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1.
J Pathol ; 247(1): 86-98, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30246301

RESUMO

Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock-out Irx3- /Irx5- mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3-/- cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/ß-catenin-signalling. In contrast, IRX5-/- cells displayed activation of Hippo and non-canonical WNT-signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Proteínas de Homeodomínio/metabolismo , Neoplasias Renais/metabolismo , Néfrons/metabolismo , Fatores de Transcrição/metabolismo , Tumor de Wilms/metabolismo , Animais , Carcinogênese , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Camundongos Knockout , Morfogênese , Néfrons/crescimento & desenvolvimento , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Tumor de Wilms/genética , Tumor de Wilms/patologia , Via de Sinalização Wnt , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo
2.
Genes Chromosomes Cancer ; 53(7): 634-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24729308

RESUMO

Whether chromosome abnormalities observed in tumor cells may in some cases reflect low-grade somatic mosaicism for anomalies present already at zygote formation, rather than acquired somatic mutations, has for long remained a speculation. We here report a patient with Wilms tumor, where constitutional somatic mosaicism of trisomy 8 was detected in a previously healthy 2 ½-year-old boy. Single Nucleotide Polymorphism (SNP) array analysis of tumor tissue revealed a complex distribution of allele frequencies for chromosome 8 that could not be explained solely by mitotic events. Combined analysis of allele frequencies, chromosome banding, and fluorescence in situ hybridization revealed that the majority of tumor cells contained four copies of chromosome 8, with three distinct haplotypes at a 2:1:1 ratio. Because the patient had not been subject to organ transplantation, these findings indicated that the tumor karyotype evolved from a cell with trisomy 8 of meiotic origin, with subsequent somatic gain of one additional chromosome copy. Haplotype analysis was consistent with trisomy 8 through nondisjunction at meiosis I. Matched normal renal tissue or peripheral blood did not contain detectable amounts of cells with trisomy 8, consistent with the complete lack of mosaic trisomy 8 syndrome features in the patient. This case provides proof of principle for the hypothesis that tumor genotypes may in rare cases reflect meiotic rather than mitotic events, also in patients lacking syndromic features. © 2014 Wiley Periodicals, Inc.


Assuntos
Aneuploidia , Neoplasias Renais/genética , Trissomia/genética , Dissomia Uniparental/genética , Tumor de Wilms/genética , Pré-Escolar , Cromossomos Humanos Par 8/genética , Humanos , Cariotipagem , Masculino , Meiose , Mosaicismo , Polimorfismo de Nucleotídeo Único
3.
Genes Chromosomes Cancer ; 53(5): 381-91, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24488803

RESUMO

Clear cell sarcoma of the kidney (CCSK) is a tumor affecting children with a median age of 3 years at diagnosis. The cell of origin of CCSK is unknown and data on the molecular changes giving rise to CCSK is scarce. This has hindered the identification of positive diagnostic markers and development of molecularly targeted treatment protocols for CCSK. We have characterized a panel of CCSK to gain information regarding its molecular profile and possible origin. High-resolution genomic analysis with single nucleotide polymorphism array of 37 tumors did not reveal any clues to the mechanisms behind tumor development as remarkably few genetic imbalances were found. Gene expression analysis revealed a highly characteristic gene signature, enriched for pathways involved in embryonic development, including kidney formation. The presence of markers for two different developmental lineages in the embryonic kidney was therefore investigated in the tumor cells. FOXD1 which identifies cells giving rise to stromal elements, and CITED1, a marker for cells primed for nephrogenic epithelial differentiation, were both highly expressed in CCSK. In addition, the early embryonic marker OSR1 was expressed at higher levels in CCSK than in Wilms tumor, normal fetal kidney or adult kidney. As this marker discriminates the intermediate mesoderm from other mesodermal structures, our study could suggest that CCSK arises from a mesodermal cell type that retains the capacity to initiate differentiation towards both nephrons and stroma, but remains locked in a primitive state.


