̽��ֱ�� of Cambridge - tumours

Sight and sound

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How photoacoustics could transform cancer detection and monitoring

Scientists can detect brain tumours using a simple urine or blood plasma test

Anonymous — Fri, 23 Jul 2021 15:05:30 +0000

̽��ֱ��team say that a test for detecting glioma using urine is the first of its kind in the world.

Although the research, published in EMBO Molecular Medicine, is in its early stages and only a small number of patients were analysed, the team say their results are promising.

̽��ֱ��researchers suggest that in the future, these tests could be used by GPs to monitor patients at high risk of brain tumours, which may be more convenient than having an MRI every three months, which is the standard method.

When people have a brain tumour removed, the likelihood of it returning can be high, so they are monitored with an MRI scan every three months, which is followed by biopsy.

Blood tests for detecting different cancer types are a major focus of research for teams across the world, and there are some in use in the clinic. These tests are mainly based on finding mutated DNA, shed by tumour cells when they die, known as cell-free DNA (cfDNA).

However, detecting brain tumour cfDNA in the blood has historically been difficult because of the blood-brain-barrier, which separates blood from the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord, preventing the passage of cells and other particles, such as cfDNA.

Researchers have previously looked at detecting cfDNA in CSF, but the spinal taps needed to obtain it can be dangerous for people with brain tumours so are not appropriate for patient monitoring.

Scientists have known that cfDNA with similar mutations to the original tumour can be found in blood and other bodily fluids such as urine in very low levels, but the challenge has been developing a test sensitive enough to detect these specific mutations.

̽��ֱ��researchers, led by Dr Florent Mouliere who is based at the Rosenfeld Lab of the Cancer Research UK Cambridge Institute and at the Amsterdam UMC, and Dr Richard Mair, who is based at Cancer Research UK Cambridge Institute and the ̽��ֱ�� of Cambridge developed two approaches in parallel to overcome the challenge of detecting brain tumour cfDNA.

̽��ֱ��first approach works for patients who have previously had glioma removed and biopsied. ̽��ֱ��team designed a tumour-guided sequencing test that was able to look for the mutations found in the tumour tissue within the cfDNA in the patient’s urine, CSF, and blood plasma.

A total of eight patients who had suspected brain tumours based on MRIs were included in this part of the study. Samples were taken at their initial brain tumour biopsies, alongside CSF, blood and urine samples.

By knowing where in the DNA strand to look, the researchers found that it was possible to find mutations even in the tiny amounts of cfDNA found in the blood plasma and urine.

̽��ֱ��test was able to detect cfDNA in 7 out of 8 CSF samples, 10 out of the 12 plasma blood samples and 10 out of the 16 urine samples.

For the second approach the researchers looked for other patterns in the cfDNA that could also indicate the presence of a tumour, without having to identify the mutations.

They analysed 35 samples from glioma patients, 27 people with non-malignant brain disorders, and 26 healthy people. They used whole genome sequencing, where all the cfDNA of the tumour is analysed, not just the mutations.

They found in the blood plasma and urine samples that fragments of cfDNA, which came from patients with brain tumours were different sizes than those from patients with no tumours in CSF. They then fed this data into a machine learning algorithm which was able to successfully differentiate between the urine samples of people with and without glioma.

̽��ֱ��researchers say that while the machine learning test is cheaper and easier, and a tissue biopsy from the tumour is not needed, it is not as sensitive and is less specific than the first tumour-guided sequencing approach.

MRIs are not invasive or expensive, but they do require a trip to the hospital, and the three-month gap between checks can be a regular source of anxiety for patients.

̽��ֱ��researchers suggest that their tests could be used between MRI scans, and could ultimately be able to detect a returning brain tumour earlier.

̽��ֱ��next stage of this research will see the team comparing both tests against MRI scans in a trial with patients with brain tumours who are in remission to see if it can detect if their tumours are coming back at the same time or earlier than the MRI. If the tests prove that they can detect brain tumours earlier than an MRI, then the researchers will look at how they can adapt the tests so they could be offered in the clinic, which could be within the next ten years.

“We believe the tests we’ve developed could in the future be able to detect a returning glioma earlier and improve patient outcomes,” said Mair. “Talking to my patients, I know the three-month scan becomes a focal point for worry. If we could offer a regular blood or urine test, not only will you be picking up recurrence earlier, you can also be doing something positive for the patient’s mental health.”

