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

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates genes involved in adaptation to hypoxia. Expression of HIF-1alpha was evaluated in rat and human prostate cancer cell lines. Increased expression of HIF-1alpha mRNA in rat prostate cancer cell lines and hypoxia-induced expression of HIF-1alpha protein in human prostate cancer cell lines are associated with increased cell growth rates and metastatic potential. HIF-1alpha mRNA was undetectable in the normal rat ventral prostate by Northern blot hybridization. HIF-1alpha protein expression and HIF-1 DNA binding activity were detected in normoxic PC-3 cells. Human prostate cancer cells plated at low density manifested higher functional HIF-1alpha expression than cells plated at high density independent of O2 tension. HIF-1alpha may become dysregulated in prostate cancer and thus drive the transcription of hypoxia-adaptive genes involved in tumor progression. This is also the first evidence that human cancer cells can express functional HIF-1alpha protein under normoxic conditions.
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PMID:Increased expression of hypoxia inducible factor-1alpha in rat and human prostate cancer. 985 48

Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, vascular endothelial growth factor, and other proteins involved in O2 homeostasis and tumor progression. The expression and transcriptional activity of the HIF-1alpha subunit is regulated by the cellular O2 concentration. We demonstrate that insulin, insulin-like growth factor (IGF)-1, and IGF-2 induce expression of HIF-1alpha, which is required for expression of genes encoding IGF-2, IGF-binding protein (IGFBP)-2 and IGFBP-3. These data provide a novel mechanism by which HIF-1alpha overexpression may occur in tumor cells and contribute to an autocrine growth factor loop.
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PMID:Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. 1046 82

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

The switch to an angiogenic phenotype is a fundamental determinant of neoplastic growth and tumor progression. We demonstrate that homozygous deletion of the p53 tumor suppressor gene via homologous recombination in a human cancer cell line promotes the neovascularization and growth of tumor xenografts in nude mice. We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. Loss of p53 in tumor cells enhances HIF-1alpha levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1alpha in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts. These results indicate that amplification of normal HIF-1-dependent responses to hypoxia via loss of p53 function contributes to the angiogenic switch during tumorigenesis.
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PMID:Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. 1064 Feb 74

Tumor progression occurs as a result of the clonal selection of cells in which somatic mutations have activated oncogenes or inactivated tumor suppressor genes leading to increased proliferation and/or survival within the hypoxic tumor microenvironment. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to reduced O2 availability, including angiogenesis and glycolysis. Expression of the O2-regulated HIF-1alpha subunit and HIF-1 transcriptional activity are increased dramatically in hypoxic cells. Recent studies indicate that many common tumor-specific genetic alterations also lead to increased HIF-1alpha expression and/or activity. Thus, genetic and physiologic alterations within tumors act synergistically to increase HIF-1 transcriptional activity, which appears to play a critical role in the development of invasive and metastatic properties that define the lethal cancer phenotype.
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PMID:Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. 1082 78

The hypoxia-inducible factor 1 (HIF-1) is known to induce the expression of several proteins linked to the maintenance of oxygen homeostasis, cellular energy metabolism, and tumor progression. Its alpha subunit (HIF-1alpha) is stabilized under hypoxic conditions and, therefore, might represent an intrinsic marker for tissue hypoxia. Here we report on the spatial relationship between HIF-1alpha and the nitroimidazole hypoxia marker EF5 in cervical carcinoma xenografts, and on their spatial relationship to tumor blood vessels. EF5 was administered to mice bearing ME180 and SiHa cervical cancer xenografts. Frozen tumor tissue sections, triple-stained for HIF-1alpha, the endothelial cell marker CD31, and EF5, were imaged using wide-field multiparameter immunofluorescence microscopy. Expression levels of EF5 and HIF-1alpha were similar in ME180 xenografts, but the percentage of tumor area stained with EF5 was significantly smaller than the percentage of HIF-1alpha-positive area in SiHa tumors. In both tumor types the EF5-HIF-1alpha overlap was statistically significant, thus confirming their spatial and temporal colocalization. Spatial distribution analysis of EF5 and HIF-1alpha is consistent with different pO2 value "thresholds" for EF5 binding and HIF-1alpha expression. Summarized, our results indicate that HIF-1alpha is a useful intrinsic marker for hypoxia in cervical carcinoma xenografts.
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PMID:Hypoxia-inducible factor-1alpha is an intrinsic marker for hypoxia in cervical cancer xenografts. 1160 68

