Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although vascular endothelial growth factor-165 (VEGF(165)) regulates numerous angiogenic cellular activities, its complex effects on vascular morphology are not highly quantified. By fractal-based, multiparametric branching analysis of 2D vascular pattern in the quail chorioallantoic membrane (CAM), we report that vessel density increased maximally at lower VEGF concentrations, but that vessel diameter and activity of endothelial nitric oxide synthase (eNOS) increased maximally at higher VEGF concentrations. Following exogenous application of human VEGF(165) to the CAM at embryonic day 7, vessel density and diameter were measured after 24 h at arterial end points by the fractal dimension (D(f)) and generational branching parameters for vessel area density (A(v)), vessel length density (L(v)) and vessel diameter (D(v)) using the computer code VESGEN. The VEGF-dependent phenotypic switch from normal vessels displaying increased vessel density to abnormal, dilated vessels typical of tumor vasculature and other pathologies resulted from an approximate threefold increase in VEGF concentration (1.25 to 5 microg/CAM) and correlated positively with increased eNOS activity. Relative to control specimens, eNOS activity increased maximally to 60% following VEGF treatment at 5 microg/CAM, compared to 10% at 1.25 microg/CAM, and was accompanied by no significant change in activity of inducible NOS. In summary, VEGF(165) induced a phenotypic switch from increased vessel density associated with low VEGF concentration, to increased vessel diameter and increased eNOS activity at high VEGF concentration.
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PMID:A VEGF165-induced phenotypic switch from increased vessel density to increased vessel diameter and increased endothelial NOS activity. 1687 39

Over the past decade, the old idea that the bone marrow contains endothelial cell precursors has become an area of renewed interest. While some still believe that there are no endothelial precursors in the blood, even among those who do, there is no consensus as to what they are or what they do. In this review, we describe the problems in identifying endothelial cells and conclude that expression of endothelial nitric oxide synthase may be the most reliable antigenic indicator of the phenotype. The evidence for two different classes of endothelial precursors is also presented. We suggest that, though there is no single endothelial cell precursor, we may be able to use these phenotypic variations to our advantage in better understanding their biology. We also discuss how a variety of genetic, epigenetic, and methodological differences can account for the seemingly contradictory findings on the physiological relevance of bone marrow-derived precursors in normal vascular maintenance and in response to injury. Data on the impact of tumor type and location on the contribution of bone marrow-derived cells to the tumor vasculature are also presented. These data provide hope that we may ultimately be able to predict those tumors in which bone marrow-derived cells will have a significant contribution and design therapies accordingly. Finally, factors that regulate bone marrow cell recruitment to and function in the endothelium are beginning to be identified, and several of these, including stromal derived factor 1, monocyte chemoattractant factor-1, and vascular endothelial growth factor are discussed.
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PMID:Biology of bone marrow-derived endothelial cell precursors. 1698 Mar 51

We investigated the ability of TZT-1027 (Soblidotin), a novel antimicrotubule agent, to induce antivascular effects, because most vascular targeting agents that selectively disrupt tumor vasculature also inhibit tubulin polymerization. Treatment with 10(-7) g/mL TZT-1027 rapidly disrupted the microtubule cytoskeleton in human umbilical vascular endothelial cells (HUVEC), and significantly enhanced vascular permeability in HUVEC monolayers. In addition, single intravenous administration of 2 mg/kg TZT-1027 to mice bearing Colon26 tumors significantly reduced tumor perfusion and caused extravascular leakage of erythrocytes 1 h after administration. Subsequently, thrombus formation with deposition of fibrin and tumor necrosis was observed 3 and 24 h after administration, respectively. These results strongly suggest that TZT-1027 possesses antivascular effects. TZT-1027 induced apoptosis not only in HUVEC but also in C26 cancer cells (cell line of Colon26 solid tumor) in vitro, suggesting it exerts direct cytotoxicity against tumor cells in addition to its antivascular effects. A single intravenous administration of 1, 2 and 4 mg/kg TZT-1027 significantly prolonged the survival of mice with advanced-stage Colon26 tumors in a dose-dependent manner. Furthermore, TZT-1027 itself less markedly enhanced the permeability of normal vessels, but was additive with vascular endothelial growth factor, indicating the possibility that TZT-1027 selectively exerts its activity on tumor vessels. In summary, these results suggest that TZT-1027 exerts both an indirect antivascular effect and a direct cytotoxic effect, resulting in strong antitumor activity against advanced-stage tumors, and that TZT-1027 may be useful clinically for treating solid tumors.
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PMID:Antivascular effects of TZT-1027 (Soblidotin) on murine Colon26 adenocarcinoma. 1699 18

