Scientists at the European Molecular Biology Laboratory (EMBL) inHeidelberg and the Institute of Biomedical Research of the ParcCientífic de Barcelona (IRB-PCB) have now added key evidence to claimsthat some types of cancer originate with defects in stem cells. Thestudy, reported this week in the on-line edition of Nature Genetics(September 4) shows that if key molecules aren't placed in the rightlocations within stem cells before they divide, the result can bedeadly tumors.
Cells in the very early embryo are interchangeable and undergorapid division. Soon, however, they begin differentiating into morespecific types, finally becoming specialized cells like neurons, blood,or muscle. As they differentiate, they should stop dividing and usuallybecome embedded in particular tissues. Some tumor cells are more likestem cells because they are identical, they divide quickly, and in theworst case – metastasize – they wander through the body and implantthemselves in new tissues.
Specialized cells may die through age or injuries, so the bodykeeps stocks of stem cells on hand to generate replacements. Usuallythe stem cell divides into two types: one that is just like the parent,which is kept to maintain the stock, and another that differentiates.This is what happens with neuroblasts. Cell division creates one largeneuroblast and a smaller cell that can become part of a nerve. Thisprocess is controlled by events that happen prior to division. Theparent cell becomes asymmetrical: it collects a set of specialmolecules, including Prospero and other proteins, in the area that willbud off and become the specialized cell.
"This asymmetry provides the new cell with molecules it needsto launch new genetic programs that tell it what to become," saysCayetano González, whose group began the project at EMBL and hascontinued the work as they moved to the IRBB-PCB. "The current studyinvestigates what happens when the process of localizing thesemolecules is disturbed."
Whether Prospero and its partners get to the right placedepends on the activity of specific genes in the stem cell. EMBL PhDstudent Emmanuel Caussinus from González's group created neuroblasts inwhich these genes were disrupted. "We no longer had normal neuroblastsand daughter cells capable of becoming part of a nerve," Caussinussays. "Instead, we had a tumor."
When these altered cells were transplanted into flies, theresults were swift and dramatic. The tissue containing the alteredcells grew to 100 times its initial size; cells invaded other tissues,and death followed. The growing tumor became "immortal", Caussinussays; cells could be retransplanted into new hosts for years,generation after generation, with similar effects.
The study proves that specific genes in stem cells – thosewhich control the fates of daughter cells – are crucial. If such genesare disrupted, the new cells may no longer be able to control theirreproduction, and this could lead to cancer. "It puts the focus on theevents that create asymmetrical collections of molecules inside stemcells," González says. "This suggests new lines of investigation intothe relationship between stem cells and tumors in other model organismsand humans."
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