Posts tagged brain tumours
Articles and news from the latest research reports.
(Image caption: In mice whose brain tumor cells (in green) couldn’t make galectin-1, the body’s immune system was able to recognize and attack the cells, causing them to die. In this microscope image, the orange areas show where tumor cells had died in just the first three days after the tumor was implanted in the brain. Six days later, the tumor had been eradicated. Credit: University of Michigan Medical School)
Brain tumors fly under the body’s radar like stealth jets
Brain tumors fly under the radar of the body’s defense forces by coating their cells with extra amounts of a specific protein, new research shows.
Like a stealth fighter jet, the coating means the cells evade detection by the early-warning immune system that should detect and kill them. The stealth approach lets the tumors hide until it’s too late for the body to defeat them.
The findings, made in mice and rats, show the key role of a protein called galectin-1 in some of the most dangerous brain tumors, called high grade malignant gliomas. A research team from the University of Michigan Medical School made the discovery and has published it online in the journal Cancer Research.
In a stunning example of scientific serendipity, the team uncovered galectin-1’s role by pursuing a chance finding. They had actually been trying to study how the extra production of galectin-1 by tumor cells affects cancer’s ability to grow and spread in the brain.
Instead, they found that when they blocked cancer cells from making galectin-1, the tumors were eradicated; they did not grow at all. That’s because the “first responders” of the body’s immune system – called natural killer or NK cells – spotted the tumor cells almost immediately and killed them.
But when the tumor cells made their usual amounts of galectin-1, the immune cells couldn’t recognize the cancerous cells as dangerous. That meant that the immune system couldn’t trigger the body’s “second line of defense”, called T cells – until the tumors had grown too large for the body to beat.
Team leader Pedro Lowenstein, M.D., Ph.D, of the U-M Department of Neurosurgery, says the findings open the door to research on the effect of blocking galectin-1 in patients with gliomas.
"This is an incredibly novel and exciting development, and shows that in science we must always be open-minded and go where the science takes us; no matter where we thought we wanted to go," says Lowenstein, whose graduate student Gregory J. Baker is the first author of the paper.
"In this case, we found that over-expression of galectin-1 inhibits the innate immune system, and this allows the tumor to grow enough to evade any possible effective T cell response," he explains. "By the time it’s detected, the battle is already lost."
The NK-evading “stealth” function of the extra-thick coating of galectin-1 came as a surprise, because glioma researchers everywhere had assumed the extra protein had more to do with the insidious ability of gliomas to invade the brain, and to evade the attacks of T cells.
Gliomas, which make up about 80 percent of all malignant brain tumors, include anaplastic oligodendrogliomas, anaplastic astrocytomas, and glioblastoma multiforme. More than 24,000 people in the U.S. are diagnosed with a primary malignant brain tumor each year.
The tiny tendrils of tumor that extend into brain tissue from a glioma are what make them so dangerous. Even when a neurosurgeon removes the bulk of the tumor, small invasive areas escape detection and keep growing, unchecked by the body.
Helping the innate immune system to recognize early stages of cancer growth, and sound the alarm for the body’s defense system to act while the remaining cancer is still small enough for them to kill, could potentially help patients.
While the new discovery opens the door to that kind of approach, much work needs to be done before the mouse-based research could help human patients, says Lowenstein, who is the Richard Schneider Collegiate Professor in Neurosurgery and also holds an appointment in the U-M Department of Cell and Developmental Biology. Galectin-1 may help other types of tumor evade the innate NK cells, too
The new research suggests that in the brain’s unique environment, galectin-1 creates an immunosuppressive effect immediately around tumor cells. The brain cancer cells seem to have evolved the ability to express their galectin-1 genes far more than normal, to allow the tumor to keep growing.
Lowenstein and co-team leader Maria Castro, Ph.D., have long studied the immune system’s interactions with brain cancer, using funding from the National Institutes of Health, and are co-leading a new clinical trial for malignant glioma (NCT01811992), that aims to translate prior research achievements into new trials for patients with brain tumors.
Most brain tumor immune research has focused on triggering the action of the adaptive immune system – whose cells control the process that allows the body to kill invaders from outside or within.
