Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1alpha subunit. In this study, HIF-1alpha expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1alpha was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1alpha expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1alpha, whereas benign tumors in breast and uterus did not. HIF-1alpha overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1alpha immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1alpha may play an important role in human cancer progression.
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PMID:Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. 1058 6

Hypoxia-inducible factor 1 (HIF-1) is a basic-helix-loop-helix transcription factor that plays essential roles in mammalian development and physiology. HIF-1 is a heterodimer composed of HIF-1alpha and HIF-1beta subunits. The expression and activity of the HIF-1alpha subunit are tightly regulated by cellular O2 concentration. Under hypoxic conditions, HIF-1 activates the transcription of genes encoding erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, and other genes whose protein products increase O2 delivery or facilitate metabolic adaptation to hypoxia. HIF-1 is essential for embryonic vascularization and survival, neovascularization in ischemic myocardium, hypoxia-induced pulmonary vascular remodeling, and tumor vascularization. HIF-1alpha is overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors. Pharmacologic manipulation of HIF-1 levels may provide a novel therapeutic approach to diseases that represent the most common causes of mortality in Western society, including cancer, chronic lung disease, and myocardial ischemia.
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PMID:Expression of hypoxia-inducible factor 1: mechanisms and consequences. 1060 34

In brain, breast, and other common human tumors there is a correlation between expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and tumor grade and vascularization. HIF-1 stimulates angiogenesis by activating transcription of the gene encoding vascular endothelial growth factor (VEGF). HIF-1 is a heterodimer consisting of a constitutively-expressed HIF-1beta subunit and an O2- and growth factor-regulated HIF-1alpha subunit. Recent studies have demonstrated that HIF-1alpha expression is increased in tumor relative to normal tissue by two mechanisms. First, decreased intratumoral O2 concentrations provide a physiological stimulus. Second, genetic alterations that activate oncogene products or inactivate tumor suppressor gene products increase HIF- 1alpha expression and/or HIF-1 transcriptional activity independent of the O2 concentration. Taken together, these recent data suggest that increased HIF-1 activity provides a molecular basis for VEGF-induced angiogenesis and other adaptations of cancer cells to hypoxia that are critical for establishment of a primary tumor and its progression to the lethal phenotype.
Cancer Metastasis Rev 2000
PMID:HIF-1: using two hands to flip the angiogenic switch. 1119 Oct 64

Hypoxia has long been recognized as detrimental to the successful treatment of malignant tumors with ionizing radiation. Because hypoxia-inducible factor (HIF)-1alpha plays an essential role in oxygen homeostasis in vitro, we explored the predictive potential of this factor in a cohort of 98 patients with squamous cell cancer of the oropharynx, who were treated by curative radiation therapy. Ninety-four % of the primary tumors showed overexpression of HIF-1alpha, relative to the surrounding tissue, as determined by immunohistochemistry. The degree of HIF-1alpha immunoreactivity correlated inversely with both the rate of complete remission of the primary tumor (odds ratio, 0.33; P = 0.03) and lymph node metastases (odds ratio, 0.34; P = 0.02) as well as with local failure-free survival (risk ratio, 2.15; P = 0.006), disease-free survival (risk ratio, 2.01; P = 0.008), and overall survival (risk ratio, 2.17; P = 0.002). The multivariate analysis revealed the predictive power of HIF-1alpha to be independent of other covariables. We conclude that HIF-1alpha is overexpressed in the vast majority of patients with squamous cell cancer of the oropharynx and that the degree of expression has predictive and prognostic significance in individuals undergoing curative radiation therapy.
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PMID:Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. 1130 67

Metastatic renal cell cancer remains a disease which is difficult to treat medically. Prognosis often depends more on intrinsic disease features than on treatment choices. In this review, we examine novel therapies and scientific directions surrounding the RCC treatment problem. Reports relating chromosomal aberrations and of comparative gene expression analyses relating to RCC, are reviewed briefly. The central role of the von Hippel Lindau protein in clear cell RCC pathogenesis is evident. The limited contribution of conventional cytotoxic chemotherapy is mentioned. Some clinically applied agents whose clinical results are highlighted include 5-FU, retinoids, thalidomide, razoxane and IL-12. Features of the pathophysiology of von Hippel Lindau protein are described, with attention to potential novel therapies targeting HIF-1alpha, VEGF, TGF-beta1 and TGF-alpha pathways. Immunotherapy is being explored in many angles. Most basic are cytokine therapies incorporating new IL-2 and IFN-alpha schedules. Newer cytokine-based drugs include pegylated forms and IL-12. Allogeneic mini-transplantation has generated much interest. Tumour-associated antigens are being used to direct therapy using both identified and non-identified epitopes. A variety of tumour-cell vaccine and dendritic-cell vaccine clinical approaches are discussed. Finally, nephrectomy for known metastatic disease has been demonstrated to be helpful in retrospective and now prospective trials. Resection of metastases is also discussed. We are optimistic that the further clinical development among these novel therapies will improve the outlook for metastatic RCC.
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PMID:Novel therapies for renal cell carcinoma. 1177 33

Hypoxia, a reduction in the normal level of tissue oxygen tension, occurs in most solid tumors in regions where tumor growth outstrips new blood vessel formation. Hypoxic cancer cells are resistant to both chemotherapy and radiation and are a major reason for the failure of cancer therapy. The cellular response to hypoxia is mediated through the hypoxia-inducible transcription factor-1 (HIF-1). HIF-1 is critically important for tumor progression and angiogenesis. In fact, HIF-1alpha is overexpressed in 70% of human cancers and their metastases. Thus, agents that inhibit angiogenesis and tumor growth via inhibition of HIF-1 represent an attractive yet unexplored new modality for cancer treatment. We will overview inhibitors of HIF-1alpha and will discuss their potential use for cancer therapy.
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PMID:Exploitation of the HIF axis for cancer therapy. 1519 42

