A NEW technique to study tissue samples in 3D has revealed that pancreatic cancers can start and grow in two distinct ways, solving a decades-old mystery of how tumours form.
The new method could help researchers to get more information from tissue biopsies and may lead to improved treatments for pancreatic cancers. The technique was developed by scientists at the Francis Crick Institute, and their results are published in Nature. The work was supported by the European Research Council and core funding from the MRC (one of the Crick’s founding partners).
The pancreas is a crucial organ that sits behind our stomach and plays a key role in digestion. It relies on a network of ducts linking it to other digestive organs, and the most common pancreatic cancers are found in the ducts. However, until now it has only been possible to see 2D slices of these ductal cancers, which contained an unexplained variety of abnormal shapes.
“To investigate the origins of pancreatic cancer, we spent six years developing a new method to analyse cancer biopsies in three dimensions,” explains Dr Hendrik Messal from the Francis Crick Institute, co-lead author of the research paper. “This technique revealed that cancers develop in the duct walls and either grow inwards or outwards depending on the size of the duct. This explains the mysterious shape differences that we’ve been seeing in 2D slices for decades.”
By analysing developing cancers in 3D, the team defined two distinct types of cancer formation: ‘endophytic’ tumours which grow inwards and ‘exophytic’ tumours which grow outwards. To find out what makes cancer cells grow in a particular way, they analysed detailed 3D images and worked with biophysicists at the Crick who created sophisticated computer models.
“We made a simulation of the ducts, describing individual cell geometry to understand tissue shape,” explains biophysicist Dr Silvanus Alt, co-lead author of the paper. “The model and experimental results both confirmed that cancer grew outwards when the diameter of the duct was less than approximately 20 micrometres, around a fiftieth of a millimetre.”
The work was made possible by an interdisciplinary collaboration between two research groups at the Crick, led by Dr Axel Behrens and Dr Guillaume Salbreux. Axel’s group works on stem cells and pancreatic cancer, while Guillaume focuses on using physics to understand biological processes.
“I think we first started discussing this when we bumped into each other in the bike shed,” says Axel. “It’s amazing what can come out of a chance encounter, we now have a patented technique to see the three-dimensional shapes of cancers and a biophysical understanding of the emergence of tumours. Now that we know pancreatic cancer can develop in these two different ways, we can start looking at whether one is likely to be more aggressive or spread in a different way. Many years from now, this could lead to improved diagnostic or treatment options.”
The team also applied the technique to other organs and found that cancers in the airways of the lungs and ducts in the liver behave in the same way. This shows that the mechanism the teams discovered is not specific to the pancreas and also applies to other cancers.
“Both the data and our models indicate that the two different mechanisms of tumour growth are purely down to the innate physics of the system,” explains Dr Guillaume Salbreux. “Like most cancers, ductal pancreatic cancer starts with a single defective cell that starts dividing. We found that very quickly, when there are only a few cells, the tumour has already started to grow either inwards or outwards depending on duct diameter. Defining this fundamental process will help us to better understand how cancer grows in many places across the body.”
Dr Mariana Delfino-Machin, Programme Manager for Cancer at the MRC, said: “Pancreatic cancer remains a very difficult disease to treat but understanding that it can grow in different ways will inform the development of more accurate treatments in the future.
“These findings came about thanks to researchers working in very different fields coming together to successfully tackle the same problem.”
The challenge of loneliness
INTERNATIONAL experts, including researchers from Swansea University, have published a letter in The Lancet medical journal calling for a unified approach to addressing the global challenge of loneliness.
In response to the growing concerns about the rates and consequences of loneliness, international experts based in universities, research and public health organisations have been working together to help address this issue.
The signatories include experts from the Institute of Public Health in Ireland; Columbia University; George Mason University; University of Auckland; Swansea University; Ulster University; St James’s Hospital; University of Chicago; Trinity College Dublin; Boston College; University of California; Vrije Universiteit Amsterdam; and Brunel University London.
The letter is based on discussions of international researchers at a meeting hosted in Belfast by the Institute of Public Health in Ireland. This has led to the establishment of an International Loneliness and Social Isolation Research Network.
While demographic shifts suggest that the number of people experiencing loneliness will increase, experts say that it is important to recognise that most older adults are not chronically lonely and that young adults are also affected.
Experts say that loneliness can be defined as a “subjective negative experience that results from inadequate meaningful connections”, and have called for a standardised approach to defining and measuring loneliness to help inform those developing policy and services in this area.
The expert group added that charities, community sectors, and governments, who are delivering programmes often have inadequate evidence to plan from and need a more coherent message from research, and a stronger evidence base.
And while more research is needed to find out the full consequences of loneliness, the evidence shows association with poor health and wellbeing, non-communicable diseases, and depression.
Professor Vanessa Burholt from the Centre for Innovative Ageing, in the College of Human and Health Sciences at Swansea University, said that in a time when as a society we have never had more opportunities to connect with people, there is a growing focus on loneliness and its association with poor health outcomes.
She said: “Our understanding of loneliness is still limited and is often stereotypical. While it is often confused with a lack of social engagement, the reality is that some people with lots of friends can still feel lonely and those who live alone may not.
Although loneliness is a very personal experience, addressing loneliness is not simply a matter for individuals but is also an issue for public health and society as a whole. By building evidence and pooling expertise, we can support governments and policymakers to make better-informed decisions to address this challenge.”
Protect your children from flu
Protect your children from flu
CAT1i-17.jpg – Flu vaccination: ‘Really important’ protection for children
PARENTS in Pembrokeshire are being urged to protect their children against flu
Flu is circulating and parents of 2 and 3-year-olds in Pembrokeshire are being asked to ensure their children receive the nasal spray flu vaccine as soon as possible.
