The discoveries reveal potential new targets for cancer drugs and could further research on stem-cell based therapies for degenerative diseases, said the researchers at Dana-Farber Cancer Institute and Brigham and Women's Hospital, who are jointly publishing two reports in the Jan. 26 issue of Cell.
The researchers at Brigham and Women's found that mice engineered to lack genes for the FoxO1, FoxO3, and FoxO4 molecules had serious blood abnormalities. Without the FoxO gene-regulating molecules, the rodents' blood stem cells – master cells that give birth to working blood cells while also renewing themselves ¬– divided too fast and "burned out," said Gary Gilliland, MD, PhD, who is senior co-author of the two papers with Ronald DePinho, MD, of Dana-Farber.
"If we didn't have these FoxO proteins to keep stem cells healthy, it is likely that we wouldn't be able to live for more than a few months," said Gilliland. Lead author of the stem cell paper is Zuzana Tothova, an MD-PhD student at Harvard Medical School working in Gilliland's lab.
In the companion paper, lead author Ji-Hye Paik, PhD, of Dana-Farber and colleagues from the DePinho lab report that the three FoxO molecules, known as transcription factors, normally function as tumor suppressors that override maverick cells threatening to grow too fast and form tumors. When FoxOs are eliminated, it may allow cancer to develop. The mice lacking FoxO proteins developed two types of cancer – thymic lymphoma and hemangiomas, tumors caused by the uncontrolled growth of endothelial cells that form blood vessels.
DePinho's group identified two genes regulated by the FoxO molecules that might serve as points of attack for new cancer drugs.
"This is going to expand our opportunities for drug discovery in what, arguably, is the most important pathway in cancer," said DePinho.
The FoxO1, O3, and O4 transcription factors regulate genes in the complicated cell signaling network known as PI3K-AKT, or simply PI3K. Scientists have discovered that PI3K signaling is intimately involved in fundamental cell processes such as metabolism, aging, and protecting the body against cancer. The PI3K circuit has been found to be disrupted in many forms of cancer, making it a hot topic in cancer research labs and drug company boardrooms.
Based on previous work in his laboratory, DePinho, working with Diego Castrillon, MD, PhD, (who is now at the University of Texas Southwest Medical Center), determined that the three FoxOs had redundant, overlapping functions: To uncover those functions, it would be necessary to engineer mice that lacked all three FoxO transcription factors.
To make the task even more difficult, mice lacking FoxO1 die in the womb. DePinho and Castrillon had to engineer mice whose FoxO genes would function normally during development, but would contain a mechanism allowing them to be switched off in adulthood at the scientists' will. It took DePinho's team about two years to get the system to work, which Gilliland hailed as a "true tour-de-force of mouse genetics."
Mutant FoxOs have been implicated in leukemia, and for Gilliland, who studies blood cancers, the triple-knockout mice were an opportunity to dig deeper into the issue.
Unexpectedly, however, deletion of FoxO1, 03, and 04 caused blood cell abnormalities but not outright leukemia. A bigger surprise was that the blood stem cells "were really in trouble without those transcription factors," he said, dividing too rapidly, losing their ability to renew themselves, and dying out. "This means that FoxOs contribute to the longevity of stem cells, and if you take them away, you dramatically shorten stem cells' lives."
Looking further, Gilliland and his colleagues found that the damage was being caused by reactive oxygen species, or ROS, a toxic byproduct of cells' energy production. When the mice were treated with anti-oxidants, the stem cells regained health and longevity. "So, the FoxOs are acting as natural antioxidants," said Gilliland. Conceivably, he added, drugs could be developed to manipulate the FoxO pathway and extend the lives of stem cells beyond their natural limits, which could aid their use in repairing diseased body tissues.
The results raised an important question: If the PI3K pathway and the FoxO factors are so prominent in cancer, why did the knockout mice lacking FoxO tumor suppressors not develop more types of cancers? It turns out that the cancer-causing pathway operates differently in different types of body tissues. For example, blood vessel cells in the mice's livers became malignant, but the same cells in the lung did not.
"There is a remarkable context-specific aspect to this pathway," DePinho said. "It is wired and regulated differently the same types of cells residing in different types of tissues." This is important knowledge, he said, for further research and for testing novel drugs in the right types of cancers.
DePinho and Gilliland emphasized the importance of the collaboration between Brigham and Women's and Dana-Farber, both of which are affiliated with Harvard Medical School, in producing the results reported in Cell.
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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...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
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22.11.2017 | Physics and Astronomy