Human neuroblastoma cells exposed to hypoxia: induction of genes associated with growth, survival, and aggressive behavior

Jögi, Annika; Vallon‐Christersson, Johan; Holmquist, Linda; Axelson, Håkan; Borg, Åke; Påhlman, Sven

doi:10.1016/j.yexcr.2004.01.013

Cited by 107 publications

(86 citation statements)

References 71 publications

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“…The fact that the cells with a neuroendocrine differentiated phenotype are positioned adjacent to necrotic zones led to the speculation that the in vivo spontaneous lineage shift from a neuronal to a neuroendocrine phenotype observed in this subset of neuroblastomas could be driven by hypoxia (68). In an effort to test this hypothesis, Jögi et al (68)(69)(70). We concluded that these cells dedifferentiated towards a neural crest-like phenotype rather than gaining chromaffin features (68).…”

Section: Hypoxia and Tumor Cell Differentiationmentioning

confidence: 79%

Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage

Mohlin

Wigerup

Påhlman

2011

Seminars in Cancer Biology

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Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage.Mohlin, Sofie; Wigerup, Caroline; Påhlman, Sven Link to publication Citation for published version (APA): Mohlin, S., Wigerup, C., & Påhlman, S. (2011). Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage. Seminars in Cancer Biology, 21(4), 276-282. DOI: 10.1016276-282. DOI: 10. /j.semcancer.2011 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Neural crest and development of the sympathetic nervous systemThe sympathetic nervous system (SNS) originates from the neural crest, an ephemeral structure during vertebrate development. Located along the neural fold, cells on the neural tube in the ectoderm give rise to the neural crest, in turn generating different derivatives, such as the cranial, hindbrain, vagal and trunk neural crest (reviewed in (9)). Trunk neural crest cells migrate from the neural tube along two defined routes, with one group of cells migrating early along a ventral pathway, giving rise to glial cells and neurons, whereas a later migrating group of cells follows a lateral pathway and gives rise to melanocytes in the skin (10, 11). These mutations were rare in all four studies indicating locus heterogeneity for predisposition of inherited disease, but still demonstrated the importance of the PHOX2B gene in neuroblastoma oncogenesis and initiation (Fig. 1) (58), and Fig. 1). Neuroblastoma differentiation stage and clinical outcomeThere is a well-documented difference in aggressive behavior between the morphologically undifferentiated (neuroblastoma proper) and the differentiated (ganglioneuroblastoma, Cellular adaptation to hypoxiaThe biological consequences of hypoxia involve induced angiogenesis, a switch in glucose metabolism and increased invasion and migration capacities, changes that stimulate tumor progression. The hypoxic response is mainly mediated by stabilization of the hypoxia inducible factor (HIF) proteins. HIFs are heterodimeric transcription factors composed of an oxygen sensitive  subunit and a constitutively expressed  subunit. At physiological oxygen levels, the  subunit is hydroxylated by the oxygen-dependent prolyl hydroxylases (PHDs), leading to interaction with the von Hippel Lindau-ubiquitin ligase complex, followed by ubiquitination and proteasomal degradation. At hypoxia, the PHDs are inactive leading to the 9 stabilization of the HIF- subunits, and by dimerization with the  subunit the comple...

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Section: Hypoxia and Tumor Cell Differentiationmentioning

confidence: 79%

Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage

Mohlin

Wigerup

Påhlman

2011

Seminars in Cancer Biology

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“…In this regard, AM could represent a putative tumor marker to predict response to radio-or chemotherapy, although this possibility has not been yet tested. AM also promotes tumor angiogenesis and enhances VEGF [35], and MMP-2 [36] levels, and is highly expressed in hypoxic tumors [37,38]. In renal cell carcinoma cells, hypoxia leads to AM and VEGF expression, which act in a coordinate way to facilitate cell growth [37].…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin prevents apoptosis in prostate cancer cells