Michelle Mitchell, Chief Executive of Cancer Research UK said, “While this is early research, it’s opened up the possibility that within the next decade we could be able to detect the presence of a brain tumour with a simple urine or blood test. Liquid biopsies are a huge area of research interest right now because of the opportunities they create for improved patient care and early diagnosis. It’s great to see Cancer Research UK researchers making strides in this important field.”

Sue Humphreys, from Wallsall, a brain tumour patient, said: "If these tests are found to be as accurate as the standard MRI for monitoring brain tumours, it could be life changing.

If patients can be given a regular and simple test by their GP, it may help not only detect a returning brain tumour in its earliest stages, it can also provide the quick reassurance that nothing is going on which is the main problem we all suffer from, the dreaded Scanxiety.

̽��ֱ��problem with three-monthly scans is that these procedures can get disrupted by other things going on, such as what we have seen with the Covid pandemic. As a patient, this causes worry as there is a risk that things may be missed, or delayed, and early intervention is the key to any successful treatment.”

Reference:
Florent Mouliere et al. ‘Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients.’ EMBO Molecular Medicine (2021). DOI: 10.15252/emmm.202012881

Adapted from a Cancer Research UK press release.

Researchers from the Cancer Research UK Cambridge Institute have developed two tests that can detect the presence of glioma, a type of brain tumour, in patient urine or blood plasma.

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Stopping tumour cells killing surrounding tissue may provide clue to fighting cancer

cjb250 — Thu, 04 Feb 2016 16:31:17 +0000

̽��ֱ��idea that different populations of cells compete within the body, with winners and losers, was discovered in the 1970s and is thought to be a ‘quality control’ mechanism to rid the tissue of damaged or poorly-performing cells. With the discovery that genes involved in cancer promote this process, scientists have speculated that so-called ‘cell competition’ might explain how tumours grow within our tissues.

Now, researchers at the Wellcome Trust/Cancer Research UK Gurdon Institute, ̽��ֱ�� of Cambridge, have used fruit flies genetically manipulated to develop intestinal tumours to show for the first time that as the tumour grows and its cells proliferate, it kills off surrounding healthy cells, making space in which to grow. ̽��ֱ��results of the study, funded by Cancer Research UK, are published in the journal Current Biology.

Image: Tumour cells (green) growing in the intestine of a fruit fly. Credit: Golnar Kolahgar

Dr Eugenia Piddini, who led the research, believes the finding may answer one of the longstanding questions about cancer. “We know that as cancer spreads through the body – or ‘metastasises’ – it can cause organ failure,” she says. “Our finding suggests a possible explanation for this: if the tumour kills surrounding cells, there will come a point where there are no longer enough healthy cells for the organ to continue to function.”

̽��ֱ��cancer cells encourage a process known as apoptosis, or ‘cell death’, in the surrounding cells, though the mechanism by which this occurs is currently unclear and will be the subject of further research.

By manipulating genetic variants within the surrounding cells to resist apoptosis, the researchers were able to contain the tumour and prevent its spread. This suggests drugs that carry out the same function – inhibiting cell death – may provide an effective way to prevent the spread of some types of cancer. This is counter to the current approach to fighting cancer: most current drugs used in chemotherapy encourage cell death as a way of destroying the tumour, though this can cause ‘collateral damage’ to healthy cells, hence why chemotherapy patients often become very sick during treatment.

In fact, some drugs that inhibit cell death are already being tested in clinical trials to treat conditions such as liver damage; if proven to be safe, they may provide options for potential anti-cancer drugs. However, further research is needed to confirm that this approach will be suitable for treating cancer.

“It sounds counterintuitive not to encourage cell death as this means you’re not attacking the tumour itself,” says Dr Eugenia Piddini. “But if we think of it like an army fighting a titan, it makes sense that if you protect your soldiers and stop them dying, you stand a better chance of containing – and even killing – your enemy.”

̽��ֱ��work, which was carried out by postdoctoral researcher Saskia Suijkerbuijk and colleagues in the Piddini group, used fruit flies because they are much simpler organisms to study than mammals; however, many of the genes being studied are conserved across species – in other words, the genes, or genes with an identical or very similar function, are found in both the fruit fly and mammals.

