In a paper published online on Jan. 18 by the journal Nature, Dana-Farber Cancer Institute researchers have mapped out a mechanism by which micronuclei could potentially disrupt the chromosomes within them and produce cancer-causing gene mutations. The findings may point to a vulnerability in cancer cells that could be attacked by new therapies.
"The most common genetic change in cancer is the presence of an incorrect number of intact chromosomes within cancer cells -- a condition known as aneuploidy," says Dana-Farber's David Pellman, MD, the study's senior author. "The significance of aneuploidy has been hard to pin down, however, because little is known about how it might trigger tumors. In contrast, the mechanism by which DNA damage and broken chromosomes cause cancer is well established -- by altering cancer genes in a way that spurs runaway cell division.
"The new study demonstrates one possible chain of events by which aneuploidy and specifically 'exiled' chromosomes could lead to cancer-causing mutations, with potential implications for cancer prevention and treatment," says Pellman, who is a Howard Hughes Medical Institute investigator and the Margaret M. Dyson Professor of Pediatric Oncology at Dana-Farber, Children's Hospital Boston and Harvard Medical School.
Whole chromosomes can end up outside the nucleus as a result of a glitch in cell division. In normal division, a cell duplicates its chromosomes and dispatches them to the newly forming daughter cells: the original set to one daughter, the twin set to the other. For a variety of reasons, the chromosomes sometimes aren't allocated evenly -- one daughter receives an extra one, the other is short one. Unlike the rest of the chromosomes, these stragglers sometimes don't make it to the nucleus. Instead, they're marooned elsewhere within the cell and become wrapped in their own membrane, forming a micronucleus.
"In some respects, micronuclei are similar to primary nuclei," Pellman remarks, "but much about their function and composition is unknown. Previous studies differ on whether micronuclei replicate or repair their chromosomes as normal nuclei do. The ultimate fate of these chromosomes is unclear as well: Are they passed on to daughter cells during cell division or are they somehow eliminated as division proceeds?"
One clue that odd-man-out chromosomes themselves may be subject to damage -- and therefore be involved in cancer -- emerged from Pellman's previous research into aneuploidy. "We found that cancer cells generated from cells with micronuclei also have a great deal of chromosome breakage," Pellman explains. But researchers didn't know if this was a sign of connection or of coincidence.
Another clue came from a recently discovered phenomenon called "chromothripsis," in which one chromosome of a cancer cell shows massive amounts of breakage and rearrangement, while the remainder of the genome is largely intact. "That finding leapt off the page of these studies -- that such extensive damage could be limited to a single chromosome or single arm of a chromosome," Pellman says. "We wondered if the physical isolation of chromosomes in micronuclei could explain this kind of highly localized chromosome damage."
To find out, Karen Crasta, PhD, of Pellman's lab and the study's lead author, used a confocal microscope to observe dividing cells with micronuclei. She found that while micronuclei do form duplicate copies of their chromosomes, the process is bungled in two respects. First, it is inefficient: part of the chromosome is replicated and part isn't, leading to chromosome damage. Second, it is out of sync: the micronucleus keeps trying to replicate its chromosomes long after replication of the other chromosomes was completed. For cell division to be successful, every step of the process must occur in the proper order, at the proper time. In fact, when study co-author Regina Dagher directly analyzed the structure of the late-replicating chromosomes, she found them to be smashed to bits -- exactly what was predicted as the first step in chromothripsis.
The final piece of the puzzle came when Pellman's colleague Neil Ganem, PhD, examined what happens to these pulverized fragments, using an imaging trick that marked the chromosome in the micronucleus with its own color.
"It has been theorized that micronuclei are garbage disposals for chromosomes that the cell doesn't need anymore," Pellman comments. "If that were true, the smashed pieces would be discarded or digested, but we found that, a third of the time, they're donated to one of the daughter cells and therefore cold be incorporated into that cell's genome.
Pellman says that the findings suggest that, unexpectedly, whole chromosome aneuploidy might promote cancer in a very similar way to other kinds of genomic alterations. The key event may be mutations in oncogenes and tumor suppressors. This mechanism may also explain how cancer cells acquire more than one such mutation at a time.
"Although chromothripsis occurs in only a few percent of human cancers, our findings suggest that it might be an extreme instance of a kind of chromosome damage that could be much more common," says Pellman, who adds that accelerating this process in cancer cells, thus generating so many mutations that the cells die, may represent a possible strategy for new therapies against certain tumors.
The research was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the Leukemia and Lymphoma Society.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Children's Hospital Boston as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber and Facebook: www.facebook.com/danafarbercancerinstitute
Bill Schaller | EurekAlert!
Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology
Migrating Cells: Folds in the cell membrane supply material for necessary blebs
23.11.2017 | Westfälische Wilhelms-Universität Münster
High-precision measurement of the g-factor eleven times more precise than before / Results indicate a strong similarity between protons and antiprotons
The magnetic moment of an individual proton is inconceivably small, but can still be quantified. The basis for undertaking this measurement was laid over ten...
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
24.11.2017 | Earth Sciences
24.11.2017 | Earth Sciences
24.11.2017 | Earth Sciences