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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factors (HIF-1 and HIF-2) are two closely related protein complexes that activate transcription of target genes in response to hypoxia. Expression of HIF-1alpha and HIF-2alpha and their effects on survival under hypoxia were studied in six human breast cancer cell lines. We also evaluated the basal and inducible expression of two hypoxically regulated genes, vascular endothelial growth factor (VEGF) and lactate dehydrogenase-A (LDH-A). All of the cell lines studied expressed HIF-1alpha at various levels, but HIF-2alpha was low or absent from the more aggressive cell lines. There was an inverse correlation between HIF-1alpha and HIF-2alpha induction and clonogenic survival under hypoxia. Thus, cell lines with reduced induction of HIF-1alpha or HIF-2alpha showed high basal levels of VEGF and improved survival under hypoxia. A reduction in HIF expression was also associated with a more aggressive phenotype in vivo. To confirm these results, we carried out stable transfection of the MDA 435 cell line with human HIF-2alpha cDNA. There was no change in the growth rate in monolayer culture. However, in vitro growth as colonies and in vivo tumor growth of the HIF-2alpha overexpressing cells were significantly impaired compared with the control transfectants. Thus, despite the fact that HIF proteins are necessary for optimal tumor growth and angiogenesis in vivo, overexpression of these molecules seems detrimental to tumor growth. A balance between the angiogenic and tumor-inhibiting levels of HIF proteins may, therefore, be necessary for optimal tumor growth.
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PMID:Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. 1115 18

Could a rational, hypothesis-driven and well-tolerated therapy drive tumor progression? This scenario can be foreseen for antiangiogenic therapy, despite it is one of the most elegant anticancer strategies. Antiangiogenic agents inhibit growth of endothelial cells resulting in tumor hypoxia and starvation which in turn inhibit tumor growth. On the other hand, it is known that hypoxia selects for a highly aggressive and metastatic cancer and is associated with unfavorable prognosis. This review attempts to reconcile these opposite notions and to revisit the thesis that antiangiogenic therapy is "resistant to resistance". The latter logical paradigm is based on the notion that endothelial cells cannot become drug resistant. Although endothelial cells may not acquire drug-resistance, cancer cells can acquire hypoxia-resistance which is also associated with the resistance to growth arrest and apoptosis as well as high metastatic potentials. Hypoxia-inducible factor (HIF-1) renders cells capable of surviving hypoxia and stimulating endothelial growth. Disruption of the HIF-1 pathway inhibits tumor growth, indicating HIF-1 as a potential anticancer target. Furthermore, inhibition of HIF-1 is a mechanism-based antiangiogenic strategy because it is the HIF-mediated response that drives tumor angiogenesis. Pharmacological approaches to HIF-1 inhibition are discussed.
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PMID:Hypoxia-inducible factor: Achilles' heel of antiangiogenic cancer therapy (review). 1144 36

A hypoxic microenvironment is characteristic of many solid tumors, including pancreatic cancer, the fifth leading cause of cancer death in the United States. Hypoxia causes the stabilization of the HIF-1 (hypoxia-inducible factor-1) transcription factor and the induction of many genes that promote angiogenesis, tumor growth, and metastasis. We performed representational difference analysis (RDA) using mRNA extracted from hypoxic and normoxic Capan-2, a human pancreatic cancer cell line. cDNAs corresponding to hypoxia-inducible genes were cloned and sequenced. We identified GPI/NLK/AMF (glucose phosphate isomerase/neuroleukin/autocrine motility factor) as a hypoxic inducible gene. In addition, hexokinase II and DEC1/Stra13, genes known to be hypoxia inducible in other systems, were found to be hypoxia inducible in our pancreatic cancer system. We thus identified three genes that are induced by hypoxia in a human pancreatic cancer, including GPI/NLK/AMF, which was not previously known to be hypoxia inducible in any other system. These genes may provide new targets for diagnosis and treatment of pancreatic cancer.
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PMID:Identification of genes differentially induced by hypoxia in pancreatic cancer cells. 1168 91

