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- Jögi, Annika, et al.
(författare)
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Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.
- 2002
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 99:10, s. 7021-7026
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Tidskriftsartikel (refereegranskat)abstract
- Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1 alpha and HIF-2 alpha are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2 alpha in embryonic regulation of tyrosine hydroxylase, a hallmark gene of the sympathetic nervous system. Neuroblastoma tumors originate from immature sympathetic cells, and therefore we investigated the effect of hypoxia on the differentiation status of human neuroblastoma cells. Hypoxia stabilized HIF-1 alpha and HIF-2 alpha proteins and activated the expression of known hypoxia-induced genes, such as vascular endothelial growth factor and tyrosine hydroxylase. These changes in gene expression also occurred in hypoxic regions of experimental neuroblastoma xenografts grown in mice. In contrast, hypoxia decreased the expression of several neuronal/neuroendocrine marker genes but induced genes expressed in neural crest sympathetic progenitors, for instance c-kit and Notch-1. Thus, hypoxia apparently causes dedifferentiation both in vitro and in vivo. These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics.
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| 4. |
- Øra, Ingrid
(författare)
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Approaches to Treatment of Children with Advanced Neuroblastoma
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Children with advanced neuroblastoma are at high risk for relapse of multidrug resistant disease, despite initial response to intensive multimodality treatment. Neuroblastomas have similarities with immature neuroblasts seen during embryonic development of the sympathetic nervous system (the origin of these tumors). Chemotherapeutic drugs have various mechanisms of action and successfully treated cancer cells eventually undergo programmed cell death (apoptosis). Hence, impaired apoptotic pathways can be one explanation for drug resistance, but also represent causes for tumor initiation, progression and metastatic spread. Tumor hypoxia (low oxygen levels) due to rapid cell overgrowth and impaired vascularization is another obstacle in cancer treatment, especially recognized by radiotherapists. Recent studies have revealed that tumor hypoxia affect malignant potential of tumor cells through increased genomic instability and metastatic ability. We have identified that the embryonic transcription factor dHAND is exclusively expressed in neuroblastomas, and this protein/gene might represent a potential diagnostic marker and target for future therapy. In addition, we have found that hypoxia alters neuroblastoma cells toward an immature phenotype and we hypothesize that hypoxic cells de-differentiate and thereby retain their migration capacities, which could be an explanation for tumor progression. Hypoxic neuroblastoma cells were found resistant to cytotoxic drugs but not to mitomycin C, and we propose that this compound might be useful for targeting the hypoxic cells in the initial treatment of neuroblastoma. Arsenic trioxide, a newly re-introduced drug in the treatment of relapsed and drug-resistant acute promyelocytic leukemia, induces a p53-independent apoptotic cell death in neuroblastoma cells, which is in contrast to conventional cytotoxic agents. We suggest that arsenic trioxide could be useful in the clinical setting in the treatment of children with advanced neuroblastoma.
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| 5. |
- Øra, Ingrid, et al.
(författare)
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Arsenic trioxide inhibits neuroblastoma growth in vivo and promotes apoptotic cell death in vitro
- 2000
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 277:1, s. 179-185
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Tidskriftsartikel (refereegranskat)abstract
- Recent clinical studies have shown that inorganic arsenic trioxide (As(2)O(3)) at low concentrations induces complete remission with minimal toxicity in patients with refractory acute promyelocytic leukemia (APL). Preclinical studies suggest that As(2)O(3) induces apoptosis and possibly differentiation in APL cells. Like APL cells, neuroblastoma (NB) cells are thought to be arrested at an early stage of differentiation, and cells of highly malignant tumors fail to undergo spontaneous maturation. Both APL and NB cells can respond with differentiation to retinoic acid (RA) treatment in vitro and probably also in vivo. For that reason we investigated the effect of As(2)O(3) alone and in combination with RA on NB cell lines. In vitro, the number of viable NB cells was reduced at As(2)O(3) concentrations around 1 microM after 72 h exposure. The IC50 in six different cell lines treated for 3 days was in the 1.5 to 5 microM concentration interval, the most sensitive being SK-N-BE(2) cells derived from a chemotherapy resistant tumor. The combined treatment with RA (1 and 3 microM) showed no consistent additional effect with regard to induced cell death. The effect of As(2)O(3) on NB cell number involved As(2)O(3)-induced apoptotic pathways (decreased expression of Bcl-2 and stimulation of caspase-3 activity) with no clear evidence of induced differentiation. The in vivo effect of As(2)O(3) on NB growth was also investigated in nude mice bearing tumors of xenografted NB cells. Although tumor growth was reduced by As(2)O(3) treatment, complete remission was not achieved at the concentrations tested. We suggest that As(2)O(3), in combination with existing treatment modalities, might be a treatment approach for high risk NB patients.
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