Posts tagged tumours
Articles and news from the latest research reports.
How neuro cells turn cancerous
Scientists from the Sloan-Kettering Institute for Cancer Research in New York with the help of Plymouth University Peninsula Schools of Medicine and Dentistry have completed research which for the first time brings us nearer to understanding how some cells in the brain and nervous system become cancerous.
The results of their study are published in the prestigious journal Cancer Cell.
The research team led by Sloan-Kettering researchers studied a tumour suppressor called Merlin.
The results of the study have identified a new mechanism whereby Merlin suppresses tumours, and that the mechanism operates within the nucleus. The research team has discovered that unsuppressed tumour cells increase via a core signalling system, the hippo pathway, and they have identified the route and method by which this signalling occurs.
By identifying the signalling system and understanding how, when present, Merlin suppresses it, the way is open for research into drug therapies which may suppress the signalling in a similar way to Merlin.
Tumour suppressors exist in cells to prevent abnormal cell division in our bodies. The loss of Merlin leads to tumours in many cell types within our nervous systems. There are two copies of a tumour suppressor, one on each chromosome that we inherit from our parents. The loss of Merlin can be caused by random loss of both copies in a single cell, causing sporadic tumours, or by inheriting one abnormal copy and losing the second copy throughout our lifetime as is seen in the inherited condition of neurofibromatosis type 2 (NF2).
No effective therapy for these tumours exists, other than repeated invasive surgery aiming at a single tumour at a time and which is unlikely to eradicate the full extent of the tumours, or radiotherapy.
Professor Oliver Hanemann, Director of the Institute of Translational and Stratified Medicine at Plymouth University Peninsula Schools of Medicine and Dentistry, and who led the Plymouth aspect of the study, commented:
“We have known for some time that the loss of the tumour suppressor Merlin resulted in the development of nervous system tumours, and we have come tantalisingly close to understanding how this occurs. Our joint study with colleagues at the Sloan-Kettering Institute for Cancer Research shows for the first time how this mechanism works. By understanding the mechanism, we can use this knowledge to develop effective drug therapies – in some cases adapting existing drugs – to treat patients for whom current therapies are limited and potentially devastating.”
(Source: www5.plymouth.ac.uk)
Study brings greater understanding of tumor growth mechanism
A study led by researchers from Plymouth University Peninsula Schools of Medicine and Dentistry has for the first time revealed how the loss of a particular tumour suppressing protein leads to the abnormal growth of tumours of the brain and nervous system.
The study is published in Brain: A Journal of Neurology.
Tumour suppressors exist in cells to prevent abnormal cell division in our bodies. The loss of a tumour suppressor called Merlin leads to tumours in many cell types within our nervous systems. There are two copies of a tumour suppressor, one on each chromosome that we inherit from our parents. The loss of Merlin can be caused by random loss of both copies in a single cell, causing sporadic tumours, or by inheriting one abnormal copy and losing the second copy throughout our lifetime as is seen in the inherited condition of neurofibromatosis type 2 (NF2).
With either sporadic loss or inherited NF2, these tumours lacking the Merlin protein develop in the Schwann cells that form the sheaths that surround and electrically insulate neurons. These tumours are called schwannomas, but tumours can also arise in the cells that form the membrane around the brain and spinal cord, and the cells that line the ventricles of the brain.
Although the schwannomas are slow-growing and benign, they are frequent and come in numbers. The sheer number of tumours caused by this gene defect can overwhelm a patient, often leading to hearing loss, disability and eventually death. Patients can suffer from 20 to 30 tumours at any one time, and the condition typically manifests in the teenage years and through into adulthood.
No effective therapy for these tumours exists, other than repeated invasive surgery or radiotherapy aiming at a single tumour at a time and which is unlikely to eradicate the full extent of the tumours.
The Brain study investigated how loss of a protein called Sox10 functions in causing these tumours. Sox10 is known to play a major role in the development of Schwann cells, but this is the first time it has been shown to be involved in the growth of schwannoma tumour cells. By understanding the mechanism, the research team has opened the way for new therapies to be developed that will provide a viable to alternative to surgery or radiotherapy.