Assuntos
Neoplasias Renais/genética , Rim/patologia , Sarcoma de Células Claras/genética , Proteínas Reguladoras de Apoptose , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/genética , Perfilação da Expressão Gênica , Humanos , Lactente , Rim/embriologia , Neoplasias Renais/embriologia , Masculino , Proteínas Nucleares/genética , Inclusão em Parafina , Polimorfismo de Nucleotídeo Único , Sarcoma de Células Claras/embriologia , Transdução de Sinais , Transativadores , Fatores de Transcrição/genética
4.
Cancer Cell ; 10(5): 413-23, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17097563

RESUMO

In neuroblastoma specimens, HIF-2alpha but not HIF-1alpha is strongly expressed in well-vascularized areas. In vitro, HIF-2alpha protein was stabilized at 5% O2 (resembling end capillary oxygen conditions) and, in contrast to the low HIF-1alpha activity at this oxygen level, actively transcribed genes like VEGF. Under hypoxia (1% O2), HIF-1alpha was transiently stabilized and primarily mediated acute responses, whereas HIF-2alpha protein gradually accumulated and governed prolonged hypoxic gene activation. Knockdown of HIF-2alpha reduced growth of neuroblastoma tumors in athymic mice. Furthermore, high HIF-2alpha protein levels were correlated with advanced clinical stage and high VEGF expression and predicted poor prognosis in a clinical neuroblastoma material. Our results demonstrate the relevance of HIF-2alpha in neuroblastoma progression and have general tumor biological implications.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neuroblastoma/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , Feminino , Perfilação da Expressão Gênica , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Transplante de Neoplasias , Neuroblastoma/genética , Neuroblastoma/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Oxigênio/metabolismo , Fenótipo , Pró-Colágeno-Prolina Dioxigenase/genética , Pró-Colágeno-Prolina Dioxigenase/metabolismo , RNA Mensageiro/metabolismo , Ativação Transcricional , Células Tumorais Cultivadas
5.
Clin Cancer Res ; 29(14): 2668-2677, 2023 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-37140929

RESUMO

PURPOSE: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors. EXPERIMENTAL DESIGN: We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments. RESULTS: Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments. CONCLUSIONS: Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.


Assuntos
Neoplasias Renais , Tumor de Wilms , Humanos , Neoplasias Renais/patologia , Anaplasia/genética , Estudos Retrospectivos , Filogenia , Tumor de Wilms/genética , Tumor de Wilms/patologia
6.
Exp Cell Res ; 315(11): 1924-36, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19254710

RESUMO

Adaptation to low oxygen conditions is essential for maintaining homeostasis and viability in oxygen-consuming multi-cellular tissues, including solid tumors. Central in these processes are the hypoxia-inducible transcription factors, HIF-1 and HIF-2, controlling genes involved in e.g. glucose metabolism and neovascularization. Tumor hypoxia and HIF expression have also been associated with a dedifferentiated phenotype and increased aggressiveness. In this report we show that the MAX interactor-1 (MXI1) gene is directly regulated by HIF proteins in neuroblastoma and breast cancer cells. HIF-binding and transactivation were detected within MXI1 gene regulatory sequences in the vicinity of the MXI1-0 promoter, leading to rapid induction of the alternate MXI1-0 isoform followed by a long-term induction of both the MXI1-0 and MXI1 isoforms. Importantly, knock-down of MXI1 had limited effect on MYC/MYCN activity under hypoxia, an observation that might be related to the different functional attributes of the two MXI1 isoforms.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Genes myc , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , Transfecção , Proteínas Supressoras de Tumor/antagonistas & inibidores , Regulação para Cima
7.
Cancer Res ; 80(7): 1512-1523, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32041836

RESUMO

Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors, and 8 rhabdomyosarcomas. Whole-genome copy-number and whole-exome mutational profiling of multiple regions per tumor were performed, followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions. This variability typically emerged through collateral phylogenetic branching, leading to spatial variability in the distribution of more than 50% (96/173) of detected diagnostically informative genetic aberrations. Single-cell sequencing of 547 individual cancer cells from eight solid pediatric tumors confirmed branching evolution to be a fundamental underlying principle of genetic variation in all cases. Strikingly, cell-to-cell genetic diversity was almost twice as high in aggressive compared with clinically favorable tumors (median Simpson index of diversity 0.45 vs. 0.88; P = 0.029). Similarly, a comparison of multiregional sampling data from a total of 274 tumor regions showed that new phylogenetic branches emerge at a higher frequency per sample and carry a higher mutational load in high-risk than in low-risk tumors. Timelines based on spatial genetic variation showed that the mutations most influencing relapse risk occur at initiation of clonal expansion in neuroblastoma and rhabdomyosarcoma, whereas in Wilms tumor, they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, whereas others grow worse over time. SIGNIFICANCE: Different pediatric cancers with a high risk of relapse share a common generic pattern of extensively branching evolution of somatic mutations. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1512/F1.large.jpg.


