Posts tagged cancer cells
Articles and news from the latest research reports.
Scientists Uncover Navigation System Used by Cancer, Nerve Cells
Duke University researchers have found a ”roving detection system” on the surface of cells that may point to new ways of treating diseases like cancer, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).
The cells, which were studied in nematode worms, are able to break through normal tissue boundaries and burrow into other tissues and organs — a crucial step in many normal developmental processes, ranging from embryonic development and wound-healing to the formation of new blood vessels.
But sometimes the process goes awry. Such is the case with metastatic cancer, in which cancer cells spread unchecked from where they originated and form tumors in other parts of the body.
“Cell invasion is one of the most clinically relevant yet least understood aspects of cancer progression,” said David Sherwood, an associate professor of biology at Duke.
Sherwood is leading a team that is investigating the molecular mechanisms that control cell invasion in both normal development and cancer, using a one-millimeter worm known as C. elegans.
At one point in C. elegans development, a specialized cell called the anchor cell breaches the dense, sheet-like membrane that separate the worm’s uterus from its vulva, opening up the worm’s reproductive tract.
Anchor cells can’t see, so they need some kind of signal to tell them where to break through. In a 2009 study, Sherwood and colleagues discovered that an extracellular cue called netrin orients the anchor cell so that it invades in the right direction.
In a new study appearing Aug. 25 in the Journal of Cell Biology, the team shows how receptors on the invasive cells essentially rove around the cell membrane ”hunting” for the missing netrin signal that will guide the cell to the correct location.
The researchers used a video camera attached to a powerful microscope to take time-lapse movies of the slow movement of the C. elegans anchor cell during its invasion (Figure 1, Figure 2).
Their time-lapse analyses reveal that when netrin production is blocked, netrin receptors on the surface of the anchor cell periodically cluster, disperse and reassemble in a different region of the cell membrane. The receptors cluster alongside patches of actin filaments — thin flexible fibers that help cells change shape and form invasive protrusions –- that pop up in each new spot.
“It’s kind of like a missile detection system,” Sherwood said.
Rather than the whole cell having to move around, its receptors move around on the outside of the cell until they get a signal. Once the receptors locate the netrin signal, they stabilize in the region of the cell membrane that is closest to the source of the signal.
The findings redefine decades-old ideas about how the cell’s navigation system works. “Cells don’t just passively respond to the netrin signal — they’re actively searching for it,” Sherwood said.
Given that netrin has been found to promote cell invasion in some of the most lethal cancers, the findings could lead to new treatment strategies. Disrupting the cell’s netrin detection system, for example, could prevent cancer cells from finding their way to the bloodstream or the lymphatic system and stop them from metastasizing, or becoming invasive and spreading throughout the body.
“One of the things we’re gearing up to do next are drug screens with our collaborators to see if we can block this detection system during invasion,” Sherwood said.
Scientists have also known for years that netrin plays a key role in wiring the brain and nervous system by guiding developing nerve cells as they grow and form connections.
This means the results could also point to new ways of treating neurological disorders like Parkinson’s and ALS and recovering from spinal cord injuries.
Tinkering with the cell’s netrin detection machinery, for example, may make it possible to encourage damaged cells in the central nervous system — which normally have limited ability to regenerate — to regrow.
(Source: today.duke.edu)
(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.
(Image caption: In brain cancer cells, the protein PARC plays a key role in long-term cell survival. In both images, the red represents the protein cytochrome c, which is released when mitochondria are damaged and trigger apoptosis – cell suicide. At left, injured brain cancer cells exhibit little cytochrome c; they use the protein PARC to degrade the released cytochrome c, allowing the cancer cells to survive. At right, when researchers reduced PARC, cytochrome c accumulated, allowing apoptosis to carry on)
Neurons, brain cancer cells require the same little-known protein for long-term survival
Researchers at the UNC School of Medicine have discovered that the protein PARC/CUL9 helps neurons and brain cancer cells override the biochemical mechanisms that lead to cell death in most other cells. In neurons, long-term survival allows for proper brain function as we age. In brain cancer cells, though, long-term survival contributes to tumor growth and the spread of the disease.
These results, published in the journal Science Signaling, not only identify a previously unknown mechanism used by neurons for their much-needed survival, but show that brain cancer cells hijack the same mechanism for their own survival.
The discovery will lead to new investigations of brain cancer treatments and provides insight into Parkinson’s disease, including a potential new research tool for scientists.
“PARC is very similar to Parkin, a protein that’s mutated in Parkinson’s disease,” said Mohanish Deshmukh, PhD, a professor of cell biology and physiology and senior author of the Science Signaling paper. “We think they might work in tandem to protect neurons.”
If so, researchers can investigate the interplay between these proteins to create better drugs to treat the second-most prevalent neurodegenerative disease after Alzheimer’s disease.
