Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Galectin-3 is a beta-galactoside-binding protein which regulates many biological processes including cell adhesion, migration, cell growth, tumor progression, metastasis, and apoptosis. Although the exact function of galectin-3 in cancer development is unclear, galectin-3 expression is associated with neoplastic progression and metastatic potential. Since studies have suggested that tumor cell survival in microcirculation determines the metastatic outcome, we examined the effect of galectin-3 overexpression in human breast carcinoma cell survival using the liver ischemia/reperfusion metastasis model. While the majority of control cells died by hepatic ischemia/reoxygenation, nearly all of galectin-3 overexpressing cells survived. We showed that galectin-3 inhibits nitrogen free radical-mediated apoptosis, one of the major death pathways induced during hepatic ischemia/reperfusion. Galectin-3 inhibition of apoptosis involved protection of mitochondrial integrity, inhibition of cytochrome c release and caspase activation. Taking these results together with the previous observation that galectin-3 inhibits apoptosis induced by loss of cell adhesion, we propose that galectin-3 is a critical determinant for anchorage-independent and free radical-resistant cell survival during metastasis.
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PMID:Galectin-3 protects human breast carcinoma cells against nitric oxide-induced apoptosis: implication of galectin-3 function during metastasis. 1154 97

Hypoxia is a critical event for higher organisms, and cells and tissues react by increasing the oxygen supply by vasodilatation, angiogenesis, and erythropoiesis and maintaining cellular energy by increasing glycolysis and inhibiting anabolic pathways. Stimulation of glycolysis has been regarded as the main response that increases energy production during hypoxia; however, there is an obvious conflict during ischemia, because both the oxygen and glucose supply are insufficient. In this study, we found that exposure of HepG2 cells and normal fibroblasts to hypoxia induces cellular tolerance to glucose starvation. The tolerance induced by hypoxia is dependent on several amino acids, indicating a switch from glucose to amino acids as the energy source. When antisense RNA expression vector for 5'-AMP-activated protein kinase or protein kinase B/Akt was transfected into HepG2 cells, the induction of tolerance to glucose was greatly inhibited, indicating that the tolerance was dependent on 5'-AMP-activated protein kinase and protein kinase B/Akt. Similar tolerance was induced by nitric oxide exposure. The tolerance induced was observed in various cells and may represent a previously unknown physiological response related to hypoxia-preconditioning and tumor progression:austerity.
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PMID:Hypoxia and nitric oxide treatment confer tolerance to glucose starvation in a 5'-AMP-activated protein kinase-dependent manner. 1209 79

Calpains are cysteine proteases first identified 50 years ago. Because they are present in the cytosol of mammalian cells and because they are activated in response to Ca2+ mobilization, they are thought to be involved mainly in cell signalling pathways. They could participate in cellular responses such as apoptosis, proliferation, extracellular matrix adhesion and motility, that have relevance to pathophysiological issues in ischemia, inflammation, repair and tumor progression. Here we consider calpain functions in inflammatory reaction. We report the recent observation that calpain inhibitors reduce the development of acute and chronic inflammation. This has opened the door for understanding how these enzymes are effective in inflammation. We present data suggesting that calpains are primarily responsible for the activation of nuclear factor-kappa B, a transcription factor with a pivotal role in inflammation. They are involved in inflammatory cell adhesion and migration, pro-inflammatory mediator release and anti-inflammatory hormone resistance as well. In addition, we emphasize the intriguing possibility that calpains are externalized during inflammatory process and that they play a role in the microenvironment of inflammatory cells. Thus, both intracellular and extracellular calpains would offer novel therapeutic targets in inflammation.
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PMID:[Calpains participate in inflammatory reaction development]. 1283 94

Among novel promising approaches that have recently entered the scene of anti-cancer therapy angiogenesis inhibition and targeting cancer-causing genes (e.g. oncogenes) are of particular interest as potentially highly synergistic. One reason for this is that transforming genetic lesions driving cancer progression (e.g. mutations of ras and/or p53) are thought to be causative for the onset of tumor angiogenesis and thereby responsible for build up of vascular supply which is essential for cancer cell survival, malignant growth, invasion and metastasis. However, many of the same genetic alterations that emerge during disease progression and repeated rounds of mutagenic and/or apoptosis causing therapy could alter cellular hypoxia-, growth factor- and apoptotic pathways in such a manner, as to also render cancer cells (partially) refractory to the detrimental consequences of poor blood vessel accessibility (density), ischemia, hypoxia and growth factor deprivation. As recent experimental evidence suggests, such cancer cells could therefore display a reduced vascular demand and remain viable even in poorly perfused regions of the tumor as well as possess an overall growth/survival advantage. The latter circumstance may lead to (predict) diminished efficacy of anti-angiogenic agents in certain malignancies. Therefore, we propose that analysis of oncogenic pathways and gene expression profiling of cancer cells may lead to important clues as to potential efficacy of anti-angiogenic therapies, the direct target of which is the host vasculature, but which are ultimately aimed at (indirect) destruction/control of the cancer cells population. We also suggest that oncogene (tumor suppressor)-directed therapies may help reverse diminished vascular demand of highly transformed cancer cells and thereby facilitate (sensitize tumors to) therapies directed against vascular supply of cancers and their metastases.
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PMID:Oncogenes and tumor angiogenesis: the question of vascular "supply" and vascular "demand". 1501 93