But that system take days or even weeks to reach full force – enough time for incipient tumors to grow too large for immune cells to eliminate solid tumor growth. The new research suggests the importance of enhancing the ability of the innate immune system’s “early warning” sentinels to spot glioma cells as early as possible.
Study reveals one reason brain tumors are more common in men
New research at Washington University School of Medicine in St. Louis helps explain why brain tumors occur more often in males and frequently are more harmful than similar tumors in females. For example, glioblastomas, the most common malignant brain tumors, are diagnosed twice as often in males, who suffer greater cognitive impairments than females and do not survive as long.
The researchers found that retinoblastoma protein (RB), a protein known to reduce cancer risk, is significantly less active in male brain cells than in female brain cells.
The study appears Aug. 1 in The Journal of Clinical Investigation.
“This is the first time anyone ever has identified a sex-linked difference that affects tumor risk and is intrinsic to cells, and that’s very exciting,” said senior author Joshua Rubin, MD, PhD. “These results suggest we need to go back and look at multiple pathways linked to cancer, checking for sex differences. Sex-based distinctions at the level of the cell may not only influence cancer risk but also the effectiveness of treatments.”
Rubin noted that RB is the target of drugs now being evaluated in clinical trials. Trial organizers hope the drugs trigger the protein’s anti-tumor effects and help cancer patients survive longer.
“In clinical trials, we typically examine data from male and female patients together, and that could be masking positive or negative responses that are limited to one sex,” said Rubin, who is an associate professor of pediatrics, neurology and anatomy and neurobiology. “At the very least, we should think about analyzing data for males and females separately in clinical trials.”
Scientists have identified many sex-linked diseases that either occur at different rates in males and females or cause different symptoms based on sex. These distinctions often are linked to sex hormones, which create and maintain many but not all of the biological differences between the sexes.
However, Rubin and his colleagues knew that sex hormones could not account for the differences in brain tumor risk.
“Male brain tumor risk remains higher throughout life despite major age-linked shifts in sex hormone production in males and females,” he said. “If the sex hormones were causing this effect, we’d see major changes in the relative rates of brain tumors in males and females at puberty. But they don’t happen then or later in life when menopause changes female sex hormone production.”
Rubin used a cell model of glioblastoma to prove it is easier to make male brain cells become tumors. After a series of genetic alterations and exposure to a growth factor, male brain cells became cancerous faster and more often than female brain cells.
In experiments designed to identify the reasons for the differences in the male and female cells, the team evaluated three genes to see if they were naturally less active in male brain cells. The genes they studied — neurofibromin, p53 and RB — normally suppress cell division and cell survival. They are mutated and disabled in many cancers.
The scientists found RB was more likely to be inactivated in male brain cells than in female brain cells. When they disabled the RB protein in female brain cells, the cells were equally susceptible to becoming cancers.
“There are other types of tumors that occur at different rates based on sex, such as some liver cancers, which occur more often in males,” Rubin said. “Knowing more about why cancer rates differ between males and females will help us understand basic mechanisms in cancer, seek more effective therapies and perform more informative clinical trials.”
(Source: news.wustl.edu)
Molecular imbalance linked to brain tumour seizures
Researchers in France may have discovered why some patients with a type of brain tumour have epileptic seizures.
“This small study is interesting and shows that glioma-linked epilepsy may be connected to certain channels found in the membranes of nerve cells” - Dr Robin Grant, Edinburgh Cancer Research UK Centre
Their study, published in Science Translational Medicine, suggests that seizures in patients with glioma may be linked to an imbalance of chloride – which is involved in nerve activity – in certain brain cells.
Whether a patient has seizures is linked to how aggressive their tumour is – with less aggressive cases being more prone to epilepsy as tumour cells slowly progress and alter brain tissue.
It is hoped that further research could explore treatments for glioma-linked epilepsy by controlling chloride levels in the brain.
Glioma develops from specialised brain cells known as ‘glial cells’ that usually help to keep brain nerve cells in place, providing support and protection to ensure correct brain function.
In the latest study, scientists from Sorbonne University studied brain tissue samples from 47 glioma patients and found that nerve tissue infiltrated by glioma cells behaves in similar ways to other forms of epilepsy.
