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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies in our laboratory have shown that the elevation of reactive oxygen species levels and the repression of the antioxidant enzyme, catalase, played a critical role in the in vitro progression of benign papilloma cells to malignant carcinoma cells. Catalase message, protein levels, and activity levels were found to be downregulated in the malignantly progressed cells. The goal of this study is to further characterize the repression of catalase in malignant progression of mouse skin tumors. To validate the in vitro observations, we examined catalase expression in tumor samples generated by the multistep chemical carcinogenesis protocol. Higher levels of catalase mRNA and protein were observed in benign papillomas versus malignant carcinomas. Nuclear run-on analysis showed that catalase repression in the cultured malignant cells was transcription-dependent. Results from luciferase reporter assays indicated that malignant cells have lower catalase promoter activities than benign papilloma cells, in part through the Wilm's tumor suppressor 1 (WT1) binding site within the proximal promoter region. The WT1 protein levels were found to be inversely correlated with the observed catalase promoter activities, with higher levels observed in the malignant cells versus the benign cells. These results led us to conclude that WT1 is acting as a transcription repressor in catalase gene regulation during tumor progression.
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PMID:Transcriptional repression of catalase in mouse skin tumor progression. 1554 52

The presence of hypoxic areas is a common feature of solid tumors and has been associated with decreased sensitivity of the tumors to radiation therapy and oxygen-dependent chemotherapeutic agents, as well as worsened outcomes, including survival. Anemia is also common in cancer patients and is believed to contribute to tumor hypoxia. Thus, the rationale exists for administering recombinant human erythropoietin (rHuEPO, epoetin alfa) in an effort to increase hemoglobin levels, correct anemia, and thereby possibly increase the sensitivity of tumors to standard cancer treatment and improve patient outcomes. The results of several preclinical studies that examined the impact of anemia prevention by rHuEPO on tumor sensitivity to radiation therapy in rodent models of cancer showed that induction of anemia increased hypoxia in tumor cells and that correction of anemia with rHuEPO could improve tumor oxygenation. Further studies in rodent models showed significantly delayed tumor growth in both irradiated mice and irradiated rats treated with rHuEPO. In those studies, the increased radiosensitivity observed was believed to be due to improved tumor oxygenation following the correction of anemia. Similarly, enhancements in chemosensitivity were found in rHuEPO-treated rodent models. In the chemosensitivity studies, as in the radiosensitivity studies, the therapeutic benefit obtained was believed to reflect improved tumor oxygenation subsequent to an rHuEPO-related increase in oxygen availability. One study evaluated the potential biologic effects of epoetin alfa on tumor progression using murine myeloma models (MOPC-315 and 5T33 MM). Treatment of MOPC-315 tumor-bearing mice with epoetin alfa induced complete tumor regression in 30%-60% of mice. Regression was found to be tumor specific, and the effect of epoetin alfa was shown to be T-cell mediated. Additionally, epoetin alfa administration prolonged survival and reduced morbidity and mortality in the 5T33 MM tumor model. Those investigators suggested that epoetin alfa may have antitumor activity in addition to its hematopoietic effects. Overall, these preclinical findings suggest that correction of anemia by rHuEPO can increase tumor sensitivity to both radiation therapy and chemotherapy and that epoetin alfa may exert an immunomodulatory effect in multiple myeloma.
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PMID:rHuEPO and treatment outcomes: the preclinical experience. 1559 22

Epidemiological studies have indicated that regular consumption of red wine and green tea is associated with a reduced risk of coronary heart disease and tumor progression. The development of tumors and of atherosclerosis lesions to advanced plaques, which are prone to rupture, is accelerated by the formation of new blood vessels. These new blood vessels provide oxygen and nutrients to neighboring cells. Therefore, recent studies have examined whether red wine polyphenolic compounds (RWPCs) and green tea polyphenols (GTPs) have antiangiogenic properties. In vitro investigations have indicated that RWPCs and GTPs are able to inhibit several key events of the angiogenic process such as proliferation and migration of endothelial cells and vascular smooth muscle cells and the expression of two major proangiogenic factors, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2, by both redox-sensitive and redox-insensitive mechanisms. Antiangiogenic properties of polyphenols have also been observed in the chick embryo chorioallantoic membrane since the local application of RWPCs and GTPs strongly inhibited the formation of new blood vessels. Moreover, intake of resveratrol or green tea has been shown to reduce corneal neovascularization induced by proangiogenic factors such as VEGF and fibroblast growth factor in mice. The ability of RWPCs and GTPs to prevent the formation of new blood vessels contributes, at least in part, to explain their beneficial effect on coronary heart disease and cancer. This review focuses on the antiangiogenic properties of natural polyphenols and examines underlying mechanisms.
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PMID:Antiangiogenic properties of natural polyphenols from red wine and green tea. 1562 34