Dr Alan Worsley, senior science information officer at Cancer Research UK, said: “Tumours often need to elbow healthy cells out of the way in order to grow. This intriguing study in fruit flies suggests that if researchers can turn off the signals that tell healthy cells to die, they could act as a barrier that boxes cancer cells in and stunts their growth. We don’t yet know if the same thing would work in patients, but it highlights an ingenious new approach that could help to keep early stage cancers in check.”

Reference
Suijkerbuijk, SJE et al. Cell competition drives the growth of intestinal adenomas in Drosophila. Current Biology; 22 Feb 2016. dx.doi.org/10.1016/j.cub.2015.12.043

Tumours kill off surrounding cells to make room to grow, according to new research from the ̽��ֱ�� of Cambridge. Although the study was carried out using fruit flies, its findings suggest that drugs to prevent, rather than encourage, cell death might be effective at fighting cancer – contrary to how many of the current chemotherapy drugs work.

It sounds counterintuitive not to encourage cell death as this means you’re not attacking the tumour itself

Eugenia Piddini

davidd

Attack of the Crab Monsters (cropped)

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New research leaves tumours with nowhere to hide

Anonymous — Thu, 24 Sep 2015 09:25:29 +0000

̽��ֱ��small tumours concealed in the adrenal gland are “unmasked” in early pregnancy, when a sudden surge of hormones fires them into life, leading to raised blood pressure and causing risk to patients.

New research published today in the New England Journal of Medicine conducted by a team led by Professor Morris Brown, professor of clinical pharmacology at Cambridge ̽��ֱ�� and a Fellow of Gonville & Caius College, identifies this small group of lurking tumours for the first time, and explains why they behave as they do.

̽��ֱ��study means that, when patients are found to have high blood pressure early in pregnancy, doctors will now be encouraged to consider that the cause could be the tumours, which can be easily treated. Currently, adrenal tumours are not usually suspected as the cause of high blood pressure in pregnancy, and so go undiagnosed.

Brown and an international group of PhD students including first-author Ada Teo of Newnham College used a combination of state-of-the-art gene “fingerprinting” technology and old-fashioned deduction from patient case histories to work out that the otherwise benign tumours harbour genetic mutations that affect cells in the adrenal gland.

̽��ֱ��mutation means the adrenal cells are given false information and their clock is effectively turned back to “childhood”, returning them to their original state as ovary cells. They then respond to hormones released in pregnancy, producing increased levels of the salt-regulating hormone aldosterone.

Aldosterone in turn regulates the kidneys to retain more salt and hence water, pushing up blood pressure. High blood pressure – also known as hypertension – can be fatal, since it greatly increases the risk of stroke and heart attack.

̽��ֱ��new findings build on a growing body of research focusing on the adrenal gland and blood pressure. Sixty years ago, the American endocrinologist Dr Jerome Conn first observed that large benign tumours in the adrenal gland can release aldosterone and increase blood pressure (now known as Conn’s Syndrome).

Brown and his team have previously found a group of much smaller tumours, arising from the outer part of the gland, that have the same effect. ̽��ֱ��latest discovery drills down still further, revealing that roughly one in ten of this group has a mutation that makes the cells receptive to pregnancy hormones.

Brown said: “This is an example of what modern scientific techniques, and collaborations among doctors and scientists, allow you to do [through a form of genetic fingerprinting]. Conditions are often around for 60 years which we have had no explanation for, and now we can get to the heart of what has gone wrong.”

But the discovery also relied on what doctors call “clinical pattern recognition” – using experience to spot similarities. Brown was able to link together the cases of two pregnant women almost ten years apart and a woman in early menopause. All suffered high blood pressure, leading him to screen their adrenal tumours and identify a matching genetic mutation.

Pregnant women found to have the newly identified subset of tumours can now be identified more readily, and the tumours either treated with drugs or potentially even removed.

̽��ֱ��research was funded by the Wellcome Trust, National Institute for Health Research, British Heart Foundation and A* Singapore.

Hidden tumours that cause potentially fatal high blood pressure but lurk undetected in the body until pregnancy have been discovered by a Cambridge medical team.