Abasolo

Montuenga

Calvo

2006

Regulatory Peptides

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The 52-aminoacid peptide adrenomedullin (AM) is expressed in the normal and malignant prostate. We have previously shown that prostate cancer cells produce and secrete AM, which acts as an autocrine growth inhibitory factor. We have evaluated in the present study the role of AM in prostate cancer cell apoptosis, induced either by serum deprivation or treatment with the chemotherapeutic agent etoposide (which acts as an inhibitor of topoisomerase II). For this purpose we over-expressed AM in PC-3, DU 145 and LNCaP cells, which were transfected with an expression vector carrying AM. We also treated the parental cell lines with synthetic AM in normal culture conditions and in conditions of induced-apoptosis. After serum removal, AM prevented apoptosis in DU 145 and PC-3 cells, but not in LNCaP cells. When treated with etoposide, AM prevented apoptosis in PC-3 and LNCaP cells, but not in DU 145 cells. Cell cycle analysis demonstrated a significant decrease in the percentage of AM-overexpressing PC-3 cells in the subG0/G1 phase after treatment with etoposide, as compared to the percentage of mocktransfected PC-3 treated cells. Western blot showed that protein levels of phosphorylated ERK1/2 increased in parental PC-3 cells after treatment with etoposide. In PC-3 cells overexpressing AM, phosphorylated ERK1/2 basal levels were lower than basal levels of parental PC-3 cells, and treatment with etoposide did not result in such an increase. Etoposide produced a significant increase in cleaved PARP in parental PC-3 cells. However, PC-3 clones overexpressing AM that were treated with etoposide only showed a mild increase in fragmented PARP. The ratio Bcl-2/Bax was reduced in parental or mock-transfected PC-3 cells after treatment with etoposide. On the contrary, this ratio was not reduced in PC-3 clones with AM overexpression that were treated with etoposide. All these data demonstrate that AM plays a protective role against induced apoptosis in prostate cancer cells. These results may have important implications in prostate cancer resistance to chemotherapeutic agents. D

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“…The target genes were CYGB and HIF1A, using FAM/MGB-labelled Taqman probes (Hs00370478_m1 and Hs00153153_m1, respectively; Applied Biosystems). The endogenous control 'housekeeping gene' was TATA-box-binding protein (Hs99999910_m1), as this was less likely to be affected by hypoxia than other possible control genes (Jogi et al, 2004;Fink et al, 2008). Each reaction was carried out in duplicate and the mean result was used.…”

Section: Real-time Mrna Expression Assaysmentioning

confidence: 99%

Cytoglobin is upregulated by tumour hypoxia and silenced by promoter hypermethylation in head and neck cancer

et al. 2009

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BACKGROUND: Cytoglobin (Cygb) was first described in 2002 as an intracellular globin of unknown function. We have previously shown the downregulation of cytoglobin as a key event in a familial cancer syndrome of the upper aerodigestive tract. METHOD: Cytoglobin expression and promoter methylation were investigated in sporadic head and neck squamous cell carcinoma (HNSCC) using a cross-section of clinical samples. Additionally, the putative mechanisms of Cygb expression in cancer were explored by subjecting HNSCC cell lines to hypoxic culture conditions and 5-aza-2-deoxycitidine treatment. RESULTS: In clinically derived HNSCC samples, CYGB mRNA expression showed a striking correlation with tumour hypoxia (measured by HIF1A mRNA expression P ¼ 0.013) and consistent associations with histopathological measures of tumour aggression. CYGB expression also showed a marked negative correlation with promoter methylation (P ¼ 0.018). In the HNSCC cell lines cultured under hypoxic conditions, a trend of increasing expression of both CYGB and HIF1A with progressive hypoxia was observed. Treatment with 5-aza-2-deoxycitidine dramatically increased CYGB expression in those cell lines with greater baseline promoter methylation. CONCLUSION: We conclude that the CYGB gene is regulated by both promoter methylation and tumour hypoxia in HNSCC and that increased expression of this gene correlates with clincopathological measures of a tumour's biological aggression.

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Human neuroblastoma cells exposed to hypoxia: induction of genes associated with growth, survival, and aggressive behavior

Cited by 107 publications

References 71 publications

Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage

Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage

Adrenomedullin prevents apoptosis in prostate cancer cells

Cytoglobin is upregulated by tumour hypoxia and silenced by promoter hypermethylation in head and neck cancer

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