Assuntos
Biomarcadores Tumorais/genética , Evolução Clonal , Taxa de Mutação , Recidiva Local de Neoplasia/genética , Neoplasias/genética , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Seguimentos , Humanos , Lactente , Neoplasias/mortalidade , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Filogenia , Prognóstico , Análise de Célula Única , Análise de Sobrevida , Sequenciamento do Exoma
8.
Biochem Biophys Res Commun ; 377(1): 98-103, 2008 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-18834862

RESUMO

Signaling by the receptor for stem cell factor (SCF), c-Kit, is of major importance for hematopoiesis, melanogenesis and reproduction, and the biological responses are commonly proliferation and cell survival. Thus, constitutive activation due to c-Kit mutations is involved in the pathogenesis of several forms of cancer, e.g. leukemias, gastrointestinal stromal tumors and testicular tumors. Tumor survival requires oxygen supply through induced neovascularization, a process largely mediated by the vascular endothelial growth factor (VEGF), a prominent target of the transcription factors hypoxia-inducible factor-1 (HIF-1) and HIF-2. Using Affymetrix microarrays we have identified genes that are upregulated following SCF stimulation. Interestingly, many of the genes induced were found to be related to a hypoxic response. These findings were corroborated by our observation that SCF stimulation of the hematopoietic cell lines M-07e induces HIF-1alpha and HIF-2alpha protein accumulation at normoxia. In addition, SCF-induced HIF-1alpha was transcriptionally active, and transcribed HIF-1 target genes such as VEGF, BNIP3, GLUT1 and DEC1, an effect that could be reversed by siRNA against HIF-1alpha. We also show that SCF-induced accumulation of HIF-1alpha is dependent on both the PI-3-kinase and Ras/MEK/Erk pathways. Our data suggest a novel mechanism of SCF/c-Kit signaling in angiogenesis and tumor progression.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator de Células-Tronco/fisiologia , Animais , Hipóxia Celular , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , MAP Quinase Quinase Quinases/metabolismo , Proteínas de Membrana/genética , Camundongos , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica , Oxigênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Fator de Células-Tronco/genética , Fator de Células-Tronco/farmacologia , Transfecção , Proteínas Supressoras de Tumor/genética , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas ras/metabolismo
9.
Nat Genet ; 50(7): 944-950, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29867221

RESUMO

A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored1-5. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns.


Assuntos
Mutação/genética , Neoplasias/genética , Criança , Cromossomos/genética , Evolução Molecular , Rearranjo Gênico/genética , Humanos , Proteína Supressora de Tumor p53/genética
10.
Oncotarget ; 7(10): 11127-36, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26848979

RESUMO

The global methylation profile and the mutational status of 633 specific epigenetic regulators were analyzed in the pediatric tumor clear cell sarcoma of the kidney (CCSK). Methylation array analyses of 30 CCSKs revealed CCSK tumor DNA to be globally hypermethylated compared to Wilms tumor, normal fetal kidney, and adult kidney. The aberrant methylation pattern of CCSKs was associated with activation of genes involved in embryonic processes and with silencing of genes linked to normal kidney function. No epigenetic regulator was recurrently mutated in our cohort, but a mutation in the key epigenetic regulator EZH2 was discovered in one case. EZH2 mRNA was significantly higher in CCSK compared to Wilms tumor and normal kidney, and the EZH2 protein was strongly expressed in more than 90 % of CCSK tumor cells in 9/9 tumors analyzed. This was in striking contrast to the lack of EZH2 protein expression in Wilms tumor stromal elements, indicating that EZH2 could be explored further as a diagnostic marker and a potential drug target for CCSK.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/biossíntese , Neoplasias Renais/genética , Sarcoma de Células Claras/genética , Adulto , Criança , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Epigênese Genética , Feminino , Humanos , Masculino
11.
Cancer Lett ; 357(2): 498-501, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-25481751