Looking at the patient samples, the team found that a particular type of nerve cell – called a pyramidal cell – released excessive amounts of chloride from inside the cells when exposed to a molecule called GABA, which is also involved in transmitting nerve signals.
GABA was released by other neighbouring nerve cells called ‘interneurons’. And the researchers believe that the release of chloride through specialised molecular channels in the membrane of nerve cells, may be responsible for the seizures experienced in some glioma patients.
Dr Robin Grant, an expert in epilepsy and glioma from the Edinburgh Cancer Research UK Centre, who was not involved in the research, said that the channels may make good drug targets for further investigation, but a finer understanding of the involvement of other processes is still needed.
“This small study is interesting and shows that glioma-linked epilepsy, as with other types of epilepsy, may be connected to certain channels found in the membranes of nerve cells.
“More research will be needed to understand the finer details of this process in glioma and whether these channels, along with other similar channels found in nerve cells, could be good targets for drugs to help control the condition.”
Tool helps guide brain cancer surgery
A tool to help brain surgeons test and more precisely remove cancerous tissue was successfully used during surgery, according to a Purdue University and Brigham and Women’s Hospital study.
The Purdue-designed tool sprays a microscopic stream of charged solvent onto the tissue surface to gather information about its molecular makeup and produces a color-coded image that reveals the location, nature and concentration of tumor cells.
”In a matter of seconds this technique offers molecular information that can detect residual tumor that otherwise may have been left behind in the patient,” said R. Graham Cooks, the Purdue professor who co-led the research team. “The instrumentation is relatively small and inexpensive and could easily be installed in operating rooms to aid neurosurgeons. This study shows the tremendous potential it has to enhance patient care.”
Current surgical methods rely on the surgeon’s trained eye with the help of an operating microscope and imaging from scans performed before surgery, Cooks said.
"Brain tumor tissue looks very similar to healthy brain tissue, and it is very difficult to determine where the tumor ends and the normal tissue begins," he said. "In the brain, millimeters of tissue can mean the difference between normal and impaired function. Molecular information beyond what a surgeon can see can help them precisely and comprehensively remove the cancer."
The mass spectrometry-based tool had previously been shown to accurately identify the cancer type, grade and tumor margins of specimens removed during surgery based on an evaluation of the distribution and amounts of fatty substances called lipids within the tissue. This study took the analysis a step further by additionally evaluating a molecule associated with cell growth and differentiation that is considered a biomarker for certain types of brain cancer, he said.
"We were able to identify a single metabolite biomarker that provides information about tumor classification, genotype and the prognosis for the patient," said Cooks, the Henry Bohn Hass Distinguished Professor of Chemistry. "Through mass spectrometry all of this information can be obtained from a biopsy in a matter of minutes and without significantly interrupting the surgical procedure."
For this study, which included validation on samples and use during two patients’ surgical procedures, the tool was tuned to identify the lipid metabolite 2-hydroxyglutarate or 2-HG. This biomarker is associated with more than 70 percent of gliomas and can be used to classify the tumors, he said.
A paper detailing the results of the National Institutes of Health-funded study will be published in an upcoming issue of the Proceedings of the National Academy of Sciences and is published online.
In mass spectrometry molecules are electrically charged and turned into ions so that they can be identified by their mass. The new tool relies an ambient mass spectrometry analysis technique developed by Cooks and his colleagues called desorption electrospray ionization, or DESI, which eliminated the need for chemical manipulations of samples and containment in a vacuum chamber for ionization. DESI allows ionization to occur directly on surfaces outside of the mass spectrometers, making the process much simpler, faster and more applicable to surgical settings.
The tool couples a DESI mass spectrometer with a software program designed by the research team that uses the results to characterize the brain tumors and detect boundaries between healthy and cancerous tissue. The program is based on earlier studies of lipid patterns that correspond to different types and grades of cancer and currently covers the two most common types of brain tumors, gliomas and meningiomas. These two types of tumors combined account for about 65 percent of all brain tumors and 80 percent of all malignant brain tumors, according to the American Brain Tumor Association.