Angiogenesis provides blood supply for tumor expansion and also increases the opportunity for tumor cells to enter the blood or lymph circulation. Several proangiogenic factors as well as the contribution of the microenvironment to tumor-induced angiogenesis have been identified. Among these, vascular endothelial growth factor (VEGF) and the angiopoietin (Ang) family play a predominant role involved in the growth for endothelial cells. Tumor vessels are structurally and functionally abnormal because of an imbalance of these angiogenic regulators. In contrast to normal vessels, tumor vasculature is highly disorganized, tortuous and dilated, with uneven diameter and excessive branching. In other words, the morphologic features are likely to carry additional clues that, when used in conjunction with more established parameters, can improve the present diagnostic approaches. In our study, we present a new method that helps to capture the morphologic features from three-dimensional (3-D) power Doppler ultrasound (PDUS) images. After narrowing down the vessels into their skeletons using a 3-D thinning algorithm, we extracted seven features including vessel-to-volume ratio, number of vascular trees, number of bifurcation, mean of radius and three tortuosity measures, from the skeleton and applied a neural network to classify the tumors by using these features. In investigations into 221 solid breast tumors, including 110 benign and 111 malignant cases, the p values using the Student's t-test for all features were less than 0.05, indicating that the proposed features were deemed statistically significant. The A(Z) values for these seven features were 0.84, 0.87, 0.84, 0.75, 0.77, 0.79 and 0.69, respectively. The accuracy, sensitivity, specificity, and positive and negative predictive values were 80.09% (177 of 221), 80.18% (89 of 111), 80% (88 of 110), 80.18% (89 of 111) and 80% (88 of 110), respectively, with an A(Z) value of 0.89. The preliminary results show that the proposed method is feasible and has a good agreement with the diagnosis of the pathologists.
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PMID:Computer algorithm for analysing breast tumor angiogenesis using 3-D power Doppler ultrasound. 1704 70

Tumor angiogenesis is a complex process that requires the coordinated activities of various effector molecules and cell types. While tumor vasculature can nourish the tumor, it is structurally and functionally abnormal, leading to elevated interstitial pressure and non-uniform tumor perfusion. The resultant hypoxia leads to the selection of more aggressive tumor cells, owing in part to an increase in the levels of the transcription factor hypoxia-inducible factor-1, which in turn leads to an increase in the expression of vascular endothelial growth factor (VEGF). The expression of VEGF is upregulated in many tumors, and the levels of this factor correlate not only with the extent of tumor angiogenesis but also with clinical prognosis. VEGF-targeted therapies, such as bevacizumab, exert their effects through a number of potential mechanisms, including (1) inhibition of new vessel growth, (2) regression of newly formed tumor vasculature, (3) alteration of vascular function and tumor blood flow ("normalization"), and (4) direct effects on tumor cells. Because of the presumed cytostatic mechanism of action of antiangiogenic agents, the efficacy of bevacizumab is most appropriately assessed through survival end points rather than the objective-response end points that have traditionally been used with cytotoxic agents. However, bevacizumab has been shown to increase the response rates with chemotherapy in almost all tumor types studied in phase III trials.
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PMID:Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. 1714 19

