of tumor microvessels was significantly decreased in the tumstatin treated primary tumors. The results demonstrated that tumstatin delayed the tumor growth and the metastasis of oral squamous cell carcinomas. However, tumstatin alone failed to achieve tumor regression. Therefore, tumstatin might have an adjuvant role in the treatment of oral cancers, in combination with the conventional therapy.
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PMID:Peritumor injections of purified tumstatin delay tumor growth and lymphatic metastasis in an orthotopic oral squamous cell carcinoma model. 1848 94

Oral Cancer Overexpressed 1 (ORAOV1) is a novel gene locating at chromosome band 11q13. Recent studies have suggested its role as a candidate oncogene in oral squamous cell carcinoma (OSCC) and its prognostic value for patients with OSCC. Till now, the detailed function of ORAOV1 in OSCC has remained undefined. In this study, we have investigated the role of ORAOV1 in OSCC tumorigenesis by down-regulating its expression. Small interfering RNA (siRNA) has been applied to inhibit the expression of ORAOV1 in OSCC cells. We found that the OSCC cells with reduced ORAOV1 showed retarded cell growth in vitro and displayed inhibition in both tumor growth and tumor angiogenesis in vivo. Further analyses reveal that the retarded cell growth is associated with an increase in apoptosis involving the activation of caspase 3-dependent pathway and a cell cycle arrest at the S-phase with a downregulation of cyclin A, cyclin B1 and cdc2. The suppressed tumor growth in vivo may be attributed to synergistic effect between inhibition in cell growth and suppression of tumor angiogenesis. The latter is most likely because of a suppression of VEGF. Taken together, we demonstrate that ORAOV1 plays pivotal roles in the growth and angiogenesis of OSCC. Thus, ORAOV1 may be a novel target that could be explored to develop therapeutic strategy in OSCC management.
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PMID:Oral cancer overexpressed 1 (ORAOV1): a regulator for the cell growth and tumor angiogenesis in oral squamous cell carcinoma. 1868 49

It is well known that tumor angiogenesis plays an important role in local growth and metastasis of oral cancer; therefore, inhibiting angiogenesis is considered to be effective for treating oral cancer. This study aimed to investigate the effectiveness of systemically available antiangiogenic gene therapy targeting vascular endothelial growth factor (VEGF), which is one of the most important angiogenesis accelerators. We administered a soluble form of VEGF receptor-expressing gene incorporated into adenovirus (AdVEGF-ExR) intraperitoneally to nude mice to which oral cancer cell lines (SAS, HSC-3, and Ca9-22) had been transplanted subcutaneously in vivo to inhibit angiogenesis and tumor proliferation. Then, we measured tumor volumes over time, and tumors were enucleated and examined histopathologically and immunohistologically at 28 days after AdVEGF-ExR administration. Compared to the controls to which we administered AdLacZ or saline, significant antiproliferative effects were observed (P < 0.05) in the AdVEGF-ExR administration group, and extensive tumor necrosis was found histopathologically. Immunohistochemical analysis with CD34 (NU-4A1) revealed tumor angiogenesis was suppressed significantly (P < 0.05), and that with ssDNA revealed apoptosis induction was significantly high (P < 0.05) in the AdVEGF-ExR group. However, analysis with Ki-67 (MIB-1) revealed tumor proliferative capacity was not significantly different between the groups. Consequently, we consider that AdVEGF-ExR administration achieved tumor growth suppression by inhibiting angiogenesis and inducing apoptosis, but not by inhibiting the proliferative capacity of tumor cells. Neither topical administration of a soluble form of VEGF receptor (sVEGFR) to the tumor nor a megadose was needed to achieve this inhibition effect. These results suggest gene therapy via sVEGFR would be an effective oral cancer therapy and benefit future clinical applications.
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PMID:Experimental study of antiangiogenic gene therapy targeting VEGF in oral cancer. 2015 8


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