Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) affects malignant tumours by promoting angiogenesis. The tumour-suppressor gene p53 has been thought to regulate VEGF. We investigated the effect of VEGF on oesophageal carcinoma and the connection between VEGF and p53. One hundred and nine resected oesophageal squamous cell carcinomas were examined. VEGF expression was analysed by immunohistochemical staining. Sixty-five tumours (59.6%, 65 out of 109) were classified as VEGF positive. A significant correlation was found between the VEGF expression and both the depth of invasion (P = 0.0001) and lymph node metastasis (P < 0.0001). With regard to p53, we compared the expression of VEGF with the mutation of p53, examined using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing in tumour samples obtained from 36 patients who we have reported previously. The VEGF expression was significantly correlated to p53 mutation (P = 0.0291). To evaluate the angiogenesis, microvascular density (MVD) was counted, and endothelial cells were stained immunohistochemically using anti-CD34 monoclonal antibody against 29 cases with invasion limited to the submucosal layer. The average MVD had a tendency to correlate to VEGF expression (P = 0.1626). The prognoses of patients with VEGF-positive primary tumours were significantly worse than for those with VEGF-negative primary tumours (P = 0.0077). We have assumed that VEGF contributes to aggressive characteristics in oesophageal carcinomas and that VEGF expression might be affected by p53 status.
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PMID:In oesophageal squamous cell carcinoma vascular endothelial growth factor is associated with p53 mutation, advanced stage and poor prognosis. 963 53

Vascular endothelial growth factor (VEGF) expression and mutations of cancer-related genes increase with cancer progression. This correlation suggests the hypothesis that oncogenes and tumour suppressors regulate VEGF, and a significant correlation between p53 alteration and increased VEGF expression in human lung cancer was reported recently. To further examine this hypothesis, we analysed VEGF protein expression and mutations in p53 and K-ras in 27 non-small-cell lung cancers (NSCLC): 16 squamous cell, six adenocarcinomas, one large cell, two carcinoids and two undifferentiated tumours. VEGF was expressed in 50% of the squamous cell carcinomas (SCC) and carcinoids but none of the others. p53 mutations occurred in 14 tumours (52%), and K-ras mutations were found in two adenocarcinomas and one SCC; there was no correlation between the mutations and VEGF expression. As nitric oxide also regulates angiogenesis, we examined NOS expression in NSCLC. The Ca2+-dependent NOS activity, which indicates NOS1 and NOS3 expression, was significantly reduced in lung carcinomas compared with adjacent non-tumour tissue (P < 0.004). Although the Ca2+-independent NOS activity, which indicates NOS2 expression, was low or undetectable in non-tumour tissues and most carcinomas, significant activity occurred in three SCC. In summary, our data do not show a direct regulation of VEGF by p53 in NSCLC. Finally, we did not find the up-regulation of NOS isoforms during NSCLC progression that has been suggested for gynaecological and breast cancers.
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PMID:Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. 968 99

Vascular endothelial growth factor (VEGF) is a cytokine that is involved in tumor angiogenesis. Wild-type p53 (wt-p53) protein has been shown in cell lines to suppress angiogenesis through thrombospondin regulation. In this study, we immunohistochemically examined the expression of VEGF, nuclear and wild-type cytoplasmic p53, bcl-2, epidermal growth factor receptor, and c-erbB-2 oncoprotein; vascular grade; proliferation index; and extent of necrosis in non-small cell lung cancer (NSCLC). We analyzed 120 cases of early-stage NSCLCs (81 squamous cell carcinomas and 39 adenocarcinomas) treated with surgery alone (median follow-up, 63 months; range, 45-74 months). VEGF expression showed a positive association with high vascular grade (microvessel score of >75 per x250 field; P = 0.008), although about half of the LVG cases also expressed VEGF. None of the p53 antibodies examined correlated with angiogenesis. However, wt-p53 expression was inversely associated with VEGF expression, suggesting that wt-p53 is involved in the suppression of the VEGF gene. Combined analysis of VEGF, wt-p53, and microvessel counting showed that, although wt-p53 loss associates with VEGF switch-on, p53 protein may not be involved in the regulation of the angiogenic events downstream of VEGF expression. Moreover, no significant association of bcl-2 and c-erbB-2 oncoprotein expression with VEGF expression was observed. T/N stage, grade, Ki67 proliferation index, and extent of necrosis were not correlated with VEGF expression. Survival analysis showed that VEGF correlated with poor survival (P = 0.04) and was significant in node-negative cases (P = 0.03). We conclude that VEGF is an important angiogenic factor in NSCLC, its expression being dependent on wt-p53 loss.
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PMID:Vascular endothelial growth factor, wild-type p53, and angiogenesis in early operable non-small cell lung cancer. 986 15