Her-2/neu (erbB-2) oncogene overexpression is associated with increased tumor progression and metastasis. Fatty acid synthase (FAS), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, has been shown to be one of the genes regulated by Her-2/neu at the level of transcription, translation, and biosynthetic activity. Interestingly, we recently established that both pharmacological inhibition of FAS activity and silencing of FAS gene expression specifically suppress Her-2/neu oncoprotein expression and tyrosine-kinase activity in breast and ovarian Her-2/neu overexpressors. Unraveling the functional organization of this novel bi-directional molecular connection between Her-2/neu and FAS-dependent neoplastic lipogenesis is a major challenge that the field is only beginning to take on. Considering that Her-2/neu overexpression correlates with increased expression of the hypoxia inducible factor-1alpha (HIF-1alpha), which, in a mitogen-activated protein kinase (MAPK)-dependent manner, plays a key role in the expression of several genes including cytokines such as vascular endothelial growth factor (VEGF), we hypothesized that FAS blockade should result in a concomitant down-regulation of VEGF. Unexpectedly, the specific inhibition of the de novo fatty acid synthesis with the small-molecule inhibitor of FAS activity C75 resulted in a dramatic dose-dependent enhancement (up to 500% increase) of VEGF secretion in Her-2/neu-overexpressing SK-Br3, BT-474, and SKOV3 cancer cells. Concurrently, FAS blockade drastically activated MAPK and promoted further a prominent accumulation of HIF-1alpha in Her-2/neu overexpressors. Moreover, U0126-induced inhibition of MAPK activity completely abolished C75-induced up-regulation of HIF-1alpha expression and VEGF secretion, whereas it did not modulate C75-induced down-regulation of Her-2/neu oncogene. Importantly, RNA interference (RNAi)-mediated silencing of the FAS gene recapitulated C75's effects by up-regulating VEGF secretion, MAPK activation and HIF-1alpha expression. Therefore, it appears that perturbation of cancer-associated endogenous fatty metabolism triggers a "hypoxia-like" (oxygen-independent) condition that actively rescues Her-2/neu-dependent MAPK --> HIP-1alpha --> VEGF cascade. It is tempting to suggest that an intact FAS-catalyzed endogenous fatty acid metabolism is a necessary metabolic adaptation to support the enhanced ability of Her-2/neu-overexpressing cancer cells to survive cellular hypoxia in a HIF-alpha-dependent manner.
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PMID:Does endogenous fatty acid metabolism allow cancer cells to sense hypoxia and mediate hypoxic vasodilatation? Characterization of a novel molecular connection between fatty acid synthase (FAS) and hypoxia-inducible factor-1alpha (HIF-1alpha)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing her-2/neu oncogene. 1566 79

Hypoxia-inducible factor (HIF)-deficient placentas exhibit a number of defects, including changes in cell fate adoption, lack of fetal angiogenesis, hypocellularity, and poor invasion into maternal tissue. HIF is a heterodimeric transcription factor consisting of alpha and beta aryl hydrocarbon receptor nuclear translocator or ARNT) subunits. We used undifferentiated trophoblast stem (TS) cells to characterize HIF-dependent adhesion, migration, and invasion. Arnt(-/-) and Hifalpha(-/-) TS cells exhibit reduced adhesion and migration toward vitronectin compared with wild-type cells. Furthermore, this defect is associated with decreased cell surface expression of integrin alphavbeta3 and significantly decreased expression of this integrin in focal adhesions. Because of the importance of adhesion and migration in tumor progression (in addition to placental development), we examined the affect of culturing B16F0 melanoma cells in 1.5% oxygen (O(2)). Culturing B16F0 melanoma cells at 1.5% O(2) resulted in increased alphavbeta3 integrin surface expression and increased adhesion to and migration toward vitronectin. Together, these data suggest that HIF and O(2) tension influence placental invasion and tumor migration by increasing cell surface expression of alphavbeta3 integrin.
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PMID:Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression. 1568 87

The generation of reactive oxygen radicals in mammalian cells profoundly affects numerous critical cellular functions, and the absence of efficient cellular detoxification mechanisms which remove these radicals can result in several human diseases. Growing evidence suggests that reactive oxygen species (ROS) within cells act as second messengers in intracellular signaling cascades which induce and maintain the oncogenic phenotype of cancer cells. ROS are tumorigenic by virtue of their ability to increase cell proliferation, survival, cellular migration, and also by inducing DNA damage leading to genetic lesions that initiate tumorigenicity and sustain subsequent tumor progression. However, it is also known that ROS can induce cellular senescence and cell death and can therefore function as anti-tumorigenic agents. Therefore, the mechanisms by which cells respond to reactive oxygen species depends on the molecular background of cell and tissues, the location of ROS production and the concentration of individual ROS species. Carcinoma cells produce ROS at elevated rates in vitro, and in vivo many tumors appear persistent to oxidative stress. Thus, the finding that a diet rich in antioxidants or the elimination of ROS by antioxidant compounds prevents the development of certain cancers provided the setting for subsequent investigation of the tumorigenic actions of reactive oxygen species. This review outlines the current knowledge on the various roles of ROS in tumor development and progression.
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PMID:Reactive oxygen species in tumor progression. 1576 73