Conditions are often around for 60 years which we have had no explanation for, now we can get to the heart of what has gone wrong

Morris Brown

11C metomidate PET CT of small Conn's tumour

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Childhood brain tumour expert to lead Cambridge Cancer Centre

cjb250 — Thu, 26 Mar 2015 13:00:01 +0000

Professor Gilbertson is currently Scientific Director, Director of the Comprehensive Cancer Center and holds the Lillian R. Cannon endowed Chair at St Jude Children’s Research Hospital in Memphis, Tennessee. At St Jude, he has led international efforts that have dramatically advanced understanding of the biology of several common childhood brain tumours.

His research has included innovative clinical trials that have translated this understanding into new therapies. He trained as a paediatric oncologist at Newcastle ̽��ֱ�� before completing his PhD. He joined St Jude in 2000 where he has served as Director of the hospital’s Molecular Clinical Trials Core, Director of the Division of Brain Tumour Research and co-leader of the Neurobiology and Brain Tumour Program.

Professor Patrick Maxwell, Regius Professor of Medicine at the ̽��ֱ�� of Cambridge, said: “We are really delighted to appoint a clinician scientist of Richard’s calibre. He joins us at an exciting time for both the Cambridge Cancer Centre and the Cambridge Biomedical Campus, the centrepiece of the largest biotech cluster outside the United States.

“Richard will replace Professor Bruce Ponder, whose exemplary leadership has placed the Cambridge Cancer Centre in an extremely strong position. Richard will build on this, playing a key role in strengthening relationships between academia and industry which we believe will revolutionise the diagnosis and treatment of cancer patients worldwide.”

“It is both exciting and a privilege to return home to England and join Cambridge ̽��ֱ�� to serve as Director of the Cancer Center,” said Professor Gilbertson. “Cambridge is an amazing research environment with world class laboratory and clinical cancer researchers. I very much look forward to working with them as together we generate the next generation of impactful cancer therapies.”

̽��ֱ��Cambridge Cancer Centre, a partnership between ̽��ֱ�� of Cambridge, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust and Cancer Research UK, was established in 2005 as a dynamic collaboration of researchers, clinicians, and the pharmaceutical and biotech industries based in the Cambridge area. ̽��ֱ��membership of the Centre includes over 150 scientific principal investigators and senior investigators as well as over 90 NHS consultants who are engaged in cancer related clinical or translational research across a number of institutes and departments.

̽��ֱ��Centre combines world-class science and technology with excellent patient care to pioneer new ways to prevent, detect and treat cancer. By working together across different disciplines, it aims to break down the barriers between the laboratory and the clinic, enabling patients to benefit from the latest innovations in cancer science.

Keith McNeil, Chief Executive of Cambridge ̽��ֱ�� Hospitals NHS Trust, one of the key partners in the Cambridge Cancer Centre, adds: “It is great news that Professor Gilbertson is joining the Cambridge Cancer Centre as its new director. Cancer is one of our major areas of focus here at the Trust and we have some of the best patient outcomes in the world. ̽��ֱ��reason for this is because of the close collaboration between the ̽��ֱ��, Cancer Research UK and other partners. Many of our staff work across these well-known organisations, which means the high-quality cancer care that we provide to patients is underpinned by leading research.

“With new therapies coming forward all the time cancer is now a treatable condition rather than a fatal disease. We know that there are different types of cancer, which can exist in a single tumour, and our focus now is on identifying these using DNA sequencing, and targeting treatment with drugs for each cancer type. Here in Cambridge we are one of the leading centres worldwide and with AstraZeneca moving here soon, we will be able to make even greater strides in medical advancement to benefit patients locally and globally.”

Professor Gilbertson will also take up the post of Senior Group Leader in the Cancer Research UK (CRUK) Cambridge Institute.

Dr Iain Foulkes, Cancer Research UK’s director for research , said: “Professor Gilbertson’s appointment is a real coup for the UK and a great benefit to Cancer Research UK’s strategy to drive more research in to brain cancer. ̽��ֱ��partnership between Cambridge ̽��ֱ��, Cancer Research UK and the NHS has made this recruitment possible and his world-class reputation in childhood brain tumour research makes him the ideal choice for driving much-needed progress for patients. As a charity, we want to drive a reverse ‘brain drain’ and bring the very best minds to work on the big problems in cancer research here in the UK – Professor Gilbertson’s appointment is another sign we are achieving this.”