Somatic inactivation of the von Hippel-Lindau (VHL) gene is the most frequent genetic event observed in clear cell renal cell carcinoma (CC-RCC). However, the prognostic relevance of somatic VHL alteration and its target, hypoxia inducible factor (HIF)-1alpha has not been defined. We investigated the genetic changes in the VHL gene and HIF-1alpha and studied their clinical implications in patients with sporadic CC-RCC. Patients who underwent nephrectomy were eligible if they had pathologically confirmed CC-RCC not associated with VHL disease or familial RCC. Tumor tissues were selected from paraffin blocks on the basis of hematoxylin and eosin (H&E)-stained sections. Polymerase chain reaction-single strand conformation polymorphism analysis was performed to detect VHL mutations and genetic changes in HIF-1alpha, which were followed by automated direct sequencing. VHL hypermethylation was examined by methylation-specific PCR. A total of 56 patients were enrolled and somatic VHL alterations were detected in 16 patients (29%); intragenic mutation in eight, hypermethylation in five, both alterations in three. The mutation types were missense in five patients, silent in three, nonsense in two, and frameshift in one. Somatic VHL alterations were not significantly associated with progression-free survival (PFS) or overall survival (OS). However, patients with 'loss-of-function' VHL mutation showed significantly decreased PFS (P=0.016) and OS (P=0.046). Although the association between VHL alteration and response to immunotherapy was not significant (P=0.486), patients with missense mutation seem to have better response to immunotherapy. The Pro582Ser change in HIF-1alpha was detected in six patients (11%) and was positively correlated with the development of metastases (P=0.023). This study did not show an association between somatic VHL alteration and prognosis in patients with sporadic CC-RCC. However, it suggests that the therapeutic and prognostic implication of somatic VHL alteration may be different according to the mutational subtype and that the Pro582Ser change in HIF-1alpha may contribute to the development of metastases.
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PMID:Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma. 1580 50

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Understanding the mechanisms regulating VEGF expression in neuroblastoma cells provides additional therapeutic options to control neuroblastoma tumor growth. VEGF mRNA is controlled by growth factors and hypoxia via the transcription factor hypoxia-inducible factor (HIF-1alpha). HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation. To determine whether the levels of VEGF in neuroblastomas are due to mutations in VHL, we evaluated genomic DNA from 15 neuroblastoma cell lines using PCR. We found no mutations in exons 1, 2, or 3 of the VHL gene. VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor. Serum/IGF-I induced increases in HIF-1alpha protein that temporally paralleled increases in VEGF mRNA, whereas HIF-1beta levels were unaffected. VEGF and HIF-1alpha levels were blocked by inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Furthermore, we confirmed that HIF-1alpha mediates approximately 40% of the growth factor activity stimulating VEGF protein expression. Topotecan blocked the IGF-I-stimulated increase in HIF-1alpha but not HIF-1beta, and this resulted in a decrease in VEGF in four neuroblastoma cell lines tested. These data indicate that growth factors in an autocrine or paracrine manner play a major role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to phosphatidylinositol 3-kinase, mammalian target of rapamycin, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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PMID:Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. 1593 Feb 97

Hypoxia inducible factor-1 (HIF-1) is an important transcription factor that stimulates tumor growth and metastases via several pathways. Activation of HIF-1 depends on the presence of its alpha-subunit. Hypoxia increases HIF-1alpha levels by inhibiting prolyl-hydroxylase--mediated hydroxylation and thereby preventing proteosome degradation. Various other mechanisms might also contribute to HIF-1alpha expression, such as mutation of the oxygen dependent degradation domain (ODD), which prevents binding of prolyl-hydroxylases. Therefore, the presence of ODD mutations was evaluated as a possible explanation for diffuse HIF-1alpha protein expression often seen in invasive breast cancer. From a group of 200 primary breast cancers, 24 strong diffusely HIF-1alpha-positive tumor samples were identified with HIF-1alpha immunohistochemistry. DNA from these tumors was extracted from microdissected paraffin material and, after nested polymerase chain reaction, sequence analysis was performed to detect hif-1alpha ODD mutations. Additionally, five perinecrotically HIF-1alpha-positive breast cancers were analyzed as controls. All 24 diffuse and perinecrotic HIF-1alpha-positive breast cancers showed wild-type DNA sequences in the ODD domain. No mutations seem to occur in the ODD of hif-1alpha in HIF-1alpha overexpressing invasive breast cancer, which rules ODD mutations out as a possible explanation for the diffuse HIF-1alpha expression pattern often seen in this cancer.
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PMID:Mutation analysis of the HIF-1alpha oxygen-dependent degradation domain in invasive breast cancer. 1633 62

A critical event in the pathogenesis of invasive and metastatic cancer is E-cadherin loss of function. Renal clear cell carcinoma (RCC) is characterized by loss of function of the von Hippel-Lindau tumor suppressor (VHL), which negatively regulates hypoxia-inducible factor-1 (HIF-1). Loss of E-cadherin expression and decreased cell-cell adhesion in VHL-null RCC4 cells were corrected by enforced expression of VHL, a dominant-negative HIF-1alpha mutant, or a short hairpin RNA directed against HIF-1alpha. In human RCC biopsies, expression of E-cadherin and HIF-1alpha was mutually exclusive. The expression of mRNAs encoding TCF3, ZFHX1A, and ZFHX1B, which repress E-cadherin gene transcription, was increased in VHL-null RCC4 cells in a HIF-1-dependent manner. Thus, HIF-1 contributes to the epithelial-mesenchymal transition in VHL-null RCC by indirect repression of E-cadherin.
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PMID:Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. 1651 May 93


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