Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymph node metastasis is a major prognostic factor in human cancer. Vascular endothelial growth factor C (VEGF-C) is a lymphangiogenic polypeptide that has been implicated in several human solid tumors. However, the clinical significance of VEGF-C has remained unknown in gallbladder carcinoma. Paraffin-embedded tumor specimens of 52 surgically resected gallbladder cancers were immunohistochemically stained for VEGF-C, VEGF, and CD34. The correlations among VEGF-C expression, VEGF expression, microvessel density (MVD), clinicopathologic features, and clinical outcomes were statistically analyzed. Thirty-three (63%) of the 52 gallbladder cancers were highly positive for VEGF-C protein by immunohistochemistry. VEGF-C expression was significantly correlated with lymphatic vessel involvement, lymph node metastasis, and worse outcomes after operation (p<0.001, p<0.001, p<0.001, respectively), but not with MVD. By the Cox regression model, lymphatic vessel involvement emerged as an independent prognostic parameter. These results suggest that VEGF-C may play a role in tumor progression via lymphangiogenesis and lymph node metastasis in human gallbladder cancer.
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PMID:Vascular endothelial growth factor-C expression in human gallbladder cancer and its relationship to lymph node metastasis. 1246 14

Angiogenesis is an essential process for tumor progression and VEGF is thought to be a critical factor for this process. VEGF is also known as a strong capillary permeability inducer, what can be important for pleural effusion development. The aim of the study was the comparative analysis of VEGF concentration in pleural effusions collected from 31 patients with various type of cancer, 8 patients with tuberculosis, 5 patients with transudates. Additionally VEGF concentrations in 11 serum specimens from patients with neoplastic disease was evaluated. VEGF concentrations was determined using a sandwich enzyme-linked immunoadsorbent assay. The VEGF level in pleural transudates as well as tuberculous effusions was significantly lower than in malignant fluid. The were no differences in VEGF level in malignant pleural fluid of different origin. The correlation between VEGF concentrations in malignant pleural fluid and sera of individual patients was not found. Our results indicate that VEGF might play an important role in accumulation of pleural fluid especially that of malignant origin. VEGF level in pleural fluid differs significantly from cancer to benign group of patients what can be important for differential diagnosis of plural effusions origin.
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PMID:[Evaluation of vascular endothelial growth factor (VEGF) in neoplastic and tuberculosis effusions--preliminary results]. 1251 24

HIF-1 is reported to transactivate expression of VEGF, which is an important angiogenic factor. To determine whether HIF-1alpha plays a role in angiogenesis through its regulation of VEGF, we examined expression of HIF-1alpha and its relation to clinicopathologic features, VEGF expression and prognosis of patients with colorectal carcinoma. Expression of HIF-1alpha and VEGF was examined in 4 colorectal carcinoma cell lines (COLO320DM, COLO201, DLD-1, WiDr) and 149 colorectal carcinoma tissues (10 fresh specimens, 139 archival, paraffin-embedded specimens). HIF-1alpha protein levels were increased by hypoxia in 3 of 4 colorectal carcinoma cell lines (COLO201, DLD-1, WiDr), and VEGF mRNA levels were also increased by hypoxia in the same cell lines. In 8 of 10 patients with colorectal cancer, expression of HIF-1alpha and VEGF was increased in tumor tissues compared to corresponding normal mucosa. Of 139 archival specimens of colorectal carcinoma, 81 (58.3%) expressed HIF-1alpha protein at a high level. HIF-1alpha expression was correlated with tumor invasion, tumor stage, lymphatic invasion, venous invasion and liver metastasis. Moreover, HIF-1alpha expression was correlated significantly with VEGF expression and microvessel density. Although there was a tendency for poorer prognosis in patients with high HIF-1alpha-expressing tumors, this correlation was not statistically significant. These findings suggest that HIF-1alpha may play a role in angiogenesis and tumor progression via regulation of VEGF in human colorectal carcinoma.
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PMID:Expression of hypoxia-inducible factor-1alpha is associated with tumor vascularization in human colorectal carcinoma. 1267 75