One of the world’s leading childhood brain tumour experts, Professor Richard Gilbertson, has been appointed as Li Ka Shing Chair of Oncology in Cambridge and Director of the Cambridge Cancer Centre. He will take up his appointment in August.

We are really delighted to appoint a clinician scientist of Richard’s calibre. He joins us at an exciting time for both the Cambridge Cancer Centre and the Cambridge Biomedical Campus, the centrepiece of the largest biotech cluster outside the United States.

Patrick Maxwell

Professor Richard Gilbertson

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Watching the death throes of tumours

cjb250 — Wed, 25 Feb 2015 12:49:11 +0000

There was a time when diagnosing and treating cancer seemed straightforward. Cancer of the breast was breast cancer, for example, and doctors could only choose treatments from a limited arsenal.

Now, the picture is much more complicated. A study published in 2012, led by Carlos Caldas, showed that breast cancer was actually at least ten different diseases. In fact, genome sequencing shows that even one ‘type’ of breast cancer differs between individuals.

While these developments illustrate the complexity of cancer biology, they also offer the promise of drugs tailored to an individual. Chemotherapy is a powerful, but blunt, instrument – it attacks the tumour, but in doing so also attacks several of the body’s other functions, which is why it makes patients so ill. ̽��ֱ��new generation of cancer drugs aim to make the tumour – and not the patient – sick.

But telling if a patient is sick is easy; telling if the tumour is sick is more challenging. “Conventionally, one assesses whether a tumour is responding to treatment by looking for evidence of shrinkage,” explained Professor Kevin Brindle from the Cancer Research UK (CRUK) Cambridge Institute, “but that can take weeks or months. And monitoring tumour size doesn’t necessarily indicate whether it is responding well to treatment.”

Take brain tumours, for example. They can continue to grow even when a treatment is working. “ ̽��ֱ��thing is that a tumour is not just tumour cells. There are lots of other cells in there, too.”

For some time now, oncologists have been interested in imaging aspects of tumour biology that can give a much earlier indication of the effect of treatment. Positron emission tomography (PET) can be used for this purpose. ̽��ֱ��patient is injected with a form (or analogue) of glucose labelled with a radioactive isotope. Tumours feed on the analogue and the isotope allows doctors to see where the tumour is.

An alternative technique that doesn’t expose the patient to ionising radiation is magnetic resonance imaging (MRI), which relies on the interaction of strong magnetic fields with a property of atomic nuclei known as ‘spin’. ̽��ֱ��proton spins in water molecules align in magnetic fields, like tiny bar magnets. By looking at how these spins differ in the presence of magnetic field gradients applied across the body, scientists are able to build up three-dimensional images of tissues.

In the 1970s, scientists realised that it was possible to use MR spectroscopy to see signals from metabolites such as glucose inside cells. “Tumours eat and breathe. If you make them sick, they don’t eat as much and the concentration of some cell metabolites can go down,” said Brindle.

Around the same time, scientists hit upon the idea of enriching metabolites with a naturally occurring isotope of carbon known as carbon-13 to help them measure how these metabolites are used by tissues. But carbon-13 nuclei are even less sensitive to detection by MRI than protons, so the signals are boosted using a machine developed by GE Healthcare, called a hyperpolariser, which lines up a large proportion of the carbon-13 spins before injection into the patient.

In 2006, Cambridge was one of the first places to show that this approach could be used to monitor whether a cancer therapy was effective or not. Combined with the latest genome sequencing techniques, this could become a powerful way of implementing personalised medicine. What’s more, because no radioactive isotopes are involved, an individual could be scanned safely multiple times.

“Because of the underlying genetics of the tumour, not all patients respond in the same way, but if you sequence the DNA in the tumour, you can select drugs that might work for that individual. Using hyperpolarisation and MRI, we can potentially tell whether the drug is working within a few hours of starting treatment. If it’s working you continue, if not you change the treatment.”

̽��ֱ��challenge has been how to deliver the carbon-13 to the patient. ̽��ֱ��metabolite has to be cooled down to almost absolute zero (–273°C), polarised, warmed up rapidly, passed into the MRI room and injected into the patient. And as the polarisation of the carbon-13 nuclei has a half-life of only 30–40 seconds, this has to be done very quickly.