The serine/threonine kinase Akt/PKB and the oxygen-responsive transcription factor HIF-1 share the ability to induce such processes as angiogenesis, glucose uptake, and glycolysis. Akt activity and HIF-1 are both essential for development and implicated in tumor growth. Upon activation by products of phosphatidylinositol 3-kinase (PI3K), Akt phosphorylates downstream targets that stimulate growth and inhibit apoptosis. Previous reports suggest that Akt may achieve its effects on angiogenesis and glucose metabolism by stimulating HIF-1 activity. We report here that, whereas serum stimulation can induce a slight accumulation of HIF-1 alpha protein in a PI3K/Akt pathway-dependent fashion, hypoxia induces much higher levels of HIF-1 alpha protein and HIF-1 DNA binding activity independently of PI3K and mTOR activity. In addition, we find the effects of constitutively active Akt on HIF-1 activity are cell-type specific. High levels of Akt signaling can modestly increase HIF-1 alpha protein, but this increase does not affect HIF-1 target gene expression. Therefore, the PI3K/Akt pathway is not necessary for hypoxic induction of HIF-1 subunits or activity, and constitutively active Akt is not itself sufficient to induce HIF-1 activity.
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PMID:Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1 alpha nor sufficient for HIF-1-dependent target gene transcription. 1185 74

Hypoxia induces tissue-specific gene products such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF), which improve the peripheral O2 supply, and glucose transporters and glycolytic enzymes, which adapt cells to reduced O2 availability. EPO has been the fountainhead in research on pO2-dependent synthesis of proteins. The EPO gene enhancer (like the flanking DNA-elements of several other pO2-controlled genes) contains a consensus sequence (CGTG) that binds the trans-acting dimeric hypoxia-inducible factor 1 (HIF-1alpha/beta). The alpha-subunit of HIF-1 is rapidly degraded by the proteasome under normoxic conditions, but it is stabilized on occurrence of hypoxia. HIF-1 DNA-binding is also increased by insulin, and by interleukin-1 and tumor necrosis factor. Thus, in some aspects there is synergy in the cellular responses to hypoxia, glucose deficiency and inflammation. In viewing clinical medicine recombinant human EPO (rHu-EPO) has become the mainstay of treatment for renal anemia. Endogenous EPO and rHu-EPO are similar except for minor differences in the pattern of their 4 carbohydrate chains. RHu-EPO is also administered to patients suffering from non-renal anemias, such as in autoimmune diseases or malignancies. The correction of anemia in patients with solid tumors is not merely considered a palliative intervention. Hypoxia promotes tumor growth. However, the benefits of the administration of rHu-EPO to tumor patients with respect to its positive effects on tumor oxygenation, tumor growth inhibition and support of chemo- and radiotherapy is still debatable ground.
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PMID:Biology of erythropoietin. 1195 Jan 37

The cellular response to low tissue oxygen concentrations is mediated by the hypoxia-inducible transcription factor HIF-1. Under hypoxic conditions, HIF-1 activates transcription of critical adaptive genes by recruitment of the general coactivators CBP/p300 through interactions with its alpha-subunit (Hif-1 alpha). Disruption of the Hif-1 alpha/p300 interaction has been linked to attenuation of tumor growth. To delineate the structural basis for this interaction, we have determined the solution structure of the complex between the carboxy-terminal activation domain (CAD) of Hif-1 alpha and the zinc-binding TAZ1 (CH1) motif of cyclic-AMP response element binding protein (CREB) binding protein (CBP). Despite the overall similarity of the TAZ1 structure to that of the TAZ2 (part of the CH3) domain of CBP, differences occur in the packing of helices that can account for differences in specificity. The unbound CAD is intrinsically disordered and remains relatively extended upon binding, wrapping almost entirely around the TAZ1 domain in a groove through much of its surface. Three short helices are formed upon binding, stabilized by intermolecular interactions. The Asn-803 side chain, which functions as a hypoxic switch, is located on the second of these helices and is buried in the molecular interface. The third helix of the Hif-1 alpha CAD docks in a deep hydrophobic groove in TAZ1, providing extensive intermolecular hydrophobic interactions that contribute to the stability of the complex. The structure of this complex provides new insights into the mechanism through which Hif-1 alpha recruits CBP/p300 in response to hypoxia.
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PMID:Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response. 1195 77