Flu can be serious for children and every year children in Wales need treatment in Intensive Care Units because of flu. If you are in a risk group and think you have flu, it is important to speak to your GP surgery or community pharmacy as soon as possible.
Ros Jervis, Director of Public Health at Hywel Dda UHB, said: “We are starting to see more cases of flu so it is really important that as many of our youngest population are protected by the nasal spray vaccine.
“Having a flu vaccine will help protect your child from flu and protection starts around two weeks after having the vaccine.
“It also helps reduce the chance of children spreading flu to others who are at high risk from flu, such as young babies, grandparents, and those with long-term health conditions.”
If your child was aged 2 or 3 years old on 31 August 2019 contact your GP as soon as possible to book an appointment.
If you think you may have flu you can check your symptoms using the NHS Direct Wales symptom checker.
Research breakthrough in schizophrenia
WHAT comes to mind when you hear ‘schizophrenia’? Hallucinations and delusions? Cognitive impairment? Feeling withdrawn from everyone around you? Apathy? With all the above being symptoms of this mental disorder, and with 1 in every 100 people affected, each individual’s life becomes a relentless battle, struggling with habitual activities, social interaction, and general wellbeing and self-care.
Current treatments help to reduce the severity of symptoms and allow patients to maintain a more functional daily life. However, antipsychotic medications, which are typically required lifelong, are not guaranteed to work for all schizophrenia patients, with only about 4 in 5 people benefitting usually.
Advances in scanning have allowed researchers for the first time to show lower levels of a protein found in the connections between neurons in the living brains of people with schizophrenia.
The researchers, who conducted the scans at the psychiatric imaging facility at the MRC London Institute of Medical Sciences, say these changes could underlie the cognitive difficulties seen in schizophrenia and provide targets for research into new treatments.
Synapses are the junctions between neurons. Neurons communicate across the synapse via neurotransmitters; chemicals that transmit the nerve signal.
Researchers investigated the relationship between synaptic density and schizophrenia, questioning whether a reduction in these brain connections is present in schizophrenia and whether they result from treatment with antipsychotic drugs.
The study was inspired by findings from previous post-mortem studies that demonstrated synaptic reductions in the brains of schizophrenia patients compared to healthy controls.
Measuring synaptic protein levels in living patients was not possible before the development of a new PET (Positron Emission Tomography) radioactive tracer that binds to a specific protein associated with synapses. Being “one of the first centres in the world” to have access to this, Professor Oliver Howes, Head of the Psychiatric Imaging Group at the MRC LMS, and his team grasped this opportunity to investigate synaptic loss in schizophrenic brains through the synaptic marker protein SV2A, which is found on the nerve terminal preceding the synapse and is involved in regulating neurotransmitter release.
The team found lower levels of SV2A in the brains of schizophrenia patients, indicating a reduction of synapses. Certain areas exhibited significantly lower levels, such as the frontal cortex which coordinates use, recall and processing of memory, planning complex cognitive behaviour and personality expression. These findings were supported by the understanding that these areas are associated with some of the major cognitive impairments seen in schizophrenia, thus providing a potential clue that synaptic loss may underlie these problems.
But to test whether the loss was a result of the illness or in fact due to treatment, a preclinical study was conducted in rat models investigating the effect of antipsychotic drugs on the levels of SV2A. They found that the antipsychotics did not contribute to the synaptic loss seen in schizophrenic patients, thereby reinforcing their overall findings.
So, what does this mean for the development of schizophrenia treatment?
If the synaptic loss is an underlying key contributor in the disease, further research into the mechanisms could lead to exploring ways to prevent this loss. Moreover, since microglia, known as the immune cells of the brain, play a role in mediating synaptic pruning, there is also potential to target microglia and see if it could introduce a way of preventing excess synaptic loss; an investigation that the team have already begun.
“The human brain, with its approximately 100 trillion synapses, is an extraordinarily complex organ,” says Dr Ellis Chika Onwordi of the Psychiatric Imaging Group and first author of this study. “Having the means to characterise the distribution of these synapses in the living brain, and to find differences in synaptic distribution between patients with schizophrenia and healthy controls, represents a significant advance in our ability to study the neurobiology of schizophrenia.”
Professor Oliver Howes, who led the study, said: “Our current treatments for schizophrenia only target one aspect of the disease – the psychotic symptoms – but the debilitating cognitive symptoms, such as loss of abilities to plan and remember, often cause much more long-term disability and there’s no treatment for them at the moment. Synaptic loss is thought to underlie these symptoms.
“Our lab at the MRC London Institute of Medical Sciences is one of the few places in the world with this new tracer, which means we’ve been able for the first time to show there are lower levels of a synaptic protein in people with schizophrenia. This suggests that loss of synapses could underlie the development of schizophrenia.
“We need to develop new treatments for schizophrenia. This protein SV2A could be a target for new treatments to restore synaptic function.”
The people with schizophrenia who were scanned had all received antipsychotic medication, so the researchers wanted to exclude this as a factor in the synaptic dysfunction. They gave antipsychotic drugs, haloperidol and olanzapine, to rats for 28 days and found it did not affect the levels of the protein SV2A.
Professor Howes said: “This is reassuring as it’s suggesting that our antipsychotic treatments aren’t leading to loss of brain connections.
“Next we hope to scan younger people in the very early stages to see how synaptic levels change during the development of the illness and whether these changes are established early on or develop over time.”
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