The study, undertaken by researchers from Plymouth University Peninsula Schools of Medicine and Dentistry with colleagues from the State University of New York and Universitat Erlangen-Nurmberg, was led by Professor David Parkinson.
He said: “We have for the first time shown that human schwannoma cells have reduced expression of Sox10 protein and messenger RNA. By identifying this correlation and gaining an understanding of the mechanism of this process, we hope that drug-based therapies may in time be created and introduced that will reduce or negate the need for multiple surgery or radiotherapy.”
(Source: eurekalert.org)
New merciful treatment method for children with brain tumours
Children who undergo brain radiation therapy run a significant risk of suffering from permanent neurocognitive adverse effects. These adverse effects are due to the fact that the radiation often encounters healthy tissue. This reduces the formation of new cells, particularly in the hippocampus – the part of the brain involved in memory and learning.
Researchers at the University of Gothenburg’s Sahlgrenska Academy have used a model study to test newer radiation therapy techniques which could reduce these harmful adverse effects. The researchers based their study on a number of paediatric patients who had undergone conventional radiation treatment for medulloblastoma, a form of brain tumour that almost exclusively affects children, and simulated treatment plans using proton therapy techniques and newer photon therapy techniques.
Each treatment plan was personalised by physician Malin Blomstrand, physicist Patrik Brodin and their colleagues. The results show that the risk of neurocognitive adverse effects can be reduced significantly using the new radiation treatment techniques, particularly proton therapy.
“This could mean a better quality of life for children who are forced to undergo brain radiation therapy,” says Malin Blomstrand.
Brain tumours: artificial stimulation of the immune system could mean less aggressive treatments
Brain metastases are common secondary complications of other types of cancer, particularly lung, breast and skin cancer. The body’s own immune response in the brain is rendered powerless in the fight against these metastases by inflammatory reactions. Researchers at the MedUni Vienna have now, for the first time, precisely characterised the brain’s immune response to infiltrating metastases. This could pave the way to the development of new, less aggressive treatment options.
“The active phagocytes are quite literally overwhelmed by the tumour and even the white blood cells are too weak to fight off these metastases on their own; they have to be stimulated before they can have any effect,” explains oncologist Matthias Preusser from the University Department of Internal Medicine I and the Comprehensive Cancer Center (CCC), a joint institution operated by the MedUni Vienna and the Vienna General Hospital.
Brain tissue was obtained for investigation from autopsies carried out on people who had metastatic disease secondary to breast, lung or skin cancer. These are also the most common types of primary tumour. Brain metastases develop because they spread from the tumours into other parts of the body right up to the brain.
The scientists at the Clinical Institute of Neurology, the Centre for Brain Research, the CCC and the University Department of Internal Medicine I have discovered that metastases in the brain do encounter a wall of phagocytes, but it is too weak to successfully arrest the tumour’s development. To do this, white blood cells (lymphocytes) need to be mobilised in greater numbers as the second instance of the immune defence system.
These findings could lead to new therapeutic strategies being developed that will aim to increase the activation of white blood cells or other parts of the immune system – perhaps through medication such as antibody treatments or vaccines.
300 to 400 patients with brain metastases are treated each year at the MedUni Vienna. The standard treatment in most cases is radiotherapy to the head or generalised irradiation of the brain – which is associated with certain risks and possible side effects. Only in very few cases are drug-based treatment methods available for certain types of cancer. Says Preusser: “Our findings could represent an important step towards the development of less aggressive forms of treatment.”
(Source: meduniwien.ac.at)
A*STAR scientists have identified a biomarker of the most lethal form of brain tumours in adults − glioblastoma multiforme. The scientists found that by targeting this biomarker and depleting it with a potential drug, they were able to prevent the progression and relapse of the brain tumour.
Lubricated nanoparticles penetrate the brain
Nanoparticles often meet a sticky end in the brain. In theory, the tiny structures could deliver therapeutic drugs to a brain tumour, but navigating the narrow, syrupy spaces between brain cells is difficult. A spot of lubrication could help.