Additional classification methodologies and metabolite biomarkers could be added to tailor the tool to different types of cancer, Cooks said.
The brain surgery was performed in the Advanced Multi-Modality Image Guided Operating suite, or AMIGO at Brigham and Women’s Hospital.
Dr. Nathalie Agar, director of the Surgical Molecular Imaging Laboratory within the neurosurgery department at Brigham and Women’s Hospital, led the study.
Study shows how brain tumor cells move and damage tissue, points to possible therapy
Researchers at the University of Alabama at Birmingham have shed new light on how cells called gliomas migrate in the brain and cause devastating tumors. The findings, published June 19, 2014 in Nature Communications, show that gliomas — malignant glial cells — disrupt normal neural connections and hijack control of blood vessels.
The study provides insight into the mechanisms of how glioma cells spread throughout the brain as a devastating form of brain cancer, and potentially offers a tantalizing opportunity for therapy.
A hallmark of gliomas is that the cells can migrate away from a central tumor, invading healthy brain tissue. Even if a tumor mass is surgically removed, malignant cells that have migrated are left behind, and can grow into a new tumor.
To grow, glioma cells need access to nutrients in the blood supply, and it is known that gliomas travel along blood vessels within the brain. Now, researchers in the lab of neuroscientist Harald Sontheimer, Ph.D., professor in the UAB Department of Neurobiology, have discovered that, as they move, gliomas dislodge astrocytic endfeet, which play a critical role in regulating blood flow in the brain.
Astrocytes are star-shaped cells in the brain that surround blood vessels and connect to them through projections called endfeet, which extend from the astrocyte and latch onto the vessel wall. The surface of nearly every blood vessel in the brain is covered by endfeet, which regulate the smooth muscle cells on the walls of blood vessels. Through that connection, instructions can be given to the muscle cells to constrict the blood vessel and limit blood flow, or dilate the vessel and increase blood flow.
Sontheimer, director of the UAB Center for Glial Biology in Medicine, says that, as a person performs different neurological functions, blood flow needs to be increased to the areas responsible for that function and correspondingly decreased in other areas to maintain balance.
The arrival of a glioma cell changes all that.
“Glioma cells traveling along blood vessels literally cut the connection of astrocytic endfeet with the vessels and push them out of the way,” said Sontheimer. “By disrupting this important neural connection, adverse cognitive effects could be expected. Additionally, our study showed that gliomas then take control of the blood vessels for their own ends. And those ends are primarily to obtain nutrients from blood so that they can continue to grow and spread.”
Sontheimer’s team says the glioma cells tend to congregate at blood vessel junctions, almost as if camping alongside a stream where it joins a river. The ready supply of nutrients would allow the cell to grow into a larger tumor mass.
By traveling on the outside of a blood vessel, glioma cells are able to access nutrients from the blood stream. As a side effect to that process, they damage the blood brain barrier. The barrier, a layer of endothelial cells, protects the brain by restricting passage of harmful substances from the blood stream into brain tissue.
“We found that, when gliomas push away the astrocytic endfeet, damage occurs to the integrity of the endothelial cells that make up the blood brain barrier,” said Stefanie Robel, Ph.D., a postdoctoral researcher in Sontheimer’s lab and co-first author of the study. “The barrier becomes weakened, and begins to leak. A leak across the barrier can cause severe damage to brain tissue.”
“That leakage appears to be a consequence of glioma cells’ migrating along the blood vessels in their search for nutrients,” said Stacey Watkins, an M.D./Ph.D. student in Sontheimer’s lab and co-first author. “When glioma cells contact the vessels, they have direct access to nutrients.”
But amid the deleterious effects that Sontheimer’s team observed — shearing away the endfeet from their blood vessels, disrupting normal brain activity, hijacking control of blood vessels and causing leaks in the blood brain barrier — he says there may be a silver lining. The idea that gliomas cause the blood brain barrier to become porous and leak might open up a new avenue to kill the malignant cells as they migrate.
Chemotherapy, usually delivered intravenously, is not considered an effective strategy for killing gliomas. Chemotherapeutic agents are very effective in killing cancer cells elsewhere in the body, but the predominant belief is that such drugs will not pass the blood brain barrier and thus will not reach their target.