Despite the routine use of adjuvant and neoadjuvant chemoradiotherapy, patients with advanced rectal tumors experience significant rates of treatment failure and disease recurrence. Resistance to radiation is a particular problem. Adding a vascular endothelial growth factor (VEGF)-targeted therapy may improve outcomes in these patients. Epidemiologic studies have shown that tumor expression of VEGF predicts disease recurrence and lower overall survival in patients treated with radiation. In tumor xenograft models in mice, VEGF-targeted agents increase the response to radiation, with a greater probability of tumor control and a greater delay in tumor growth. In addition to killing cancer cells indirectly by damaging tumor blood vessels (antivascular effect), VEGF-targeted therapy may sensitize tumors to radiation through two mechanisms: by normalizing the tumor vasculature, leading to greater tumor oxygenation, and thereby increasing the cytotoxicity of radiation to cancer cells, and by increasing the radiosensitivity of tumor-associated endothelial cells. In addition, anti-VEGF agents may inhibit the regrowth of tumors after radiation by decreasing the number of circulating endothelial cells and endothelial progenitor cells. A phase I dose-escalation study has shown the safety of bevacizumab at a dose of 5 mg/kg in combination with 5-fluorouracil and radiation in patients with rectal carcinoma, and has provided evidence of both vascular normalization and antivascular mechanisms. Phase II evaluation of bevacizumab in this setting is under way.
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PMID:Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice. 1714 23

Bevacizumab, the first approved vascular endothelial growth factor (VEGF)-targeted agent for metastatic colorectal cancer, continues to be developed in phase III trials in other tumor types. Its use is being explored not only in advanced disease, but also in earlier-stage disease in the adjuvant setting. Preclinical and clinical research is also addressing several potential strategies for maximizing the benefits of bevacizumab and other VEGF-targeted agents, including (1) dual inhibition of VEGF and platelet-derived growth factor signaling to target both the endothelial and the pericyte components of tumor vasculature; (2) combining VEGF-targeted agents with other targeted agents, such as inhibitors of HER2 or epidermal growth factor receptor signaling, which affect several angiogenic pathways; and (3) combining VEGF-targeted agents with low-dose, metronomic chemotherapy. The optimal dose and schedule of VEGF-targeted agents is another unanswered question. Further investigation of the mechanism of action and vascular effects of VEGF-targeted agents in humans will help to address these questions. Mechanistic studies in humans will be aided by the development and validation of surrogate clinical end points such as noninvasive assessment of hemodynamics and vascular changes within tumors, using imaging studies.
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PMID:Future directions in vascular endothelial growth factor-targeted therapy for metastatic colorectal cancer. 1714 24

Therapies aimed at destruction of the tumor vasculature are now recognized as a promising approach against cancer, and it has been reported that the combination treatment with an angiogenic inhibitor and conventional chemotherapeutic drug exerted synergistic anti-cancerous effects. We previously reported that the clinically used angiotensin-converting enzyme inhibitor (ACE-I) exerted potent-anti-angiogenic activities. The aim of our current study was to examine the combined effect of ACE-I and 5-fluorouracil (5-FU), which is widely used for hepatogastrointestinal tumors, on hepatocellular carcinoma (HCC) growth and hepatocarcinogenesis. When used individually at low doses, neither 5-FU nor ACE-I exerted significant inhibitory effects on the HCC growth. However, the combination treatment of 5-FU and ACE-I showed a potent inhibitory effect on HCC growth along with suppression of neovascularization in the tumor. The expression level of the vascular endothelial growth factor, a potent angiogenic factor, was also suppressed, almost in conjunction with tumor growth inhibition. Furthermore, 5-FU and ACE-I treatment resulted in a marked increase of apoptosis in the tumor. In the hepatocarcinogenesis model, the combination treatment with 5-FU and ACE-I also showed a marked inhibitory effect on the development of preneoplastic lesions. The in vitro study demonstrated that this combination treatment inhibited endothelial cell tubular formation. Collectively, the combination treatment of 5-FU and ACE-I exerted a marked synergistic inhibitory effect on HCC growth via suppression of angiogenesis. This regimen also showed a chemopreventive effect against hepatocarcinogenesis. Since both 5-FU and ACE-I are widely used in clinical practice, this combination therapy may be an effective new therapeutic strategy against HCC in the future.
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PMID:Synergistic inhibition of hepatocellular carcinoma growth and hepatocarcinogenesis by combination of 5-fluorouracil and angiotensin-converting enzyme inhibitor via anti-angiogenic activities. 1720 85