This problem has largely been solved and, with funding from the Wellcome Trust and CRUK, Brindle and colleagues will this year begin trialling the technique with cancer patients at Addenbrooke’s Hospital. If successful, it could revolutionise both the evaluation of new drugs and ultimately – and most importantly – the treatment of patients.

“Some people have been sceptical about whether we could ever get a strong enough signal. I’m sure we will. But will we be able to do something that is clinically meaningful, that is going to change clinical practice? That’s the big question we hope to answer in the coming years.”

Inset image: Kevin Brindle and Stefanie Reichelt.

A clinical trial due to begin later this year will see scientists observing close up, in real time – and in patients – how tumours respond to new drugs.

Using hyperpolarisation and MRI, we can potentially tell whether the drug is working within a few hours of starting treatment

Kevin Brindle

Kevin Brindle; published in Nature Medicine (2014) 20, 93-97

An abdominal tumour (outlined in white) 'feeding on' carbon-13-labelled glucose (orange) provides a means of testing when cancer drugs are effective enough to affect the health of the tumour

Lighting up the body

In many ways, light microscopy is a much better imaging technique than MRI and PET to study the nature of biological materials: it provides higher resolution and higher specificity as fluorescent markers can be used to highlight specific cancer cells and molecules in cells and tissues.

However, as Dr Stefanie Reichelt, Head of Light Microscopy at the Cancer Research UK Cambridge Institute, points out, there’s an obvious drawback: “Light doesn’t penetrate tissue, so we can’t see deep beneath the skin.”

Reichelt and colleagues are working on ways to correlate light microscopy with Kevin Brindle’s medical imaging techniques. One technique that shows promise for bridging the gap is light sheet microscopy, a fluorescence microscopy technique with an intermediate optical resolution.

A thin slice of the sample is illuminated perpendicularly to the direction of observation; this reduces photo damage, thus allowing high-speed, high-resolution, three-dimensional imaging of live animals and tissues.

“ ̽��ֱ��key for us is to be able to image whole biopsy samples or tumours rapidly and at a high level of detail.”

Reichelt is also exploring new techniques such as Coherent Anti-Raman Stokes, which uses the nuclear vibrations of chemical bonds in molecules. This can provide a highly specific but label-free imaging contrast. This capability will allow the investigation of unlabelled live tissues from tumour biopsies with high specificity.

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Scientists discover a molecular ‘switch’ in cancers of the testis and ovary

gm349 — Thu, 01 Aug 2013 06:19:00 +0000

Cambridge scientists have identified an ‘on/off’ switch in a type of cancer which typically occurs in the testes and ovaries called ‘malignant germ cell tumours’. ̽��ֱ��research was published today, 01 August, in the journal Cancer Research.

Malignant germ cell tumours arise in sperm- or egg-forming cells and usually occur in the reproductive organs, the testes or ovaries. ̽��ֱ��cancerous tumours are seen in patients of all ages, both in childhood and adulthood.

Although many patients do well after treatment, current chemotherapy treatments can have severe long-term side effects, including hearing loss and damage to the kidneys, lungs and bone marrow. For some patients, outcomes remain poor and testicular cancer continues to be a leading cause of death in young men.

̽��ֱ��scientists found that all malignant germ cell tumours contain large amounts of a protein called LIN28. This results in too little of a family of tiny regulator molecules called let-7. In turn, low levels of let-7 cause too much of numerous cancer-promoting proteins in cells. Importantly, the cancer-promoting proteins include LIN28 itself, so there is a vicious cycle that acts as an ‘on’ switch to promote malignancy. ̽��ֱ��researchers have likened these changes to a ‘cascade effect’, extending down from the large amounts of LIN28 to affect many properties of the cancer cells.

̽��ֱ��researchers also discovered that by reducing amounts of the protein LIN28, or by directly increasing amounts of let-7, it is possible to reverse the vicious cycle. Both ways reduced levels of the cancer-promoting proteins and inhibited cell growth. Because the level of LIN28 itself goes down, the effects are reinforced and act as an ‘off’ switch to reduce cancerous behaviour.