“Chemotherapy is typically not tried in cases of glioma until after other therapies such as surgery and radiation have been employed,” Sontheimer said. “Our findings, which suggest that gliomas actually weaken the blood brain barrier and cause leakage, might indicate that high-dose, intravenous chemotherapy used early on following a diagnosis of brain cancer would be beneficial.”
The study, funded by the National Institutes of Health and the American Brain Tumor Association, was conducted on a clinically relevant mouse model of human malignant glioma.
Sontheimer says logical next steps would be to further examine the cognitive impact of severing the astrocytic endfeet connection to blood vessels.
Cancer by remote-control: Overlooked DNA shuffling drives deadly paediatric brain tumour
One of the deadliest forms of paediatric brain tumour, Group 3 medulloblastoma, is linked to a variety of large-scale DNA rearrangements which all have the same overall effect on specific genes located on different chromosomes. The finding, by scientists at the European Molecular Biology Laboratory (EMBL), the German Cancer Research Centre (DKFZ), both in Heidelberg, Germany, and Sanford-Burnham Medical Research Institute in San Diego, USA, is published online today in Nature.
To date, the only gene known to play an important role in Group 3 medulloblastoma was a gene called MYC, but that gene alone couldn’t explain some of the unique characteristics of this particular type of medulloblastoma, which has a higher metastasis rate and overall poorer prognosis than other types of this childhood brain tumour. To tackle the question, Jan Korbel’s group at EMBL and collaborators at DKFZ tried to identify new genes involved, taking advantage of the large number of medulloblastoma genome sequences now known.
“We were surprised to see that in addition to MYC there are two other major drivers of Group 3 medulloblastoma – two sister genes called GFI1B and GFI1,” says Korbel. “Our findings could be relevant for research on other cancers, as we discovered that those genes had been activated in a way that cancer researchers don’t usually look for in solid tumours.”
Rather than take the usual approach of looking for changes in individual genes, the team focused on large-scale rearrangements of the stretches of DNA that lie between genes. They found that the DNA of different patients showed evidence of different rearrangements: duplications, deletions, inversions, and even complex alterations involving many ‘DNA-shuffling’ events. This wide array of genetic changes had one effect in common: they placed GFI1B close to highly active enhancers – stretches of DNA that can dramatically increase gene activity. So large-scale DNA changes relocate GFI1B, activating this gene in cells where it would normally be switched off. And that, the researchers surmise, is what drives the tumour to form.
“Nobody has seen such a process in solid cancers before,” says Paul Northcott from DKFZ, “although it shares similarities with a phenomenon implicated in leukaemias, which has been known since the 80s.”
GFI1B wasn’t affected in all cases studied, but in many patients where it wasn’t, a related gene with a similar role, GFI1, was. GFI1B and GFI1 sit on different chromosomes, and interestingly, the DNA rearrangements affecting GFI1 put it next to enhancers sitting on yet other chromosomes. But the overall result was identical: the gene was activated, and appeared to drive tumour formation.
To confirm the role of GFI1B and GFI1 in causing medulloblastoma, the Heidelberg researchers turned to the expertise of Robert Wechsler-Reya’s group at Sanford-Burnham. Wechsler-Reya’s lab genetically modified neural stem cells to have either GFI1B or GFI1 turned on, together with MYC. When they inserted those modified cells into the brains of healthy mice, the rodents developed aggressive, metastasising brain tumours that closely resemble Group 3 medulloblastoma in humans.
These mice are the first to truly mimic the genetics of the human version of Group 3 medulloblastoma, and researchers can now use them to probe further. The mice could, for instance, be used to test potential treatments suggested by these findings. One interesting option to explore, the scientists say, is that highly active enhancers – like the ones they found were involved in this tumour – can be vulnerable to an existing class of drugs called bromodomain inhibitors. And, since neither GFI1B nor GFI1 is normally active in the brain, the study points to possible routes for diagnosing this brain tumour, too.
