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- Cifani, Paolo, et al.
(författare)
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Hunting for Protein Markers of Hypoxia by Combining Plasma Membrane Enrichment with a New Approach to Membrane Protein Analysis
- 2011
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 10:4, s. 1645-1656
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Tidskriftsartikel (refereegranskat)abstract
- Nontransient hypoxia is strongly associated with malignant lesions, resulting in aggressive behavior and resistance to treatment. We present an analysis of mRNA and protein expression changes in neuroblastoma cell lines occurring upon the transition from normoxia to hypoxia. The correlation between mRNA and protein level changes was poor, although some known hypoxia-driven genes and proteins correlated well. We present previously undescribed membrane proteins expressed under hypoxic conditions that are candidates for evaluation as biomarkers.
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| 2. |
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| 3. |
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| 4. |
- Löfstedt, Tobias, et al.
(författare)
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Hypoxia inducible factor-2alpha in cancer.
- 2007
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Ingår i: Cell Cycle. - 1551-4005. ; 6:8, s. 919-926
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Tidskriftsartikel (refereegranskat)abstract
- 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-2 alpha subunit is accumulated and active under non - hypoxic conditions as exemplified by HIF-2 alpha expressing tumor macrophages and neuroblastoma cells located in seemingly well - vascularized tumor regions and how this phenomenon is related to tumor aggressiveness.
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| 5. |
- Noguera, Rosa, et al.
(författare)
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HIF-1{alpha} and HIF-2{alpha} Are Differentially Regulated In vivo in Neuroblastoma: High HIF-1{alpha} Correlates Negatively to Advanced Clinical Stage and Tumor Vascularization.
- 2009
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 15:23, s. 7130-7136
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Hypoxia is considered to be a major driving force behind tumor angiogenesis. The stabilization and activation at hypoxia of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha and the concomitant induction of expression of vascular endothelial growth factor (VEGF) and other proangiogenic factors provide a molecular frame for hypoxia-driven tumor angiogenesis. This study has investigated how HIF and VEGF protein levels relate to each other with regard to vascularization, tumor stage, and overall survival in neuroblastoma. EXPERIMENTAL DESIGN: Tissue cores taken from tumor specimens representing 93 children with neuroblastoma were arranged on a microarray and stained for HIF-1alpha, HIF-2alpha, VEGF, and CD31 proteins. Both fraction of positive cells and staining intensity were evaluated and protein levels were correlated with each other and with clinical variables. RESULTS: Although high levels of both HIF-1alpha (P < 0.001) and HIF-2alpha (P < 0.001) correlated positively to VEGF expression, they did not fully correlate with each other. Moreover, HIF-1alpha (P = 0.002) and VEGF (P < 0.001), but not HIF-2alpha, correlated negatively to vascularization as determined by CD31 staining abundance. VEGF expression or degree of vascularization did not correlate with tumor stage or overall survival. High HIF-1alpha levels correlated with low tumor stage (P < 0.001) and were associated with a favorable patient prognosis (P = 0.08). CONCLUSIONS: The discordant results on expression of HIF-1alpha and HIF-2alpha suggest that these two proteins are differentially regulated in vivo, thus reflecting distinctive protein expression/stabilization mechanisms. The association between HIF-1alpha and favorable outcome stresses the importance of discriminating HIF-2alpha from HIF-1alpha expression and has implications for using HIFs as treatment targets. (Clin Cancer Res 2009;15(23):OF1-7).
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| 6. |
- Pietras, Alexander, et al.
(författare)
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HIF-2 alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells
- 2009
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 106:39, s. 16805-16810
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Tidskriftsartikel (refereegranskat)abstract
- High hypoxia-inducible factor-2 alpha (HIF-2 alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2 alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2 alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2 alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2 alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2 alpha is an attractive target for neuroblastoma therapy.
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