RESUMO

Clear cell sarcoma of the kidney (CCSK) is a rare tumor type affecting infants and young children. Most CCSKs display few genomic aberrations, and no general underlying mechanism for tumor initiation has yet been identified, although a YWHAE-NUTM2B/NUTM2E fusion gene has been observed in a minority of cases. We performed RNA-sequencing of 22 CCSKs to investigate the presence of additional fusion transcripts. The presence of the YWHAE-NUTM2B/NUTM2E fusion was confirmed in two cases. In addition, a novel IRX2-TERT fusion transcript was identified in one case. SNP-array analyses revealed the underlying event to be an interstitial deletion in the short arm of chromosome 5 (5p15.33). TERT was dramatically upregulated under the influence of the IRX2 promoter. In line with TERT expression being driven by active IRX2 regulatory elements, we found a high expression of IRX2 in CCSKs irrespective of fusion gene status. IRX2 was also expressed in human fetal kidney - the presumed tissue of origin for CCSK. We conclude that in addition to promoter mutations and epigenetic events, TERT can also be activated in tumors via formation of fusion transcripts.


Assuntos
Neoplasias Renais/genética , Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/genética , Sarcoma de Células Claras/genética , Telomerase/genética , Adulto , Sequência de Bases , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Rim/embriologia , Rim/metabolismo , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA , Fatores de Transcrição/genética
12.
Cancer Med ; 3(4): 1038-40, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24740962

RESUMO

Wolmer-Solberg et al., reported that six human neuroblastoma cell lines and the vast majority of clinical neuroblastoma samples contained HCMV DNA and expressed HCMV proteins. We could not replicate the data and therefore remain skeptical towards the prevalence of HCMV DNA in neuroblastomas.


Assuntos
Neoplasias Encefálicas/virologia , Citomegalovirus/isolamento & purificação , Meduloblastoma/virologia , Animais , Feminino , Humanos , Masculino
13.
Virchows Arch ; 459(5): 547-53, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21947875

RESUMO

Wilms' tumor (WT), the most common kidney tumor among children, is characterized by a triphasic morphology consisting of blastemal, epithelial, and stromal components. Adult WT is a rare malignancy displaying similar histological features. We here present the first published high-resolution genomic analysis of a mixed-type adult WT. This revealed a more pronounced genetic complexity than usually observed in children with mixed-type WT. The majority of chromosomes displayed uniparental disomies, and microdeletions were present in genes with known importance for tumor formation (LRP1B, FHIT, and WWOX) or organogenesis (NEGR1 and ZFPM2), abnormalities not previously reported for pediatric WT. Our results indicate that adult WT is a biological entity distinct from the corresponding pediatric tumor type.


Assuntos
Genoma Humano , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Tumor de Wilms/genética , Idoso , Bandeamento Cromossômico , Feminino , Humanos , Neoplasias Renais/patologia , Tumor de Wilms/patologia
14.
Cancer Res ; 68(22): 9212-20, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19010893

RESUMO

Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Neoplasias da Mama/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/análise , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Pessoa de Meia-Idade , Metástase Neoplásica , Oxigênio/farmacologia , Fator A de Crescimento do Endotélio Vascular/análise
15.
Cell Cycle ; 6(8): 919-26, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17404509

RESUMO

Poorly oxygenated (hypoxic) tumors are frequently more aggressive compared to corresponding tumors that are better oxygenated. Adaptation to hypoxia is primarily mediated by two closely related hypoxia inducible transcription factor complexes, HIF-1 and HIF-2, which become stabilized and activated at low oxygen levels. Whether HIF-1 and HIF-2 have different roles in tumorigenesis is an open question and an issue we discuss. With focus on HIF-2, we summarize reported phenotypical changes of HIF genetic models and HIF expression patterns during normal development, in adult non-malignant tissues and in tumors. We further address the much-discussed subject of target gene preferences between HIF-1 and HIF-2, given that both transcription factors bind to the same DNA motif. Finally, we also discuss the observations that the oxygen-sensitive HIF-2alpha subunit is accumulated and active under non-hypoxic conditions as exemplified by HIF-2alpha expressing tumor macrophages and neuroblastoma cells located in seemingly well-vascularized tumor regions and how this phenomenon is related to tumor aggressiveness.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Neoplasias/etiologia , Adaptação Biológica/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação Neoplásica da Expressão Gênica , Crescimento e Desenvolvimento/genética , Humanos , Hipóxia/genética , Fator 1 Induzível por Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia/fisiologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Neuroblastoma/genética , Neuroblastoma/patologia
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