But the mice also raised another question the scientists are still untangling. For the rodents to develop medulloblastoma-like tumours, activating GFI1 or GFI1B was not enough; MYC also had to be switched on. In human patients, however, scientists have found a statistical link between MYC and GFI1, but not between MYC and GFI1B, so the team is now following up on this partial surprise.
“What we’re learning from this study is that clearly one has to think outside the box when trying to understand cancer genomes,” Korbel concludes.
(Source: embl.de)
Stopping tumours in their path
Glioblastoma (GBM) is the most common and deadly form of primary malignant brain cancer accounting for approximately 15% of all brain tumours and occurring mostly in adults between the ages of 45 and 70. The aggressive recurrent nature of this cancer is only temporarily contained by combined surgery, chemotherapy and radiation treatment. The recurrence of GBM is usually fatal, resulting in an average patient survival time of less than two years. A new study from the Montreal Neurological Institute and Hospital – The Neuro - at McGill University, published in Nature Communications, identifies two specific key players in the growth of GBM.
A GBM tumour contains a complex combination of different cell types, including ‘stem-like’ cells that are able to initiate brain tumour growth, even when present in very small numbers. These cells, known as brain-tumour initiating cells (BTICs), are believed to be among the cells that can re-initiate GBM if they are not completely eradicated through surgery, radiation and chemotherapy. Thus, BTICs represent an important therapeutic target for GBM treatment strategies.
“We wanted to find out how GBM-derived BTICs are able to initiate a tumour with the ultimate goal of preventing the re-growth of this deadly form of brain cancer,” says Dr. Stefano Stifani, neuroscientist at The Neuro and senior investigator on the paper. “What we found is that by impairing the activity of two transcription factors (proteins that control gene expression), termed FOXG1 and TLE, we can significantly reduce the ability of BTICs to give rise to brain tumours.” The researchers studied brain tumour growth in an in vivo mouse model using human GBM-derived BTICs. This approach provides what is called an in vivo environment that closely resembles the original human brain tumours. The demonstration that the FOXG1 and TLE proteins are important for the tumour-forming ability of human GBM-derived BTICs has long-term implications because FOXG1 and TLE control the expression of numerous genes. Identifying the genes whose expression is controlled by FOXG1 and TLE is expected to provide further information on the mechanisms involved in GBM tumourigenesis. In the long term, researchers hope to identify multiple important regulators, in order to find new potential therapeutic targets to impair the tumourigenic ability of BTICs.
“The implication of transcription factors FOXG1 and TLE in the tumour-forming ability of BTICs opens the door to possible strategies to block tumour growth – a major advance in the fight against GBM.”
(Image: ALAMY)
Malignant brain tumours can be transformed into benign forms
Cells of malignant brain tumours deceive our immune system so effectively that it starts working for them. But who lives by the sword, dies by the sword. Researchers from the Nencki Institute in Warsaw show how to deceive brain tumours and change malignant gliomas into benign forms.
The research team of Prof. Bożena Kamińska from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw developed – so far only in animal model – a method of converting malignant gliomas (brain tumours) into benign forms. Since the cells of benign gliomas are subdued and sometimes even eliminated by the host’s immune system, the prospects for survival of sick animals significantly increase. This novel research was funded by the Polish National Science Centre.
The nervous system, including the brain, is inhabited, besides neurons and glial cells, by microglial cells. They support the nervous cells but also have important protective functions, patrolling the surroundings with their extenses and eliminating damaged or unnecessary cells. As macrophages of our immune system they also fight foreign bacteria, viruses and tumorous cells. Unfortunately, sometimes the glia cells themselves become cancerous. This is how brain tumours called gliomas form. However, they are not uniform entity and could differ significantly with respect to their behaviour and degree of malignancy. In benign variants the survival prospects for patients are quite high, while in the case of malignant gliomas few patients are expected to live longer than a year.
In 2007 the group of Prof. Kamińska showed that malignant gliomas can “re-program” the brain immune cells (microglia) to support tumour development instead of fighting it. Similarly the tumour even changed the protective immune cells recruited to the brain from blood and bone marrow (peripheral macrophages). The research to understand how the tumour deceives the host’s immune system and forces the microglial cells to support and foster its growth has taken several years.
