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Protein discovery promises to improve mapping of brain tumors

One of the problems with removing brain tumors is ensuring no cancerous tissue remains so they do not regrow. Now, a new study promises to reduce this problem – scientists have discovered a way to highlight a protein on brain scans so the edges of a tumor can be seen more clearly.
mri scanner
Researchers have found a promising way to show the edges of brain tumors in MRI scans more clearly.

The study, which offers scientists the most complete picture of brain tumors yet, is the work of a team from the University of Oxford in the UK, and was presented on Monday at the National Cancer Research Institute (NCRI) Cancer Conference 2015, in Liverpool, UK.

The edges of a tumor contain the most invasive cancercells. For surgery or radiation therapy to succeed, doctors need good maps that show not only where the tumor sits in the brain, but also where its edges are – a clear delineation between cancerous and healthy tissue.

This is important not only in order to remove all the cancerous tissue, but also because the most invasive cells are at the edge of a tumor, as one of the researchers, Cancer Research UK scientist Nicola Sibson, a professor in the Institute for Radiation Oncology at Oxford, explains:

“If we can’t map the edge of the tumor, surgery and radiotherapy often fail to remove aggressive tumor cells – and the brain tumor can grow back.

Currently, on magnetic resonance imaging (MRI) scans, you can see where the brain tumor is, but its edges are blurred. This is because the MRI spots leaky blood vessels inside the tumor. But on the edges of the tumor, the blood vessels are intact, so they do not show as clearly on the scans.

Highlights edges of both primary and secondary brain tumors

Now, for the first time, Prof. Sibson and her team have discovered a useful protein inside the blood vessels at the invasive edge of brain tumors.

In tests on rats, they showed it is possible to use the protein to define the edges of both primary and secondary tumors on MRI scans.

The protein – called VCAM-1 – is released as part of an inflammatory response caused by the brain tumor. The researchers developed a special dye that recognizes and sticks to the protein. The dye highlights the protein – and thus the edges of the tumor – on MRI scans.

An added advantage, note the researchers, is that the protein is on the inside of the vessels, so the dye can access it from the bloodstream.

Prof. Sibson concludes:

“This research shows that we can improve imaging of brain tumors, which could help both surgeons and radiotherapists with more effective treatment.”

Every year, around 256,000 people worldwide are diagnosed with cancer in the brain or another part of the central nervous system. In the UK, where the study was conducted, this figure is around 9,700, or 27 people a day.

“Brain cancers continue to have very poor survival rates,” says Harpal Kumar, chief executive of Cancer Research UK, which co-funded the study with the Medical Research Council. Kumar adds:

“The holy grail would be to be able to completely remove brain tumors with the help of this new imaging technique – reducing recurrence of the disease and saving more lives.”

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Blood of world’s oldest woman hints at limits of life

Death is the one certainty in life – a pioneering analysis of blood from one of the world’s oldest and healthiest women has given clues to why it happens.

Hendrikje van Andel-Schipper reached the ripe old age of 115 <i>(Image: Continental/AFP/Getty Images)</i>

Born in 1890, Hendrikje van Andel-Schipper was at one point the oldest woman in the world. She was also remarkable for her health, with crystal-clear cognition until she was close to death, and a blood circulatory system free of disease. When she died in 2005, she bequeathed her body to science, with the full support of her living relatives that any outcomes of scientific analysis – as well as her name – be made public.

Researchers have now examined her blood and other tissues to see how they were affected by age.

What they found suggests, as we could perhaps expect, that our lifespan might ultimately be limited by the capacity for stem cells to keep replenishing tissues day in day out. Once the stem cells reach a state of exhaustion that imposes a limit on their own lifespan, they themselves gradually die out and steadily diminish the body’s capacity to keep regenerating vital tissues and cells, such as blood.

Two little cells

In van Andel-Schipper’s case, it seemed that in the twilight of her life, about two-thirds of the white blood cells remaining in her body at death originated from just two stem cells, implying that most or all of the blood stem cells she started life with had already burned out and died.

“Is there a limit to the number of stem cell divisions, and does that imply that there’s a limit to human life?” asks Henne Holstege of the VU University Medical Center in Amsterdam, the Netherlands, who headed the research team. “Or can you get round that by replenishment with cells saved from earlier in your life?” she says.

The other evidence for the stem cell fatigue came from observations that van Andel-Schipper’s white blood cells had drastically worn-down telomeres – the protective tips on chromosomes that burn down like wicks each time a cell divides. On average, the telomeres on the white blood cells were 17 times shorter than those on brain cells, which hardly replicate at all throughout life.

The team could establish the number of white blood cell-generating stem cells by studying the pattern of mutations found within the blood cells. The pattern was so similar in all cells that the researchers could conclude that they all came from one of two closely related “mother” stem cells.

Point of exhaustion

“It’s estimated that we’re born with around 20,000 blood stem cells, and at any one time, around 1000 are simultaneously active to replenish blood,” says Holstege. During life, the number of active stem cells shrinks, she says, and their telomeres shorten to the point at which they die – a point called stem-cell exhaustion.