RNA interference is being developed to treat cancer. Although highly target specific, its use has been limited by its short duration of expression. To overcome this shortcoming, we constructed an oncolytic adenovirus (Ad)-based short hairpin RNA (shRNA) expression system (Ad-DeltaB7-shVEGF) against vascular endothelial growth factor (VEGF), a key mediator in angiogenesis. To demonstrate the VEGF-specific nature of this Ad-based shRNA, replication-incompetent Ad expressing VEGF-specific shRNA (Ad-DeltaE1-shVEGF) was also generated. Ad-DeltaE1-shVEGF was highly effective in reducing VEGF expression, and elicited an antiangiogenic effect in vitro and in vivo. Similarly, Ad-DeltaB7-shVEGF exhibited potent antiangiogenic effects in the matrigel plug assay. Moreover, Ad-DeltaB7-shVEGF demonstrated a greater antitumor effect and enhanced survival compared to the cognate control oncolytic Ad, Ad-DeltaB7. Ad-DeltaB7-shVEGF induced significant reduction in tumor vasculature, verifying the antiangiogenic mechanism. Furthermore, both the duration and magnitude of gene silencing by Ad-DeltaB7-shVEGF was greater than Ad-DeltaE1-shVEGF. These results suggest that the combined effects of oncolytic viral therapy and cancer cell-specific expression of VEGF-targeted shRNA elicits greater antitumor effect than an oncolytic Ad alone.
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PMID:VEGF-specific short hairpin RNA-expressing oncolytic adenovirus elicits potent inhibition of angiogenesis and tumor growth. 1723 98

We have shown previously that endogenous deficiency of interleukin (IL)-12 promotes photocarcinogenesis in mice. To characterize the role of IL-12 deficiency in tumor angiogenesis, we developed IL-12p35 knockout (IL-12 KO) mice on a C3H/HeN background. IL-12 KO mice and their wild-type (WT) counterparts were subjected to a photocarcinogenesis protocol. When tumor yield was stabilized, samples of tumor and tumor-uninvolved UVB-exposed skin were collected and subjected to immunohistochemistry, gelatinolytic zymography, real-time PCR, and Western blot analysis of angiogenic factors. We found that the protein, mRNA expression and/or activity of the matrix metalloproteinases (MMP)-2, MMP-3, MMP-7, and MMP-9, and basic fibroblast growth factor, which play crucial roles in tumor growth, were significantly higher in UVB-exposed skin and tumors of IL-12 KO mice compared with WT mice. With respect to the tumor vasculature, the expression of CD31-positive cells and the expression of vascular endothelial growth factor were higher in the tumors of IL-12 KO mice than WTs. The proliferative capacity of tumor cells of the IL-12 KO mice was significantly higher than their WT counterparts when determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by analyzing the expression of cyclin D1. The level of the proinflammatory cytokine IL-6 and the expression of IL-23 in tumors of IL-12 KO mice were markedly higher than in the tumors of WT mice. IL-23 has been shown to promote tumor growth. Together, these data indicate for the first time that IL-12 deficiency promotes proangiogenic stimuli in UVB-induced skin tumors and suggest that endogenous enhancement of IL-12 levels may be effective in the prevention and treatment of UV-induced skin cancers.
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PMID:Interleukin-12 deficiency is permissive for angiogenesis in UV radiation-induced skin tumors. 3050 58


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