Nick Coleman, Professor of Molecular Pathology, Cambridge ̽��ֱ�� said: “We need new ways of treating patients with malignant germ cell tumours to minimise the toxic effects of chemotherapy and to improve survival rates when tumours are resistant to treatment. Having identified this ‘on/off’ switch, it will now be important to identify new drugs that can be used to keep it in the ‘off’ position.”

Dr Matthew Murray, Academic Consultant in Paediatric Oncology, Addenbrooke’s Hospital, Cambridge said: “ ̽��ֱ��switch effect that we have discovered is present in all malignant germ cell tumours, whether they occur in males or females, young or old. Such a fundamental abnormality makes an excellent new target for treating these tumours.”

Susanne Owers, Director of Fundraising at Addenbrooke’s Charitable Trust, which funded this research, said: “We are delighted to have supported this study, which has identified a key protein that triggers this type of cancer. ACT funds clinical academic researchers, like Dr Murray and Prof Coleman, because they are perfectly positioned to understand the clinical problems, working closely with patients, an insight not available to all researchers. Studies like this have the potential to make a tangible difference to patients, by identifying targets for the development of new drugs which may improve survival and have less side-effects compared with standard chemotherapy treatments. By funding this research, ACT – with the help of our supporters – can make a powerful contribution, enabling ground breaking research to be performed.”

Research could lead to new drugs to turn ‘switch’ off.

We need new ways of treating patients with malignant germ cell tumours to minimise the toxic effects of chemotherapy and to improve survival rates when tumours are resistant to treatment.

Professor Nick Coleman

Nick Coleman

Cancerous cells

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Unraveling tumour growth one stem cell at a time

gm349 — Tue, 04 Jun 2013 16:06:35 +0000

Researchers at the ̽��ֱ�� of Cambridge have discovered that a single mutation in a leukaemia-associated gene reduces the ability of blood stem cells to make more blood stem cells, but leaves their progeny daughter cells unaffected. Their findings have relevance to all cancers that are suspected to have a stem cell origin as they advance our understanding of how single stem cells are subverted to cause tumours.

Published this week in PLOS Biology, the study by Professor Tony Green and his team at the Cambridge Institute for Medical Research (CIMR) is the first to isolate highly purified single stem cells and study their individual responses to a mutation that can predispose individuals to a human malignancy. This mutation is in a gene called JAK2, which is present in most patients with myeloproliferative neoplasms (MPNs)—a group of bone marrow diseases that are characterized by the over-production of mature blood cells and by an increased risk of developing leukaemia.

Using a unique mathematical modelling approach, carried out in collaboration with Professor Ben Simons at the Cavendish Laboratory in Cambridge, in combination with experiments on single mouse stem cells, the researchers identified a distinct cellular mechanism that operates in stem cells but not in their daughter cells.

“This study is an excellent example of an inter-disciplinary collaboration pushing the field forward,” says lead author Dr David Kent. “Combining mathematical modelling with a large number of single stem cell assays allowed us to predict which cells lose their ability to expand. We were able to reinforce this prediction by testing the daughter cells of single stem cell divisions separately and showing that mutant stem cells more often undergo symmetric division to give rise to two non-stem cells.”

Characterizing the mechanisms that link JAK2 mutations with this pattern of stem cell division—a pattern that eventually leads to the development of MPNs—will inform our understanding of the earliest stages of tumour establishment and of the competition between tumour stem cells, say the authors. ̽��ֱ��next step, currently underway at the Cambridge Institute for Medical Research, is to understand the effect that acquiring additional mutations has on blood stem cells, as these are thought to drive the expansion of blood progenitor cells, leading to the eventual transformation to leukaemia that occurs in patients with MPNs.

Citation: Kent DG, Li J, Tanna H, Fink J, Kirschner K, et al. (2013) Self-Renewal of Single Mouse Hematopoietic Stem Cells Is Reduced by JAK2V617F Without
Compromising Progenitor Cell Expansion. PLoS Biol 11(6): e1001576. doi:10.1371/journal.pbio.1001576

Press release provided by PLOS Biology.

Study has relevance to all cancers that are suspected to have a stem cell origin

David Kent, Tony Green Lab

A small colony of cells derived from a single blood stem cell. Hundreds of such colonies were assessed for their proliferation kinetics and blood cell types produced.

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