Nanoparticles (green) coated with poly(ethylene-glycol) (PEG) (Image: Elizabeth Nance, Graeme Woodworth, Kurt Sailor)
Justin Hanes at Johns Hopkins University in Baltimore, Maryland, was surprised to discover just how impermeable brain tissue is to nanoparticles. “It’s very sticky stuff,” he says, similar in adhesiveness to mucus, which protects parts of the body – such as the respiratory system – by trapping foreign particles.
It was thought that the adhesiveness of brain tissue limited the size of particles that can smoothly spread through the brain. Signalling molecules, nutrients and waste products below 64 nanometres in diameter can pass through the tissue with relative ease, but larger nanoparticles – suitable for delivering a payload of drugs to a specific location in the brain – quickly get stuck.
Now Hanes and his colleagues have doubled that size limit. They coated their nanoparticles with a densely-packed polymer shield, which lubricates their surface by preventing electrostatic and hydrophobic interactions with the surrounding tissue. “A nice hydrated shell around the particle prevents it from adhering to cells,” says Hanes.
Tracking the particles
Using this approach, they were able to observe the diffusion of nanoparticles 114 nanometres in diameter through live mouse brains and dissected human and rat brain tissue. Hanes believes the true upper size limit now lies somewhere between 114 nm and 200 nm. “Things were starting to slow down at 114,” he says.
But further research is needed before the team can progress to clinical trials in humans. “At this scale, it is very important to understand where our nanoparticles go once injected into the body,” says team member Elizabeth Nance, also of Johns Hopkins University. “We will need to show that, when combined with a therapeutic agent, these particles are getting to our site of interest, are having the intended effect and are not causing any side effects or toxicity to healthy normal tissue.”
"The effect of this work should be long-term," says Paul Wilson at the University of Warwick in Coventry, UK. The result represents significant progress in the battle to administer drugs within the brain, he says. "More effective and longer-lasting treatments against brain diseases, such as tumours and strokes, will no doubt soon follow."
Source: NewScientist
Neural precursor cells induce cell death in certain brain tumors
July 23, 2012
Neural precursor cells (NPC) in the young brain suppress certain brain tumors such as high-grade gliomas, especially glioblastoma (GBM), which are among the most common and most aggressive tumors. Now researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Charité – Universitätsmedizin Berlin have deciphered the underlying mechanism of action with which neural precursor cells protect the young brain against these tumors. They found that the NPC release substances that activate TRPV1 ion channels in the tumor cells and subsequently induce the tumor cells to undergo stress-induced cell-death. (Nature Medicine http://dx.doi.org/10.1038/nm.2827)*.
Despite surgery, radiation or chemotherapy or even a combination of all three treatment options, there is currently no cure for glioblastoma. In an earlier study the research group led by Professor Helmut Kettenmann (MDC) showed that neural precursor cells migrate to the glioblastoma cells and attack them. The neural precursor cells release a protein belonging to the family of BMP proteins (bone morphogenetic protein) that directly attacks the tumor stem cells. The current consensus of researchers is that tumor stem cells are the actual cause for continuous tumor self-renewal.
Kristin Stock, Jitender Kumar, Professor Kettenmann (all MDC), Dr. Michael Synowitz (MDC and Charité), Professor Rainer Glass (Munich University Hospitals, formerly MDC) and Professor Vincenzo Di Marzo (Istituto di Chimica Biomolecolare Pozzuoli, Naples, Italy) now report a new mechanism of action of NPC in astrocytomas. Like glioblastomas, astrocytomas are brain tumors that belong to the family of gliomas. Gliomas are most common in older people and are almost invariably fatal.