Osteopontin (OPN) is a glyco-phosphoprotein that is expressed and secreted by numerous human cancers. OPN functions in cell adhesion, chemotaxis, macrophage-directed interleukin-10 (IL-10) suppression, stress-dependent angiogenesis, prevention of apoptosis, and anchorage-independent growth of tumor cells by regulating cell-matrix interactions and cellular signaling through binding with integrin and CD44 receptors. While constitutive expression of OPN exists in several cell types, induced expression has been detected in T-lymphocytes, epidermal cells, bone cells, macrophages, and tumor cells in remodeling processes such as inflammation, ischemia-reperfusion, bone resorption, and tumor progression. Recently, substantial evidence has linked OPN with the regulation of metastatic spread by tumor cells. However, the molecular mechanisms that define the role of OPN in tumor metastasis are incompletely understood. Transcriptional regulators that contribute to the induction of OPN expression have received significant attention as potential modulators of the OPN-mediated metastatic phenotype. The following review will discuss the molecular structure of OPN, the evidence for its functional role in tumor cell metastasis, the downstream signals that activate invasive mechanisms, and the recent reports concerning regulation of OPN transcription.
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PMID:The role of Osteopontin in tumor metastasis. 1550 63

Hepatocellular carcinoma is the fifth leading cause of cancer worldwide and its incidence is increasing. Surveillance programs allow doctors to identify patients at early stages of the disease, when the tumor may be curable by radical treatments such as resection, liver transplantation, or local ablation. In the West, these treatments can be applied to 30% to 40% of patients. Resection yields favorable results in patients with single tumors and a well-preserved liver function (5-year survival rate is 60%). Recurrence complicates two thirds of the cases, and there is no effective adjuvant treatment. Liver transplantation is the best treatment for patients with single tumors that are less than 5 cm in diameter and liver failure, or in those presenting with three nodules less than 3 cm, but organ shortage greatly limits its applicability. Long-term survival is expected to be around 50% to 70% at 5 years depending upon the drop-out rate of patients on the waiting list. Chemoembolization and local ablation are the neo-adjuvant treatments applied to patients on the waiting list to prevent tumor progression; no controlled study proving their efficacy has yet been published. In nonsurgical candidates, percutaneous treatments (ethanol injection or radiofrequency ablation) are the best therapeutic approach and improve survival in Child-Pugh A class patients with small tumors that achieve initial complete response (5-year survival rate is 40% to 50%). At more advanced stages, chemoembolization, a technique combining intra-arterial chemotherapy and selected ischemia, has shown to slightly improve survival in a meta-analysis of randomized trials. No survival advantages have been demonstrated with intra-arterial or systemic chemotherapy, hormonal compounds, or radiation. New agents, such as inhibitors of the tyrosine kinase receptors of growth factors and antiangiogenic agents, are currently being tested in phase II/III trials.
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PMID:Treatment of Hepatocellular Carcinoma. 1552 9

Mutation of the K-ras gene is one of the most common genetic alterations in solid tumors, including colorectal cancer. The relatively late emergence of K-ras mutations in colorectal cancer is particularly striking in the class of mismatch repair-deficient tumors associated with early-onset microsatellite instability. We, therefore, tested the hypothesis that the microsatellite instability phenotype itself does not efficiently trigger K-ras mutations in colorectal cancer cells, but rather that tumor-associated microenvironmental conditions (e.g., hypoxia and hypoglycemia) contribute to this event by modulating genetic instability. We examined K-ras(G13D) mutation using PCR-RFLP analysis in two different microsatellite instability colorectal cancer cell lines (HCT116 and DLD-1) and their variants in which the mutant (but not the wild-type) K-ras allele has been genetically disrupted (Hkh-2 and Dks-8). We found K-ras(G13D) mutation to occur at far greater incidence in cells derived from xenografted tumors or exposed to conditions of combined hypoxia and hypoglycemia in vitro. Interestingly, this mutagenesis was neither enhanced by induced oxidative damage nor prevented by the antioxidant vitamin E. Moreover, the accumulation of K-ras mutations was paralleled by down-regulation of the key mismatch repair protein MSH2 in xenografted tumors, particularly in hypoperfused areas and under hypoglycemic conditions (in vitro). In contrast, the microsatellite stable colorectal cancer cell line Caco-2 neither accumulated K-ras mutations nor showed down-regulation of MSH2 under these conditions. Thus, our study suggests that ischemia may not simply select for, but can actually trigger, increased mutation rate in crucial colorectal cancer oncoproteins. This finding establishes a novel linkage between genetic instability, tumor ischemia, and genetic tumor progression and carries important implications for applying anticancer therapies involving tumor hypoxia (e.g., antiangiogenesis) in microsatellite instability cancers.
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PMID:Ischemia-induced K-ras mutations in human colorectal cancer cells: role of microenvironmental regulation of MSH2 expression. 1616 87