Measurement of tumor angiogenesis to predict and/or to assess the efficacy of antiangiogenic therapies is mainly based on the evaluation of microvessel density (MVD). We developed a novel flow cytometry procedure to measure circulating endothelial cells (CECs) and circulating endothelial cells progenitors (CECPs) in either preclinical and clinical studies. Preclinical studies were performed on an animal model of human lymphoma. A trend toward higher CECs values was observed on day 7 and 14 after transplant, and differences vs controls were highly significant on day 21 (p = 0.0061). A strong correlation was found between CECs and tumor volume (r = 0.942, p = 0.004) and between CECs and tumor-generated VEGF (r = 0.669, p = 0.02). In mice given cyclophosphamide, most of circulating apoptotic cells were hematopoietic and not endothelial. Conversely, in mice given endostatin, all of the increase in apoptotic cells was in the endothelial cell compartment. In a parallel study, we looked for CECs in the peripheral blood of 20 healthy controls and 76 newly diagnosed cancer patients by means of four-color flow cytometry. In breast cancer (n = 46) and lymphoma (n = 30) patients, both resting and activated CECs were increased by 5 fold (P < 0.0008 vs control). CECs significantly correlated with plasma levels of VCAM-1 and VEGF. Resting and activated CECs were similar to healthy controls in 7 lymphoma patients achieving complete remission after chemotherapy, and activated CECs were found to decrease in 13 breast cancer patients evaluated before and 24h after quadrantectomy. In conclusion, our findings indicate a close relation between CEC increase and tumor progression, and support CECs evaluation as a clinically relevant, non invasive angiogenesis marker. Furthermore, this assay offers insight into anti-angiogenic activity of different drugs.
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PMID:Circulating endothelial cells as a novel marker of angiogenesis. 1267 13

Neovascularization is a hallmark of cancer progression. Suppression of the angiogenic response in tumors has been associated with inhibition and even regression of total tumor mass. Therefore, the derivation of synthetic or natural products that could interfere with proangiogenic signaling pathways can greatly impact cancer therapy. Using the antiangiogenic motifs in thrombospondin-1, we have recently cloned METH1/ADAMTS1, a secreted metalloproteinase with three thrombospondin-1, and shown that the protein inhibits endothelial cell proliferation in vitro and blocks the neovascular response induced by growth factors in vivo. The mechanism of action responsible for these events has not been elucidated. In this report, we present evidence to support two effects of METH1/ADAMTS1 that impact proangiogenic signaling events. ADAMTS1 binds to VEGF and dampens VEGFR2 phosphorylation. The ability of ADAMTS1 to bind VEGF and functionally inactivate VEGFR2 is reversible as dissociation of the complex results in active growth factor. A second activity of ADAMTS1 requires the catalytic domain as a single point mutation in the metalloproteinase domain renders the protein inactive in tumor xenograft assays. The emerging theme is that both domains are likely required for the antiangiogenic/antitumor activities of ADAMTS1.
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PMID:ADAMTS1: a matrix metalloprotease with angioinhibitory properties. 1281 50

The phenotypic characteristics and function of microvascular endothelium differs from tissue to tissue because of the organ specific microenvironment. Even the neovasculature in tumors differs depending upon tumor location. These findings indicate that local regulatory pathways modulate endothelial-cell growth and -function in a tissue specific manner. This might be mediated by novel tissue-specific regulators or the tissue specific regulation of known proteins. One of the major proangiogenic factors is VEGF. Its importance for tumor vascularisation and growth has been shown in several studies. VEGF is expressed in several subtypes and its impact on initial tumor growth and tumor progression has been discussed. Many of these results have been obtained by xenotransplantation studies in mice. The influence of the mouse microenvironment on the VEGF-subtype expression has not been previously analyzed. In the present study we analyzed the impact of the nude mouse microenvironment on the expression of the VEGF-subtypes after subcutaneous xenotransplantation. Our study was performed on seven squamous cell carcinoma (SCC) cell lines. We analyzed by quantitative PCR the mRNA-expression levels and the proportion of the subtypes -121, -165, -189, and of VEGF-total of established xenotransplanted tumors and compared them to the cell lines prior to transplantation. We found high VEGF-165 fractions in the cell lines leading to fast growing, large tumors. The proportion of the VEGF-isoforms remaining in the cell lines and xenotransplanted tumors were generally unchanged, but an overall decrease of VEGF by about 50% was observed. We conclude that the VEGF-subtypes expressed by the transplanted tumors are not differentially regulated by the nude mouse subcutaneous microenvironment and that the tumor growth characteristics are not dependent on VEGF-subtype regulation of the host.
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PMID:Role of the host microenvironment on the expression of VEGF-subtypes in squamous cell carcinoma. 1288 31

To reveal the functional significance of hypoxia and angiogenesis in astrocytoma progression, we created genetically engineered transformed astrocytes from murine primary astrocytes and deleted the hypoxia-responsive transcription factor HIF-1alpha or its target gene, the angiogenic factor VEGF. Growth of HIF-1alpha- and VEGF-deficient transformed astrocytes in the vessel-poor subcutaneous environment results in severe necrosis, reduced growth, and vessel density, whereas when the same cells are placed in the vascular-rich brain parenchyma, the growth of HIF-1alpha knockout, but not VEGF knockout tumors, is reversed: tumors deficient in HIF-1alpha grow faster, and penetrate the brain more rapidly and extensively. These results demonstrate that HIF-1alpha has differential roles in tumor progression, which are greatly dependent on the extant microenvironment of the tumor.
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PMID:The hypoxic response of tumors is dependent on their microenvironment. 1295 88