The initiation of angiogenesis, called the angiogenetic switch, is a crucial early step in tumor progression and propagation, ensuring an adequate oxygen supply. The rapid growth of tumors is accompanied by a reduced microvessel density, resulting in chronic hypoxia that often leads to necrotic areas within the tumor. These hypoxic and necrotic regions exhibit increased expression of angiogenetic growth factors, eg, vascular endothelial growth factor, and may also attract macrophages, which are known to produce a number of potent angiogenetic cytokines and growth factors. A group of molecules that may act as mediators of angiogenesis are the so-called high-mobility group proteins. Recent studies showed that HMGB1, known as an architectural chromatin-binding protein, can be extracellularly released by passive diffusion from necrotic cells and activated macrophages. To examine the angiogenetic effects of HMGB1 on endothelial cells an in vitro spheroid model was used. The results of the endothelial-sprouting assay clearly show that exogenous HMGB1 induced endothelial cell migration and sprouting in vitro in a dose-dependent manner. Thus, this is the first report showing strong evidence for HMGB1-induced sprouting of endothelial cells.
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PMID:Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule. 1579 4

Being key regulator of oxygen homeostasis hypoxia-inducible factor 1 (HIF-1) plays significant roles in cancer progression as well as in cardiovascular diseases. The modulation of HIF-1alpha activity in vivo may represent a valuable therapeutic approach to these disorders. In order to monitor HIF-1 transcriptional activity, we have developed HIF-1alpha-responsive reporter constructs, in which lacZ gene expression is driven by minimal Hsp70 gene promoter or minimal immediate early promoter of cytomegalovirus (CMV) and a combination of hypoxia response elements from regulatory regions of PGK1, ENO1 and LDHA genes. For the efficient delivery to a wide variety of cell types we chose retroviral and lentiviral vectors as carriers of the reporter cassette. We demonstrate that the obtained reporter system i) has a high inducibility in response to treatments leading to HIF-1alpha activation, ii) shows upregulation in response to HIF-1 activation and downregulation following inhibition of HIF-1alpha expression by small interfering RNA, iii) follows the dynamics of endogenous HIF-1 target gene expression. The retrovirus- and lentivirus-based reporters can be used for high-throughput screening of HIF-1alpha modulators and for the study of crosstalk between HIF-1 and different related signal transduction pathways. Potential applications for the reporters are discussed.
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PMID:Virus-based reporter systems for monitoring transcriptional activity of hypoxia-inducible factor 1. 1579 24

Tumor oxygenation status is an independent prognostic indicator in cancer because it influences tumor progression and treatment outcome. Its quantitative value is determined by a number of tumor vascular parameters such as microvascular density, blood flow, blood volume, blood oxygen saturation, tumor tissue pO2, and resistance to oxygen diffusion within the tumor. Over the past several years, considerable time and effort have been invested into developing techniques to effectively and reliably measure the oxygenation status of a tumor. The measurement and interpretation of data obtained with currently available methods is complicated by the heterogeneity in tumor oxygenation. Currently available techniques can be broadly classified into direct invasive methods, direct non-invasive methods, and measurement of surrogate endogenous markers of tumor oxygenation. Of these methods, the Eppendorf pO2 histograph is considered the 'gold standard' and even so has several limitations. Given the importance of tumor oxygenation status in therapy and in predicting disease progression, it is imperative that reliable, globally usable, and technically simplistic methods be developed to yield a consistent, comprehensive, and reliable profile of tumor oxygenation. Until newer more reliable techniques are developed, existing independent techniques or appropriate combinations of techniques should be optimized and validated using known endpoints in tumor oxygenation status and/or treatment outcomes.
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PMID:Tumor oxygenation status as a prognostic marker. 1580 8

In locally advanced solid tumors, oxygen (O2) delivery is frequently reduced or even abolished. This is due to abnormalities of the tumor microvasculature, adverse diffusion geometries, and tumor-associated and/or therapy-induced anemia. Up to 50-60% of locally advanced solid tumors may exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumor mass. In approximately 30% of pretreatment patients, a decreased O2 transport capacity of the blood as a result of tumor-associated anemia can greatly contribute to the development of tumor hypoxia. While normal tissues can compensate for this O2 deficiency status by a rise in blood flow rate, locally advanced tumors (or at least larger tumor areas) cannot adequately counteract the restriction in O2 supply and thus the development of hypoxia. Hypoxia-induced alteration in gene expression and thus in the proteome (< 1% O2, or < 7 mmHg), and/or genome changes (< 0.1% O2, or < 0.7 mmHg) may promote tumor progression via mechanisms enabling cells to overcome nutritive deprivation, to escape from the hostile metabolic microenvironment and to favor unrestricted growth. Sustained hypoxia may thus lead to cellular changes resulting in a more clinically aggressive phenotype. In addition, hypoxia is known to directly or indirectly confer resistance to X- and gamma-radiation, and some chemotherapies leading to treatment failures. Whereas strong evidence has accumulated that hypoxia plays a pivotal role in tumor progression and acquired treatment resistance, the mechanism(s) by which treatment efficacy and survival may be compromised by anemia (independent of hypoxia) are not fully understood.
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PMID:Hypoxia and anemia: effects on tumor biology and treatment resistance. 1581 85


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