Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), in cooperation with colleagues at the University of Zurich and the Ruhr-Universität Bochum, have for the first time successfully tested a new tumour diagnosis method under near-real conditions. The new method first sends out an antibody as a ‘spy’ to detect the diseased cells and then binds to them. This antibody in turn attracts a subsequently administered radioactively labelled probe. The scientists could then clearly visualize the tumour by utilizing a tomographic method. This procedure could improve cancer treatment in the future by using internal radiation.

The human immune system forms antibodies that protect the body from pathogens. Antibodies can also, however, be produced in a laboratory to precisely bind to tumour cells. They are used in cancer research to detect and fight malignant tumours. For example, antibodies can serve as transport vehicles for radionuclides, with which the affected regions can be visualized or can even be damaged. Until recently, a stumbling block has been their large molecular mass. “This causes them to circulate in the body for too long before they reach the diseased cells,” explains Dr Holger Stephan from the Institute of Radiopharmaceutical Cancer Research at HZDR. ‘This is a disadvantage because organs that are not affected by the disease are exposed to radiation. It also makes the exact localization of the tumour in the body more difficult because the resulting images are less sharp.”

Together with colleagues at the University of Zurich and the Ruhr-Universität Bochum, the researchers from Dresden therefore chose an alternative strategy. “By using what is known as ‘pre-targeting’, the antibodies’ task is divided into two steps,” Dr Kristof Zarschler, a member of Stephan’s team, explains. “In a figurative sense, we first send spies out in advance, over a longer period of time, to scout out the enemy – the tumour cells. The ‘spies’ then share their position with their troops, which we subsequently send out so that they will directly reach their target with the radioactive material.” The researchers fall back on the cetuximab antibody as the scout, which binds selectively to the epidermal growth factor receptor (EGFR). In various types of tumours, there is an increase in this molecule’s formation or it might be found in a mutated form, which then leads the cells to grow and multiply uncontrolled.

The Dresden researchers combined the antibody with a peptide nucleic acid (PNA) derivative which Prof Gilles Gasser and Prof Nils Metzler-Nolte developed together with their respective working groups in Switzerland and Germany. “It is a very stable synthetic variant of DNA,’ says Holger Stephan. “Similar to a single strand of DNA, it consists of a certain sequence of the four organic bases. Complementary PNA with matching sequence binds to it in a highly precise and stable manner.” During their experiments, the scientists first injected the PNA-EGFR antibody into tumour-bearing mice and gave this “spy” time to accumulate at the tumour site. They then administered the PNA counterpart, labelled with the radioactive substance technetium-99m. “Images we took using single photon emission computed tomography show that both the antibody and its counterpart located each other quickly,” says Zarschler, pleased with the results.

The tumour could thus be clearly visualized within a short period of time. “Furthermore, the radioactively labelled probes had already disappeared from the bloodstream after sixty minutes,” explains Holger Stephan. “This minimizes radioactive exposure risk of healthy body tissue. By pre-targeting, we can overcome limitations of conventional, radioactively marked antibodies.” According to the researchers, it will, however, take some time before the combination of PNA antibodies and their matching PNA counterparts can be used in diagnosing tumours in humans.

“Our results however show that the PNAs we tested are suitable candidates for further preclinical studies,” Stephan sums up. They could provide new possibilities not only for visualizing diseased cells but also for fighting them. “If the method is proven to work, it could also be used to transport therapeutically effective radioactive substances to the tumour in order to irradiate it from within and ultimately damage it.” Helmholtz-Zentrum Dresden-Rossendorf

A ‘pill on a string’ developed by researchers at the University of Cambridge could help doctors detect oesophageal cancer – cancer of the gullet – at an early stage, helping them overcome the problem of wide variation between biopsies, suggests research.

The ‘Cytosponge’ sits within a pill which, when swallowed, dissolves to reveal a sponge that scrapes off cells when withdrawn up the gullet. It allows doctors to collect cells from all along the gullet, whereas standard biopsies take individual point samples.

Oesophageal cancer is often preceded by Barrett’s oesophagus, a condition in which cells within the lining of the oesophagus begin to change shape and can grow abnormally. The cellular changes are cause by acid and bile reflux – when the stomach juices come back up the gullet. Between one and five people in every 100 with Barrett’s oesophagus go on to develop oesophageal cancer in their life-time, a form of cancer that can be difficult to treat, particularly if not caught early enough.

At present, Barrett’s oesophagus and oesophageal cancer are diagnosed using biopsies, which look for signs of dysplasia, the proliferation of abnormal cancer cells. This is a subjective process, requiring a trained scientist to identify abnormalities. Understanding how oesophageal cancer develops and the genetic mutations involved could help doctors catch the disease earlier, offering better treatment options for the patient.

An alternative way of spotting very early signs of oesophageal cancer would be to look for important genetic changes. However, researchers from the University of Cambridge have shown that variations in mutations across the oesophagus mean that standard biopsies may miss cells with important mutations. A sample was more likely to pick up key mutations if taken using the Cytosponge, developed by Professor Rebecca Fitzgerald at the Medical Research Council Cancer Unit at the University of Cambridge.

“The trouble with Barrett’s oesophagus is that it looks bland and might span over 10cm,” explains Professor Fitzgerald. “We created a map of mutations in a patient with the condition and found that within this stretch, there is a great deal of variation amongst cells. Some might carry an important mutation, but many will not. If you’re taking a biopsy, this relies on your hitting the right spot. Using the Cytosponge appears to remove some of this game of chance.” Cambridge University

Scientists at the University of British Columbia have discovered a gene that could be an important cause of obesity.