As the MDC researchers showed, the NPC also migrate to the astrocytomas. There they do not secrete proteins, but rather release fatty-acid substances (endovanilloids) which are harmful to the cancer cells. However, in order to exert their lethal effect, the endovanilloids need the aid of a specific ion channel, the TRPV1 channel (transient receptor potential vanilloid type 1), also called the vanilloid receptor 1. TRPV1 is already known to researchers as a transducer of painful stimuli. It has, among other things, a binding site for capsaicin, the irritant of hot chili peppers, and is responsible for the hot sensation after eating them. Clinical trials are currently underway to develop new pain treatments by blocking or desensitizing this ion channel.
MDC researchers describe an additional role of the TRPV1 ion channel
In contrast to its use in pain management, this ion channel, which is located on the surface of glioblastoma cells and is much more abundant there than on normal glial cells, must be activated to trigger cell death in gliomas. The activated ion channel mediates stress-induced cell-death in tumor cells. If however TRPV1 is downregulated or blocked, the glioma cells are not destroyed. The MDC researchers are thus the first to identify neural precursor cells as the source of fatty acids that induce tumor cell death and to describe the role of the TRPV1 ion channel in the fight against gliomas.
However, the activity of neural precursor cells in the brain and thus of the body’s own protective mechanism against gliomas diminishes with increasing age. This could explain why these tumors usually develop in older adults and not in children and young people. How can the natural protection of neural precursor cells be harnessed for older brains? According to the researchers, neural precursor cell therapy is not a solution. The benefit this obviously brings in the treatment of young people can have the opposite effect in older adults and may trigger brain tumors.
One possible treatment would be to use drugs to activate the TRPV1 channels. In mice, the group showed that a synthetic substance (arvanil), which is similar to capsaicin, reduced tumor growth. However, this substance has not yet been approved as a drug because the adverse side effects for humans are too severe. It is only used in basic research on mice, which tolerate the substance well. “In principle, however,” the researchers suggest, “synthetic vanilloid compounds may have clinical potential for brain tumor treatment.”
Source: Science Codex
Brain satnav helps surgeons travel to a tumour
SATNAV is good at finding the easiest route to where you want to go. Now a version for the brain could allow a flexible probe to take the safest route to reach deep tissue. Together, the algorithm and probe could provide access to brain tumours that were previously deemed inoperable.
When surgeons want to take a biopsy from deep inside the brain, they face a problem - how to get there without damaging the brain tissue en route. Flexible needles are one solution. Ferdinando Rodriguez y Baena at Imperial College London and colleagues created such a probe in 2009, basing the design on the needle-like ovipositor that female wasps use to deposit eggs inside trees.
Just like the wasp’s ovipositor, the probe has a number of interlocking flexible shafts, each of which can slide independently of the others. The probe naturally sticks to the soft brain tissue, providing traction, which means that when one of the shafts slides further into the tissue the probe will flex. By controlling the relative movement of each shaft it is possible to send the probe snaking along a path through the tissue.
Rodriguez y Baena’s team has now begun to think about exactly which paths are best to take. “Some areas of the brain are more important than others and we needed a way to decide what route caused the least amount of damage to vital areas,” says team member Seong Young Ko at Chonnam National University in Gwangju, South Korea. “You would want to stay well away from major blood vessels and sensory areas, for example.”
The team has now developed an algorithm to direct the probe around these obstacles. It considers three factors: the distance from the scalp to the desired brain tissue, the proximity of the route to vital areas such as blood vessels or nerve bundles, and the accumulated risk along the way.
There is controversy over how to rate the importance of different parts of the brain, so the team tested the algorithm by giving arbitrary levels of importance to different areas. It revealed the path which should theoretically bring the least risk to a patient. Ko presented the algorithm at the BioRob 2012 conference in Rome, Italy, last month.
"The ability to take a curved path through the brain, selecting the most forgiving route to avoid critical regions, represents an intriguing breakthrough," says Katrina Firlik, a neurosurgeon in Greenwich, Connecticut, who was not involved in the research. "It could not only enhance safety but might even expand the surgical repertoire to include cases currently deemed inoperable."
That is the hope, says Ko. So far the probe has only been tested in animal tissue, but he says the goal is to use the algorithm to guide the safe implantation of electrodes deep in the brain and to improve the safety of taking biopsies from hard-to-reach tumours.