Potential new insights into aggressive childhood cancer
The study reveals new insights into human neuroblastoma
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Tuesday, 06, Jan 2009 12:01
A new study has revealed critical molecular mechanisms associated with the development and progression of human neuroblastoma – the most common cancer in young children.
The authors of the report, published in the journal Cancer Cell today, claim the finding may lead to the development of future strategies for treatment of the aggressive cancer.
They explain how neuroblastoma cells are derived from migratory neural crest cells that give rise to the peripheral sympathetic nervous system.
During normal development, neural crest cells stop dividing and differentiate. However, neuroblastoma cells seem to have lost this capacity, the authors write.
Previous studies have shown that amplification of the MYCN gene - which disrupts control of cell division and differentiation - is a strong predictor of poor prognosis in neuroblastoma.
"We speculated that genes that are expressed in a MYCN-dependent manner might be required specifically for the growth of MYCN-amplified neuroblastomas and that MYCN-amplified neuroblastomas might depend not only on N-Myc itself, but also on upstream regulatory factors or downstream target genes," said senior author, Dr Martin Eilers, from the University of Wurzburg in Germany.
Dr Eilers and his colleagues performed a genetic screen of nearly 200 genes that are dependent on amplified MYCN in human neuroblastoma or are direct targets of Myc.
They found that the oncogene AURKA is required for growth of MYCN-amplified neuroblastoma cells, but not cells lacking amplified MYCN.
"AURKA encodes the kinase Aurora A which is dysregulated in multiple types of cancer cells," the authors write.
"Interestingly, Aurora A kinase activity was not required for N-Myc stabilisation. Instead, elevated Aurora A levels in MYCN-amplified neuroblastoma cells interfered with the PI3-kinase-dependent and mitosis-specific degradation of N-Myc. This suggests that small molecule inhibitors of Aurora A kinase may not be effective at inhibiting the oncogenic functions of Aurora A."
Dr Eilers claims the results show stabilisation of N-Myc is a critical oncogenic function of Aurora A in childhood neuroblastoma and states: "The challenge will now be to find ways to interfere with this function in order to find new approaches for the therapy of these tumors."
"The findings also suggest that the current views about why Aurora A is oncogenic may need to be re-evaluated," he added.