Tumor ischemia participates in angiogenesis and cancer progression through cellular responses to hypoxia and nutrient deprivation. However, the contribution of amino acids limitation to this process remains poorly understood. Using serum-free cell culture conditions, we tested the impact of L-glutamine deprivation on metabolic and angiogenic responses in A549/8 carcinoma cells. In these cells, lowering glutamine concentration modified the cell cycle distribution and significantly induced apoptosis/necrosis. Although glutamine deprivation led to a HIF-independent increase in VEGF-A mRNA, the corresponding protein level remained low and correlated with the inhibition of protein synthesis and activation of the GCN2/eIF2alpha pathway. Limitation of glutamine availability also hampers hypoxia- and hypoglycemia-induced VEGF-A protein upregulation. Thus, glutamine deprivation may have no direct effect on VEGF-dependent angiogenesis, compared to hypoxia or to glucose deprivation, and may instead be detrimental to cancer progression by antagonizing ischemia-induced stresses.
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PMID:Acute L-glutamine deprivation compromises VEGF-a upregulation in A549/8 human carcinoma cells. 1734 20

The migration of macrophages through peripheral tissues is an essential step in the host response to infection, inflammation, and ischemia as well as in tumor progression and tissue repair. The mannose receptor (MR; CD206, previously known as the macrophage MR) is a 175-kDa type I transmembrane glycoprotein and is a member of a family of four recycling endocytic receptors, which share a common extracellular domain structure but distinct ligand-binding properties and cell type expression patterns. MR has been shown to bind and internalize carbohydrate and collagen ligands and more recently, to have a role in myoblast motility and muscle growth. Given that the related Endo180 (CD280) receptor has also been shown to have a promigratory role, we hypothesized that MR may be involved in regulating macrophage migration and/or chemotaxis. Contrary to expectation, bone marrow-derived macrophages (BMM) from MR-deficient mice showed an increase in random cell migration and no impairment in chemotactic response to a gradient of CSF-1. To investigate whether the related promigratory Endo180 receptor might compensate for lack of MR, mice with homozygous deletions in MR and Endo180 were generated. These animals showed no obvious phenotypic abnormality, and their BMM, like those from MR-deficient mice, retained an enhanced migratory behavior. As MR is down-regulated during macrophage activation, these findings have implications for the regulation of macrophage migration during different stages of pathogenesis.
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PMID:Mannose receptor regulation of macrophage cell migration. 1759 37

In cancer, the extensive methylation found in the bulk of chromatin is reduced, while the normally unmethylated CpG islands become hypermethylated. Regions of solid tumors are transiently and/or chronically exposed to ischemia (hypoxia) and reperfusion, conditions known to contribute to cancer progression. We hypothesized that hypoxic microenvironment may influence local epigenetic alterations, leading to inappropriate silencing and re-awakening of genes involved in cancer. We cultured human colorectal and melanoma cancer cell lines under severe hypoxic conditions, and examined their levels of global methylation using HPLC to quantify 5-methylcytosine (5-mC), and found that hypoxia induced losses of global methylation. This was more extensive in normal human fibroblasts than cancer cell lines. Cell lines from metastatic colorectal carcinoma or malignant melanoma were found to be markedly more hypomethylated than cell lines from their respective primary lesions, but they did not show further reduction of 5-mC levels under hypoxic conditions. To explore these epigenetic changes in vivo, we established xenografts of the same cancer cells in immune deficient mice. We used Hypoxyprobe to assess the magnitude of tissue hypoxia, and immunostaining for 5-mC to evaluate DNA methylation status in cells from different regions of tumors. We found an inverse relationship between the presence of extensive tumor hypoxia and the incidence of methylation, and a reduction of 5-mC in xenografts compared to the levels seen in the same cancer cell lines in vitro, verifying that methylation patterns are also modulated by hypoxia in vivo. This suggests that epigenetic events in solid tumors may be modulated by microenvironmental conditions such as hypoxia.
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PMID:Induction of DNA hypomethylation by tumor hypoxia. 1796 19


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