The gene, which encodes a protein called 14-3-3zeta, is found in every cell of the body. But when scientists silenced the gene in mice, it resulted in a 50 per cent reduction in the amount of a specific kind of unhealthy “white fat” – the kind associated with obesity, heart disease and diabetes. The fat reduction occurred despite the mice consuming the same amount of food. Mice that were bred to have higher levels of the 14-3-3zeta protein were noticeably bigger and rounder, having an average of 22 per cent more white fat when fed a high calorie diet.

Earlier this year, a consortium of scientists found over 100 regions on the human genome that correlate with obesity, likely through regulating the brain’s perception of hunger and the distribution of fat throughout the body. That study, however, did not identify the gene that encodes 14-3-3zeta, which controls the production of fat cells (known as adipogenesis) and the growth of those cells.

Discovery of this direct link between a protein and fat production, described in Nature Communications, points the way to a possible drug therapy. Scientists theorize that by suppressing the gene or blocking the protein, they could prevent fat accumulation in people who are overweight, or are on their way to becoming so.

“People gain fat in two ways – through the multiplication of their fat cells, and through the expansion of individual fat cells,” said Gareth Lim, a postdoctoral fellow in UBC’s Life Sciences Institute. “This protein affects both the number of cells and how big they are, by playing a role in the growth cycle of these cells.”

Lim and James Johnson, a professor of cellular and physiological sciences, began investigating the 14-3-3 family of proteins four years ago as it often shows up in the unhealthy fat tissue of obese people. This study not only identified zeta as the operative protein, but demonstrated a clear cause-and-effect between 14-3-3zeta and fat accumulation.

“Until now, we didn’t know how this gene affected obesity,” Johnson said. “This study shows how fundamental research can address major health problems and open up new avenues for drug discovery.”

Obesity is linked to increased risk of diabetes, heart disease, and some forms of cancer. Worldwide, obesity costs society $2 trillion each year. More than one in four Canadians are obese, and that number continues to grow, according to Statistics Canada. Alarmingly, the obesity rate is also increasing in children.

We don’t fully understand how fat cells are made, and its clear that this information would be useful in efforts to prevent obesity.

Find other stories about: 14-3-3zeta, Faculty of Medicine, James Johnson, obesity, Obesity gene University of British Columbia

After generating new brain tumour models, Cedars-Sinai scientists in the Board of Governors Regenerative Medicine Institute identified the role of a family of genes underlying tumour growth in a wide spectrum of high grade brain tumours.

‘With these new genetic findings, our group of researchers plan to develop targeted therapeutics that we hope will one day be used treat patients with high grade brain tumours and increase their survival,’ said Joshua Breunig, PhD, a research scientist in the Brain Program at the Cedars-Sinai Board of Governors Regenerative Medicine Institute and lead author of the research study published in the journal Cell Reports.

High grade brain tumours, known as gliomas, are difficult to treat with only a single digit five-year survival rate. Most patients treated for primary gliomas develop into secondary gliomas, which are almost always fatal.

‘Any given tumour can harbour a variety of different combinations of mutations,’ said Moise Danielpour, MD, Vera and Paul Guerin Family Chair in Pediatric Neurosurgery, director of the Pediatric Neurosurgery Program and the Center for Pediatric Neurosciences in the Maxine Dunitz Children’s Health Center and last author on the study. ‘Despite advances in radiation and chemotherapy, there are currently no effective curative regimens for treatment for these diverse tumours.’

Researchers first modelled high grade brain tumours from resident stem cells inside the brain, using a cutting edge method of rapid modelling that can create up to five distinct tumour models within 45 minutes.

After effectively modelling high grade brain tumours, researchers identified the Ets family of genes as contributors to glioma brain tumours. These Ets factors function to regulate the behaviour of tumour cells by controlling expression of genes necessary for tumour growth and cell fate. When expression of the Ets genes is blocked, researchers can identify and strategize novel treatment therapies.

‘The ability to rapidly model unique combinations of driver mutations from a patient’s tumour enhances our quest to create patient-specific animal models of human brain tumours,’ added Danielpour.

Immediate next steps involve testing the function of each individual Ets factor to determine their specific role in tumour progression and recurrence after treatment. Cedars-Sinai

Scientists have identified a new biomarker in the blood that could help identify more women at an increased risk of breast cancer. Such women might benefit from risk-reducing measures.

In a prospective study, researchers from Imperial College London and the Human Genetics Foundation (HuGeF) in Torino, Italy, have concluded that DNA methylation levels in blood cells are associated with breast cancer risk, and could be used to identify women at increased risk of developing the disease.

DNA methylation is the process by which methyl groups are added to the DNA, modifying its function and regulating how much of a gene’s protein product gets made, something that is essential for normal cell development. The team’s findings build on a growing body of evidence suggesting that lower than normal methylation of white blood cell DNA could be predictive of a heightened breast cancer risk.

The studies analysed by the researchers took blood samples from healthy women who were then monitored for an average period of around nine years. The women who developed breast cancer during this time had a lower level of DNA methylation in their white blood cells, compared to the women who didn’t develop the disease.

The research highlights DNA methylation as a key player in our understanding of breast cancer risk – adding to a growing list of known genetic variants associated with an increased risk of the disease – which will ultimately help us refine and improve the ways we assess, and monitor, an individual’s breast cancer risk.

Whilst this research is at a very early stage, it is hoped that one day scientists could potentially be able to proactively change methylation patterns, underlining the importance of research into epigenetics.

Further studies will now be required to understand why the methylation patterns observed in blood cell DNA are linked to breast cancer risk, as this is not currently known. It is hoped that women already known to be at increased risk of developing the disease could be given a blood test to assess and monitor methylation levels in order to better understand their risk and inform decisions around preventative treatments. Imperial College London