We have previously demonstrated that vascular count significantly increases in the preneoplastic lesions of the bronchial tree, starting from very low levels in the normal epithelium to a significantly higher number of microvessels in moderate dysplastic lesions and in situ carcinomas. Vascular endothelial growth factor (VEGF) protein expression has shown to be strictly associated with neovascularization both in human cancer and in various type of preinvasive lesions. A number of studies have demonstrated that mutant p53 is involved in the regulation of angiogenesis, and immunohistochemical detection of the p53 protein is associated with p53 gene mutations. In this study we looked for possible correlation between p53 protein detection, VEGF expression and vascular count in a series of preneoplastic and neoplastic lesions of the bronchial tree in order to investigate the angiogenic pattern and its genetic control in the early steps of bronchial cancer development. Twenty-four retrospective bronchial lesions with different grades of dysplasia and a case of normal bronchial epithelium were analysed. Surgical specimens removed from patients either confirmed, or suspect for lung carcinoma were stained immunohistochemically for CD34, VEGF, and p53. There were significant increases in microvascular density (MVD), VEGF, and p53 expression from normal bronchial epithelium through moderate dysplasia to in situ carcinoma to invasive cancer and these factors were significantly associated with moderate dysplastic lesions. A statistically significant difference was observed in MVD between hyperplastic-metaplastic, moderate dysplastic lesions and in situ carcinoma. A similar pattern was also observed for VEGF and p53 protein expression but no significant difference was observed between moderate dysplastic lesions and in situ carcinoma with regard to VEGF protein expression. The association between MVD, VEGF expression, p53 mutations and preinvasive lesions of the bronchial tree suggests that neoangiogenesis is early in non-small cell lung cancer (NSCLC) development and that p53 may have an important role in promoting angiogenesis in this human model of carcinogenesis.
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PMID:Modulation of neoangiogenesis in bronchial preneoplastic lesions. 1037 62

Vascular endothelial growth factor (VEGF) is a most potent angiogenic molecule. In this article, we demonstrated that VEGF is participated in the tumor angiogenesis of hepatocellular carcinoma, esophageal cancer, and pancreatic cancer. Furthermore, we revealed that VEGF is one of the molecules which are responsible for metastasis and prognosis in esophageal cancer and colon cancer. Although the mechanism on the induction of VEGF gene is still unclear in human cancer tissue, we obtained the informative evidence indicating that p53 mutation is involved in VEGF expression of esophageal cancer. Our experimental study with stable transfectant of VEGF gene provided the confirmative results showing that VEGF gene induces neovascularization in and around tumor and that VEGF augment metastastic potential by accelerating proliferative activity after reaching the target organ.
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PMID:Implication of vascular endothelial growth factor in the development and metastasis of human cancers. 1045 2

Inadequate function of dendritic cells (DCs) in tumor-bearing hosts is one mechanism of tumor escape from immune system control and may compromise the efficacy of cancer immunotherapy. Vascular endothelial growth factor (VEGF), produced by most tumors, not only plays an important role in tumor angiogenesis but also can inhibit the maturation of DCs from hematopoietic progenitors. Here, we investigate a novel combination of antiangiogenic and immunotherapy based on this dual role of VEGF. Two s.c. mouse tumor models were used: D459 cells, expressing mutant human p53; and MethA sarcoma with point mutations in the endogenous murine p53 gene. Therapy with anti-mouse VEGF antibody (10 microg i.p. twice a week over 4 weeks) was initiated when tumors became palpable. Treatment of established tumors with anti-VEGF antibody alone did not affect the rate of tumor growth. However, anti-VEGF antibody significantly improved the number and function of lymph node and spleen DCs in these tumor-bearing animals. To investigate the possible effects of this antibody on the immunotherapy of established tumors, tumor-bearing mice were immunized with DCs pulsed with the corresponding mutation-specific p53 peptides, together with injections of anti-VEGF antibody. Therapy with peptide-pulsed DCs alone resulted in considerable slowing of tumor growth but only during the period of treatment, and tumor growth resumed after the end of the therapy. Combined treatment with peptide-pulsed DCs and anti-VEGF antibody resulted in a prolonged and much more pronounced antitumor effect. This effect was associated with the induction of significant anti-p53 CTL responses only in this group of mice. These data suggest that inhibition of VEGF may be a valuable adjuvant in the immunotherapy of cancer.
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PMID:Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. 1053 66