The results of other research groups showed that in the case of breast cancer the factor responsible for changing the behaviour of tumour-infiltrating macrophages is the CSF1 protein, controlling the maturation of macrophages. Researchers from the Nencki Institute asked, whether a similar substance is not produces by the cells of the malignant gliomas.
Studies conducted by Prof. Kamińska’s group has shown that gliomas do not produce larger amounts of the CSF1 protein and this protein does not significantly impact tumour development. They were however lucky to discover the production of a different protein from the same family, the CSF2 protein. In benign tumours this protein was present in small amounts, while in malignant gliomas large amounts of it were discovered. Researchers from the Nencki Institute decided to investigate, whether this protein really influences tumour invasiveness. With the help of self-developed tools they turned off the gene responsible for the production of the CSF2 protein in glioma cells.
“We have observed that after turning off a single gene – the gene producing the CSF2 protein – the tumour cells stopped attracting the microglia and were not capable of converting these cells to support the tumour’s development. As a result the immune system started working as expected and the malignant tumour was transformed into a benign form. It did not disappear, but stopped growing”, says a PhD candidate Małgorzata Sielska from the Nencki Institute.
The protein responsible for “re-programming” the anti-tumour response and for high invasiveness of gliomas is present only in cancerous cells and is practically absent from healthy brain. Therefore researchers from the Nencki Institute suspect that when the gene responsible for its production is turned off in the brain, it would affect only the tumour.
Research on taming malignant brain tumours and converting them into benign forms has been conducted on mouse glioma cells growing in the brains of experimental animals, and published in the Journal of Pathology. Presently the group of Prof. Kamińska is checking the effectiveness of this method in the cells of human malignant gliomas. Preliminary results confirm that silencing one gene in human glioma cells growing in mouse brains also stops the growth of the tumour. Developing tools to turn off this gene’s expression, following the creation of appropriate carriers, will in the future open new possibilities for gene therapy in humans.
The findings has helped Nencki researchers develop small molecules (short peptides) which interfere with binding the CSF2 protein (expressed by tumorous cells) to the appropriate receptors on microglial cells. This way the signal coming from tumorous cells gets blocked and the microglia is prevented from “re-programming” itself. The developed molecules, together with relevant genetic tools, are covered by an international patent. Presently researchers work towards starting preclinical and clinical trials of this method.
The proposed solution holds great potential for therapies using small molecules – short peptides or in the case of gene therapy, short RNA silencing gene expression. Will this method really work? This will be confirmed by further experiments and tests. For Nencki researchers it is important that the patented molecules target only one fragment of the signalling pathway which functions between the cells of the malignant tumour and the microglia, thus guaranteeing that no other functions of the organism are affected. Moreover discovery of such an important signalling pathway encourages scientists to search for ways of blocking it in other places, which could be technically more feasible.
“Our research is investigative in nature and above all aims to explain why and how tumours develop. We conducted our research mostly on experimental models, mouse glioma cells or human glioma cells growing in mice. Therefore the road to develop drugs and therapies limiting the invasiveness of gliomas in human is still very long. Luckily we already discovered the molecule that is worth targeting”, sums up Prof. Kamińska.
Brain-penetrating particle attacks deadly tumors
Scientists have developed a new approach for treating a deadly brain cancer that strikes 15,000 in the United States annually and for which there is no effective long-term therapy. The researchers, from Yale and Johns Hopkins, have shown that the approach extends the lives of laboratory animals and are preparing to seek government approval for a human clinical trial.
“We wanted to make a system that would penetrate into the brain and deliver drugs to a greater volume of tissue,” said Mark Saltzman, a biomedical engineer at Yale and principal investigator of the research. “Drugs have to get to tumor cells in order to work, and they have to be the right drugs.”
Results were published July 1 in the Proceedings of the National Academy of Sciences.
Glioblastoma multiforme is a malignant cancer originating in the brain. Median survival with standard care — surgery plus chemotherapy plus radiation — is just over a year, and the five-year survival rate is less than 10 percent.
Current methods of drug delivery have serious limitations. Oral and intravenously injected drugs have difficulty accessing the brain because of a biological defense known as the blood-brain barrier. Drugs released directly in the brain through implants can’t reach migrating tumor cells. And commonly used drugs fail to kill the cells primarily responsible for tumor development, allowing regrowth.