We reported previously that vascular endothelial growth factor isoform A (VEGF-A) expression by Mel57 human melanoma cells led to tumor progression in a murine brain metastasis model in an angiogenesis-independent fashion by dilation of co-opted, pre-existing vessels and concomitant enhanced blood supply (B. Kusters et al., Cancer Res., 62: 341-345, 2002). Here, we compare the activities of the 121, 165, and 189 VEGF-A isoforms in this model by transfecting Mel57 cells with the respective cDNAs and by injecting the resulting stably transfected cell lines in the internal carotid arteries of nude mice (n = 10 for each isoform). Although the three isoforms had similar potency to induce endothelial cell proliferation, VEGF(121) expression did not result in sprouting angiogenesis but rather led to extensive vasodilation and increased permeability of pre-existing, predominantly peritumoral vessels. Sometimes, proliferating endothelial cells accumulated in vessel lumina, giving these a microvascular, glomeruloid, proliferation-like appearance. Expression of VEGF(165) or VEGF(189) was associated with induction of an intratumoral neovascular bed. In VEGF(165)-expressing tumors, daughter endothelial cells were distributed among newly formed vessels that were extensively dilated. This also occurred in VEGF(189) tumors, but there, vasodilation was less pronounced. Using contrast-enhanced magnetic resonance imaging, the different vascular phenotypes were visualized on characteristic radiological images. VEGF(165) expression was the most unfavorable of the three. Mice carrying VEGF(165) tumors became moribund earlier than those carrying VEGF(121)-expressing tumors (16 +/- 4 days versus 22 +/- 3 days). Our data demonstrate that VEGF-A isoforms differ in angiogenic properties that can be visualized by contrast-enhanced magnetic resonance imaging.
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PMID:Differential effects of vascular endothelial growth factor A isoforms in a mouse brain metastasis model of human melanoma. 1450 Mar 75

Aberrant cell survival and resistance to apoptosis are hallmarks of tumor invasion and progression to metastatic disease, but the mechanisms involved are poorly understood. The epithelial-mesenchymal transition (EMT), a process that facilitates progression to invasive cancer, provides a superb model for studying such survival mechanisms. Here, we used a unique spheroid culture system that recapitulates the structure of the colonic epithelium and undergoes an EMT in response to cytokine stimulation to study this problem. Our data reveal that the EMT results in the increased expression of both VEGF and Flt-1, a tyrosine kinase VEGF receptor, and that the survival of these cells depends on a VEGF/Flt-1 autocrine pathway. Perturbation of Flt-1 function by either a blocking antibody or adenoviral expression of soluble Flt-1, which acts in a dominant-negative fashion, caused massive apoptosis only in cells that underwent EMT. This pathway was critical for the survival of other invasive colon carcinoma cell lines, and we observed a correlative upregulation of Flt-1 expression linked to in vivo human cancer progression. A role for Flt-1 in cell survival is unprecedented and has significant implications for Flt-1 function in tumor progression, as well as in other biological processes, including angiogenesis and development.
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PMID:Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids. 1452 39

Angiogenesis, the formation of blood vessels, is a major factor influencing tumor growth and metastatic capacity, and VEGF is the prototype angiogenic factor. VEGF expression is also found in the dermis and tumor stroma during the course of melanoma progression. Various oncogenes such as c-Src, v-Raf, and Ras, and multiple environmental stimuli, including hypoxia and ultraviolet radiation (UVR), can regulate VEGF expression under certain conditions. We have constructed several cell lines from a radial growth phase, primary human melanoma cell line, WM35. We have stably transfected WM35 cells with mutant activated H-ras, N-ras, dominant negative p53, or empty vector. In this report, we determined how VEGF expression and release from these melanoma cell lines were affected by the following important factors associated with melanoma initiation and progression: hypoxia, UVR, activated Ras, dominant negative p53, and culture conditions mimicking radial growth phase melanoma (monolayer culture) and vertical growth phase melanoma (spheroid culture). We found that hypoxia, but not UVR, up-regulates VEGF mRNA expression and protein release in these melanoma cells. In addition, activated Ras and dominant negative p53 enhances the hypoxia-induced VEGF protein release. We propose that hypoxia-induced VEGF release promotes tumor progression, especially in melanomas with Ras or p53 mutations.
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PMID:Release of vascular endothelial growth factor from a human melanoma cell line, WM35, is induced by hypoxia but not ultraviolet radiation and is potentiated by activated Ras mutation. 1463 12


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