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two important determinants of angiogenesis in human cancers. Expression of VEGF and bFGF was examined by immunohistochemistry in 120 colorectal cancers. Neoplasms were classified according to the presence or absence of microsatellite instability determined at six microsatellite loci and labelled as a high microsatellite instability (MSI-H), low microsatellite instability (MSI-L) or microsatellite stable (MSS). Only 4/30 MSI-H cancers expressed VEGF (13 per cent), compared with 24/64 MSS cancers (38 per cent; p< 0.01). Fewer MSI-H cancers showed bFGF expression (38 per cent) than MSS cancers (53 per cent; p< 0.09). MSI-L cancers showed the same pattern as MSS cancers. Western blotting and immunohistochemistry showed that the tumour suppressor gene p53 was mutated infrequently in MSI-H cancers (8 per cent; p< 0. 001). Microvessel density counts using CD31 and UEA-1 demonstrated no difference in the number of blood vessels in MSI-H and MSS cancers. Although these results are consistent with the known role of wild-type p53 in down-regulating VEGF, no association was found between a mutation in p53 and VEGF or bFGF levels in all colonic neoplasms. This is the first evidence that MSI-H cancers may follow a different pathway to angiogenesis. The low frequency of VEGF expression amongst MSI-H cancers may partially explain why these cancers are less aggressive, with a better overall prognosis.
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PMID:Angiogenic factor VEGF is decreased in human colorectal neoplasms showing DNA microsatellite instability. 1054 92

Tumor angiogenesis is an essential step for tumor cell growth, progression and metastasis. Vascular endothelial growth factor (VEGF) is mitogen specific for endothelial cells, and therefore is believed to play a key role in tumor angiogenesis. However, the mechanisms underlying the regulation of VEGF expression remain virtually unknown and the only major regulator of VEGF expression has been reported to be hypoxia. Recently, it was reported that a mutant p53 in#duced the expression of VEGF mRNA, and that wild-type p53 down-regulated endogenous VEGF mRNA levels. In contrast, it has also been reported that mutant ras oncogenes were associated with the marked up-regulation of VEGF in transformed epithelial cells. Based on these results, we performed a retrospective study of the p53 and K-ras genes status and VEGF gene expression in the tumor tissues from 181 patients with non-small cell lung cancer using SSCP, sequencing, RT-PCR and immunohistochemical techniques. Forty-six carcinomas (25.4%) were evaluated as having high VEGF expression, and 135 tumors (74.6%) had low VEGF expression. Of the 181 primary NSCLC studied, 63 carcinomas (34.8%) contained mutations of p53, whereas only 14 carcinomas (7.7%) had mutations of K-ras. There were no significant relationships between VEGF expression and p53 status or each mutant exon of p53. In contrast, a significant difference was found between VEGF expression and K-ras status. Of the 14 tumors with mutant K-ras genes, 7 cases (50.0%) had high VEGF expression whereas only 39 of the 167 tumors with wild-type K-ras (23.4%) had high VEGF expression (p=0.0278). The mean VEGF conservation rate for the 14 tumors with mutant K-ras genes was 0.77+/-0.58 and the rate of the 167 tumors with wild-type K-ras genes was 0.49+/-0.46 (p=0. 0350). Moreover, the overall survival rate of patients with high VEGF expression was lower than patients with low VEGF expression (45.7% vs 60.7%, p=0.0419). On the other hand, there was no significant difference in the overall survival rate between patients with a mutant p53 and those with a wild-type p53; there was also no difference in the overall survival between patients with a mutant K-ras and those with a wild-type K-ras. The Cox regression model analysis indicated that three variables, VEGF status, K-ras status and nodal status, were found to be significant indicators for prognosis (p=0.0236, p=0.0172 and p<0.0001, respectively). Our data suggest that a high expression of VEGF in lung cancer may be associated with a poor prognosis. This may be a clue to improving lung cancer diagnoses and therapies aimed at inhibiting tumor angiogenesis due to VEGF.
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PMID:The K-ras gene regulates vascular endothelial growth factor gene expression in non-small cell lung cancers. 1067 82