The researchers developed a new, ultra-small drug-delivery particle that more nimbly navigates brain tissue than do existing options. They also identified and tested an existing FDA-approved drug — a fungicide called dithiazanine iodide (DI) — and found that it can kill the most aggressive tumor-causing cells.
“This approach addresses limitations of other forms of therapy by delivering drugs directly to the area most needed, obviating systemic side-effects, and permitting the drug to reside for weeks,” said neurosurgeon Dr. Joseph M. Piepmeier, a member of the research team. Piepmeier leads clinical research for Yale Cancer Center’s brain tumor program.
The drug-loaded nanoparticles are administered in fluid directly to the brain through a catheter, bypassing the blood-brain barrier. The particles’ tiny size — their diameter is about 70 nanometers — facilitates movement within brain tissue. They release their drug load gradually, offering sustained treatment.
In tests on laboratory rats with human brain cancers, DI-loaded nanoparticles significantly increased median survival to 280 days, researchers report. Maximum median survival time for rats treated with other therapies was 180 days, and with no treatment, survival was 147 days. Tests on pigs established that the new drug-particle combination also diffuses deep into brains of large animals.
The nanoparticles are made of polymers, or strings of repeating molecules. Their size, ability to control release, and means of application help them permeate brain tissues.
Researchers screened more than 2,000 FDA-approved drugs in the hunt for candidates that would kill the cells most responsible for human tumor development, brain cancer stem cells. Overall, DI worked best.
The scientists believe the particles can be adapted to deliver other drugs and to treat other central nervous system diseases, they said.
The paper is titled “Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.”
Virus-like particles provide vital clues about brain tumours
Exosomes are small, virus-like particles that can transport genetic material and signal substances between cells. Researchers at Lund University, Sweden, have made new findings about exosomes released from aggressive brain tumours, gliomas. These exosomes are shown to have an important function in brain tumour development, and could be utilised as biomarkers to assess tumour aggressiveness through a blood test.
“Current wisdom says that cells are closed entities that communicate through the secretion of soluble signalling molecules. Recent findings indicate that cells can exchange more complex information – whole packages of genetic material and signalling proteins. This is an entirely new conception of how cells communicate”, says Dr Mattias Belting, Professor of Oncology at Lund University and senior consultant in oncology at Skåne University Hospital, Lund, Sweden.
Exosomes are small vesicles of only 30–90 nm. They are produced inside cells and act as “transport vehicles” of genetic material that can be transferred to surrounding cells. Since their first discovery, exosomes have been found in blood, saliva, urine, breast milk and other body fluids.
Mattias Belting’s research group has investigated exosomes released from tumour cells of patients with gliomas. The tiny exosome particles are delivered from the tumour to healthy cells of the brain and may prime normal tissue for efficient spreading of the tumour. The researchers in Lund have now shown that the aggressiveness of the tumour is reflected in the exosome molecular profile.
“We have succeeded in developing a method for the isolation of exosomes from brain tumour patients through a relatively simple blood test. Our analyses indicate that the content of exosomes mirrors the aggressiveness of the tumour in a unique manner”, says postdoctoral researcher Paulina Kucharzewska.
Exosomes could thus be utilised as biomarkers, i.e. to provide guidance on how the patient should be treated and to monitor treatment response. This possibility is particularly attractive with brain tumours that are not readily accessible for tissue biopsy. However, analysis of exosomes from the blood may also prove important with other tumour types. The value of conventional tumour biopsies is limited by the heterogeneity of tumour tissue, i.e. the tissue specimen may not be fully representative of the biological characteristics of a particular tumour. Exosomes, however, may offer more comprehensive information, according to the researchers.
The second international meeting on exosomes has just opened in Boston, and Mattias Belting and members of his team are there.
“It is very exciting to be part of the emergence of a novel research field. It can be anticipated that the most influential researchers in this area may one day be awarded the Nobel Prize”, says Dr Belting.
The results are published in Proceedings of the National Academy of Sciences (PNAS).
(Source: lunduniversity.lu.se)