Hypoxia-inducible factor 1 (HIF-1) mediates transcriptional responses to hypoxia. HIF-1 is composed of an O2- and growth factor-regulated HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Four lines of evidence indicate that HIF-1 contributes to tumor progression. First, HIF-1 controls the expression of gene products that stimulate angiogenesis, such as vascular endothelial growth factor, and promote metabolic adaptation to hypoxia, such as glucose transporters and glycolytic enzymes, thus providing a molecular basis for involvement of HIF-1 in tumor growth and angiogenesis. Second, in mouse xenograft models, tumor growth and angiogenesis are inhibited by loss of HIF-1 activity and stimulated by HIF-1alpha overexpression. Third, immunohistochemical analyses of human tumor biopsies indicate that HIF-1alpha is overexpressed in common cancers and that the level of expression is correlated with tumor grade, angiogenesis, and mortality. Fourth, in addition to intratumoral hypoxia, genetic alterations in tumor suppressor genes and oncogenes induce HIF-1 activity.
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PMID:Involvement of hypoxia-inducible factor 1 in human cancer. 1186 12

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1 alpha and HIF-1 beta/aryl hydrocarbon nuclear translocator subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. In response to hypoxia, HIF-1 activates the expression of many genes including vascular endothelial growth factor (VEGF) and erythropoietin. HIF-1 and VEGF play an important role in angiogenesis and tumor progression. Vanadate is widely used in industry, and is a potent inducer of tumors in humans and animals. In this study, we demonstrate that vanadate induces HIF-1 activity through the expression of HIF-1alpha but not HIF-1 beta subunit, and increases VEGF expression in DU145 human prostate carcinoma cells. We also studied the signaling pathway involved in vanadate-induced HIF-1 alpha and VEGF expression and found that phosphatidylinositol 3-kinase/Akt signaling was required for HIF-1 and VEGF expression induced by vanadate, whereas mitogen-activated protein kinase pathway was not required. We also found that reactive oxygen species (ROS) were involved in vanadate-induced expression of HIF-1 and VEGF in DU145 cells. The major species of ROS responsible for the induction of HIF-1 and VEGF expression was H(2)O(2). These results suggest that the expression of HIF-1 and VEGF induced by vanadate through PI3K/Akt may be an important signaling pathway in the vanadate-induced carcinogenesis, and ROS may play an important role.
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PMID:Vanadate-induced expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species. 1207 Jan 40

Adaptation to hypoxia is essential for tumor progression. Transcriptional activation of hypoxia-regulated genes is mediated by hypoxia-inducible factor 1 (HIF-1), a heterodimer of HIF-1alpha and ARNT (Ah receptor nuclear translocator; HIF-1beta). Using representational difference analysis, we identified three novel hypoxia-inducible genes: MIG-6 (gene 33), adipophilin and tuftelin. The mRNAs for these genes were inducible by 1% O(2) in the human HepG2 and MCF-7 cell lines. Hypoxic induction of the MIG-6 and tuftelin proteins was also observed. Induction was ARNT-dependent. Induction also occurred in livers of mice treated with CoCl(2), which mimics hypoxia. The potential roles of these genes in adaptation to hypoxia and in tumorigenesis will be of considerable interest.
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PMID:Mitogen-inducible gene 6 (MIG-6), adipophilin and tuftelin are inducible by hypoxia. 1238 90

HIF-1 is reported to transactivate expression of VEGF, which is an important angiogenic factor. To determine whether HIF-1alpha plays a role in angiogenesis through its regulation of VEGF, we examined expression of HIF-1alpha and its relation to clinicopathologic features, VEGF expression and prognosis of patients with colorectal carcinoma. Expression of HIF-1alpha and VEGF was examined in 4 colorectal carcinoma cell lines (COLO320DM, COLO201, DLD-1, WiDr) and 149 colorectal carcinoma tissues (10 fresh specimens, 139 archival, paraffin-embedded specimens). HIF-1alpha protein levels were increased by hypoxia in 3 of 4 colorectal carcinoma cell lines (COLO201, DLD-1, WiDr), and VEGF mRNA levels were also increased by hypoxia in the same cell lines. In 8 of 10 patients with colorectal cancer, expression of HIF-1alpha and VEGF was increased in tumor tissues compared to corresponding normal mucosa. Of 139 archival specimens of colorectal carcinoma, 81 (58.3%) expressed HIF-1alpha protein at a high level. HIF-1alpha expression was correlated with tumor invasion, tumor stage, lymphatic invasion, venous invasion and liver metastasis. Moreover, HIF-1alpha expression was correlated significantly with VEGF expression and microvessel density. Although there was a tendency for poorer prognosis in patients with high HIF-1alpha-expressing tumors, this correlation was not statistically significant. These findings suggest that HIF-1alpha may play a role in angiogenesis and tumor progression via regulation of VEGF in human colorectal carcinoma.
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PMID:Expression of hypoxia-inducible factor-1alpha is associated with tumor vascularization in human colorectal carcinoma. 1267 75


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