Angiogenesis is esential for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and is an important component of the angiogenic stimulus in a range of human neoplasias. In addition to its mitogenic activities, VEGF has also been found to stimulate migration in macrophages via the flt-1 VEGF receptor. It has previously been shown that increased focal tumour macrophage infiltration is associated with increased angiogenesis and worsened relapse-free and overall survival in breast cancer. Macrophages are able to stimulate angiogenesis by their production of a range of factors including VEGF, tumour necrosis factor-alpha (TNF-alpha), and thymidine phosphorylase (TP). Thus, in breast cancer, VEGF could have a dual role in the regulation of angiogenesis, by direct mitogenic stimulation of endothelial cells, and also indirectly by attracting macrophages into avascular tumours. The purpose of this study was to localize VEGF protein in a series of 96 consecutive primary breast carcinomas and to determine its relationship to focal macrophage infiltration (macrophage index). These two variables were also compared with the pathological features of the tumours, as well as oestrogen receptor (ER), epidermal growth factor receptor (EGFR), microvessel density, macrophage index, and survival. An inverse relationship (p=0.0006) was noted between VEGF and EGFR, with high VEGF expression correlating with low EGFR levels. In the EGFR-negative group of cases (n=56), positive associations were observed between VEGF expression and macrophage index (p=0.005), ER (p=0.05), p53 (p=0. 006), tumour grade (p=0.02), and tumour necrosis (p=0.03). Macrophage counts were higher in EGFR-positive tumours (p=0.0006) and no associations were found between VEGF expression and increased microvessel density. These results show that in breast cancers there are two types of macrophage infiltrates, one associated with the presence of EGFR and low VEGF expression in tumours and the other with high VEGF expression in EGFR-negative tumours. VEGF expression may be an important factor in the recruitment of tumour-associated macrophages into breast carcinomas and may thus have an additional, indirect, pathway of angiogenic stimulation in this type of tumour.
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PMID:Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. 1069 91

Vascular endothelial growth factor (VEGF) has potent angiogenic activity and has been identified in a wide variety of malignancies, including head and neck squamous cell carcinoma (HNSCC). The tumour-suppressor gene p53 has been thought to regulate VEGF. Cryostat sections of 33 head and neck squamous cell carcinomas (HNSCC) were immunostained for VEGF using a standard streptavidin-biotin complex procedure. To evaluate angiogenesis, microvascular density was counted by staining endothelial cells immunohistochemically using anti-vWF monoclonal antibody. The p53 gene status was analysed using a PCR-SSCP analysis and direct sequencing. VEGF positive staining was detected in 18 (55%) out of 33 tumours. VEGF immunoreactivity did not correlate with the main clinicopathological characteristics of the patients (localization, T-stage, N-status, histological grading). Statistical analysis gave a clear correlation between the tumour vascularity and the VEGF protein expression (p = 0.0036). VEGF negative tumours showed a lower mean number of microvessels per microscopic field (60.3 +/- 15.5) than VEGF positive tumours (79.6 +/- 22.9). P53 mutations were identified in 12 (36.4%) of 33 tumours. The association of p53 mutations and VEGF expression level was significant (0.027). The higher microvessel density in VEGF positive tumours supports the importance of VEGF for tumour angiogenesis in HNSCC. Our results support the hypothesis of a p53 regulation on the angiogenic process through a VEGF up-regulation.
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PMID:Vascular endothelial growth factor expression correlates with p53 mutation and angiogenesis in squamous cell carcinoma of the head and neck. 1077 96


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