Holstege says the other remarkable finding was that the mutations within the blood cells were harmless – all resulted from mistaken replication of DNA during van Andel-Schipper’s life as the “mother” blood stem cells multiplied to provide clones from which blood was repeatedly replenished.

She says this is the first time patterns of lifetime “somatic” mutations have been studied in such an old and such a healthy person. The absence of mutations posing dangers of disease and cancer suggest that van Andel-Schipper had a superior system for repairing or aborting cells with dangerous mutations.

Opportunity in mutation

The study is novel because it is the first to investigate the accumulation of somatic mutations within the tissues of an old individual, says Chris Tyler-Smith of the Wellcome Trust Sanger Institute in Hinxton, UK. “This contrasts to the germ-line mutations [present at birth] measured in previous studies,” he says.

“When there is mutation, there’s an opportunity for selection and some somatic mutations lead to cancer,” says Tyler-Smith. “Now we see the range of somatic mutations in normal, non-cancerous tissues like blood, so we can start to think about the health consequences.”

Tantalisingly, Holstege says the results raise the possibility of rejuvenating ageing bodies with re-injections of stem cells saved from birth or early life. These stem cells would be substantially free of mutations and have full-length telomeres. “If I took a sample now and gave it back to myself when I’m older, I would have long telomeres again – although it might only be possible with blood, not other tissues,” she says.

Next, Holstege hopes to hunt for clues to genes that protect against Alzheimer’s disease by comparing van Andel-Schipper’s genome to that of people who succumb abnormally early to the disease.

Journal reference: Genome Research, DOI: 10.1101/gr.162131.113


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Deletion of a gene reduces body fat, slows down aging in mice

A single gene appears to play a crucial role in coordinating the immune system and metabolism, and deleting the gene in mice reduces body fat and extends lifespan, according to new research by scientists at the Jean Mayer USDA Human Nutrition Research Center (USDA HNRCA) on Aging at Tufts University and Yale University School of Medicine. Their results are reported online today in the Proceedings of the National Academy of Sciences.

Based on gene expression studies of fat tissue conducted at the USDA HNRCA, the Tufts University researchers initiated studies of the role of FAT10 in adipose tissue and metabolism. “No one really knew what the FAT10 gene did, other than it was ‘turned on’ by inflammation and that it seemed to be increased in gynecological and gastrointestinal cancers.” said co-author Martin S. Obin, Ph.D., an adjunct scientist in the Functional Genomics Core Unit at the USDA HNRCA at Tufts University. “Turning off the FAT10 gene produces a variety of beneficial effects in the mice, including reduced body fat, which slows down aging and extends lifespan by 20 percent.”
Typically, mice gain fat as they age. The authors observed that activation of the FAT10 gene in normal mice increases in fat tissue with age. Mice lacking FAT10 consume more food, but burn fat at an accelerated rate. As a result, they have less than half of the fat tissue found in normal, aged mice. At the same time their skeletal muscle ramps up production of an immune molecule that increases their response to insulin, resulting in reduced circulating insulin levels, protection against type 2 diabetes and longer lifespan.
The authors note that eliminating FAT10 will not fully address the dilemma of aging and weight gain. “Laboratory mice live in a lab under ideal, germ-free conditions,” said Obin, who is also an associate professor at the Friedman School of Nutrition Science and Policy at Tufts University. “Fighting infection requires energy, which can be provided by stored fat. Mice without the FAT10 gene might be too lean to fight infection effectively outside of the laboratory setting. More research is needed to know how to achieve that balance in mice and then hopefully, at some point, people.”
The possibilities for future research of FAT10 are exciting. Recent high-profile studies reported that FAT10 interacts with hundreds of other proteins in cells. Now the Tufts and Yale researchers have demonstrated that it impacts immune response, lipid and glucose metabolism, and mitochondrial function.
“Now there is dramatic road map for researchers looking at all of the proteins that FAT10 gets involved with,” said co-first and corresponding author Allon Canaan, Ph.D., an associate scientist in the Department of Genetics at Yale. “Blocking what FAT10 does to coordinate immunity and metabolism could lead to new therapies for metabolic disease, metabolic syndrome, cancer and healthy aging, because when we knock it out the net result is mice live longer.”
Canaan and colleagues initially developed the FAT10-deficient mouse to study the role of FAT10 in sepsis. In an attempt to increase sensitivity for sepsis, Canaan aged the FAT10 knockout mice and made the discovery that mice lacking the gene were lean and aged more slowly. The mice appear younger and more robust than comparably-aged normal mice, have better muscle tone, and do not develop age-related tumors.

More information: Canaan A; Defuria J; Perelman E; Schulz V; Seay M; Tuck D; Flavell R; Snyder M; Obin M; and Weissman S. “Extended Lifespan and Reduced Adiposity in Mice Lacking the FAT10 Gene.” Proceedings of the National Academy of Sciences. Published online ahead of print March 24, 2014. http://www.pnas.org/cgi/doi/10.1073/pnas.1323426111