Angiogenesis is an essential prerequisite for tumor growth, invasion, and metastasis. In ovarian carcinoma cells, endothelin-1 (ET-1) stimulates the secretion of vascular endothelial growth factor (VEGF), a major mediator of tumor angiogenesis. In OVCA 433 and HEY ovarian carcinoma cell lines, ET-1 treatment increases VEGF mRNA expression and induces VEGF protein levels in a time- and dose-dependent fashion, and do so to a greater extent under hypoxic conditions. ET-1 also increases hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation and activates the HIF-1 transcription complex under both normoxic and hypoxic conditions, suggesting a role for HIF-1 in the induction of VEGF expression. These effects are inhibited by the selective ET(A) receptor (ET(A)R) antagonist, BQ123. The ET-1-induced increase in HIF-1alpha protein levels is due to the enhanced HIF-1alpha stabilization. These results implicate HIF-1alpha in the induction of VEGF expression in ET-1-stimulated ovarian carcinoma cells, and provide a mechanism whereby ET-1 acting selectively through ET(A)R can interact with the HIF-1alpha-dependent machinery of angiogenesis. Our results suggest that new therapeutic strategies using specific ET(A)R antagonists could provide an additional approach to the treatment of ovarian carcinoma by inhibiting neovascularization as well as tumor cell growth.
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PMID:Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1alpha in ovarian carcinoma cells. 1202 62

Inhibition of angiogenesis is an important new modality for cancer treatment. 2-methoxyestradiol (2ME2) is a novel antitumor and antiangiogenic agent, currently in clinical trials, whose molecular mechanism of action remains unclear. Herein, we report that 2ME2 inhibits tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) in vivo. Mechanistically, we found that 2ME2 downregulates hypoxia-inducible factor-1 (HIF) at the posttranscriptional level and inhibits HIF-1-induced transcriptional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-alpha downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton and inhibition of angiogenesis.
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PMID:2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. 1272 62

Her2/neu regulates angiogenesis in human breast cancer, in part by stabilizing hypoxia-inducible factor 1alpha (HIF-1alpha), causing accumulation of the HIF-1 heterodimer and thus increasing expression of the proangiogenic cytokine VEGF. Her2/neu has recently been shown to be overexpressed in a subset of Wilms tumors. Using her2/neu (+) and her2/neu (-) Wilms tumor cell lines, we tested the effect of blocking anti-her2/neu antibody in vitro and in vivo. Blocking antibody did not alter VEGF expression in vitro, but decreased expression of VEGF in her2/neu (+) Wilms tumor xenografts. Tumor suppression was less marked than in parallel experiments using agents directly blocking VEGF. HIF-1alpha immunostaining was not altered in her2/neu (+) xenografts exposed to blocking antibody. These results suggest that her2/neu contributes to Wilms tumor angiogenesis in vivo by regulating VEGF, but other processes may act to rescue HIF-1alpha and thus to support tumor growth in this system.
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PMID:Blockade of her2/neu decreases VEGF expression but does not alter HIF-1 distribution in experimental Wilms tumor. 1288 92

Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. To examine whether HIF-1alpha is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in A549 cells. We find that IL-1beta up-regulated HIF-1alpha protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor (VEGF) via a pathway dependent on nuclear factor kappaB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL-1 mediated HIF-1alpha induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1alpha degradation, which results in increased HIF-1alpha protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1alpha induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1alpha induction, prostaglandin E2 (PGE2), a physiological product of COX-2, induced HIF-1alpha protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1beta up-regulates functional HIF-1alpha protein through a classical inflammatory signaling pathway involving NFkB and COX-2, culminating in up-regulation of VEGF, a potent angiogenic factor required for tumor growth and metastasis. Thus, HIF-1 is identified as a pivotal transcription factor linking the inflammatory and oncogenic pathways.
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PMID:IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. 1295 48


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