An enzyme found at elevated levels in several human cancers has been linked to abnormal tumor growth in fruit flies//, a discovery that provides a new model for understanding the link between stem cell biology and cancer, according to researchers.
Using fluorescent staining and laser-scanning microscopy, the eight-member research team studied various mutations in a gene called aurora-A to observe how changes in protein expression affected the ability of Drosophila neuroblasts, a type of neural stem cell, to maintain their stem cell character without forming tumors.
Reporting in the Dec. 20 issue of the journal Genes & Development, Chris Doe and colleagues detail how an overproduction of renewed neuroblasts in the flies can be traced to misregulation by the aurora-A kinase. This enzyme under normal conditions appears to be critical as a traffic cop for various proteins during mitosis in neuroblasts, they concluded.
“In humans, there has been a lot of thought that maybe stem cell populations are at the heart of many cancers,” said Ryan O. Andersen, a doctoral student in Doe’s lab. “The numbers are off drastically. Instead of properly dividing, they are overproducing more stem cells rather than maintaining a steady population. This loss of regulation leads to tumors populated with these overproduced cells.”
Andersen and Cheng-Yu Lee, a postdoctoral fellow, were lead authors on the paper. Doe, a Howard Hughes Medical Institute investigator, is a professor of biology in the UO Institute of Neuroscience and Institute of Molecular Biology.
In Drosophila, Doe’s team found that a mutation in aurora-A, an evolutionary conserved gene in fruit flies and humans, results in two distinguishing problems: Proteins (Numb) involved in the differentiation into neurons and neuroblast self-renewal (aPKC) are not sorted to their proper sides of the cell, and the mitotic spindle that provides cortical polarity becomes misaligned. T
he subsequent splitting leads to new cells with improper proteins mixes, including an overproduction – in this case 10 times more than normal – of new neuroblasts that lead to tumors in the brain.
“We conclude that the aurora-A kinase is required to coordinate the position of proteins within the neuroblasts,” Doe said. “When it is absent, too little neuron-promoting proteins are delivered into the young neurons and they never lose their stem-cell nature. This leads to a stem-cell tumor in the fly brain.”
The team’s findings appear to reverse traditional thinking that too much activation of aurora-A leads to tumors, including those in more than half of colorectal cancers. Instead, Doe and colleagues argue that aurora-A and numb are tumor suppressants under normal conditions, and that a loss of aurora-A is what prompts overproduction of new neuroblasts and, thus, tumor development.
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