Vivian Gama, PhD, a postdoctoral fellow in Deshmukh’s lab, led the experiments in cell cultures and animal models. First, she used external stimuli to promote the damage of mitochondria – the energy sources for cells. In most cell types, when mitochondria are damaged, they release a protein called cytochrome c, which triggers a cascade of biochemical steps that end in cell death – a process known as apoptosis.
Working with neurons, though, Gama found that the protein PARC/CUL9 blocked this process; it degraded cytochrome c, halted apoptosis, and allowed for long-term cell survival. “In this setting, we want PARC to do that because we want neurons to survive as long as possible,” said Gama, first author of the Science Signaling paper.
Deshmukh, a member of the UNC Neuroscience Center and the UNC Lineberger Comprehensive Cancer Center, said, “In Parkinson’s disease, we know that Parkin targets damaged mitochondria for degradation. However, exactly what happens to the proteins, such as cytochrome c, that are released from the damaged mitochondria has been unknown. Now, we think PARC plays a role in this process.”
Deshmukh and Gama’s work could lead to an alternative way to study Parkinson’s disease. Other researchers have created mouse models that lack the Parkin gene, but Gama said these models don’t have many of the hallmark symptoms that human patients have, making the model less than desirable for researchers. “Our hypothesis is that in the absence of Parkin, PARC still does the job,” Gama said, “as it may allow cells to survive.”
Gama and Deshmukh are now creating a model that lacks both the Parkin and PARC genes.
They will also investigate PARC as a target for cancer treatment.
“We tested several cancer cell lines and found that PARC degrades cytochrome c in medulloblastoma, a cancer of the central nervous system and in neuroblastoma, a cancer of the peripheral nervous system,” Gama said. “Not all cytochrome c is degraded; there are likely other factors involved. But PARC is an important player.”
When Gama and colleagues triggered the apoptotic process in brain cancer cells, they found that PARC allowed the cells to survive. When PARC was inhibited, the cells were more vulnerable to stress and damage, which means they could be more vulnerable to compounds aimed at destroying them.
Deshmukh said, “We show that brain cancer cells co-opt PARC to bypass apoptosis in the same way that neurons do and for the exact same purpose.”
Brain cell find points to new therapies
Insights into how brain cells are produced could lead to treatments for brain cancer and other brain-related disorders.
Scientists have gained new understanding of the role played by a key molecule that controls how and when nerve and brain cells are formed - a process that allows the brain to develop and keeps it healthy.
Their findings could help explain what happens when cell production goes out of control, which is a fundamental characteristic of many diseases including cancer.
Regulatory systems
Researchers have focused on a RNA molecule, known as miR-9, which is linked to the development of brain cells, known as neurons and glial cells.
They have shown that a protein called Lin28a regulates the production of miR-9, which in turn controls the genes involved in brain cell development and function.
Scientists carried out lab studies of embryonic cells, which can develop into neurons, to determine how Lin28a controls the amount of miR-9 that is produced.
Complex pathways
They found that in embryonic cells, Lin28a prevents production of miR-9 by triggering the degradation of its precursor molecule.
In developed brain cells, Lin28a is no longer produced, which enables miR-9 to accumulate and function.
In cancer cells, Lin28a production is re-established, and as a result this natural process is disrupted.
Lab experiments
Researchers used a series of lab tests to unravel the complex processes that are directed by the Lin28a protein.
They say further studies could help explain fully the role of Lin28a and miR-9 in brain development, and pave the way to the development of novel therapies.
The study, published in Nature Communications, was supported by the Wellcome Trust and the Medical Research Council.
Understanding more of the complex science behind the fundamental processes of cell development will helps us learn more about what happens when this goes wrong – and what might be done to prevent it. -Dr Gracjan Michlewski (School of Biological Sciences)
(Image: iStock)
New approach makes cancer cells explode
Researchers at Karolinska Institutet have discovered that a substance called Vacquinol-1 makes cells from glioblastoma, the most aggressive type of brain tumour, literally explode. When mice were given the substance, which can be given in tablet form, tumour growth was reversed and survival was prolonged. The findings are published in the journal Cell.
The established treatments that are available for glioblastoma include surgery, radiation and chemotherapy. But even if this treatment is given the average survival is just 15 months. It is therefore critical to find better treatments for malignant brain tumours.
Researchers at Karolinska Institutet and colleagues at Uppsala University have discovered an entirely new mechanism to kill tumour cells in glioblastoma. Researchers in an initial stage have exposed tumour cells to a wide range of molecules. If the cancer cells died, the molecule was considered of interest for further studies, which initially applied to over 200 kinds of molecules. Following extensive studies, a single molecule has been identified as being of particular interest. The researchers wanted to find out why it caused cancer cell death.
It was found that the molecule gave the cancer cells an uncontrolled vacuolization, a process in which the cell carries substances from outside the cell into its interior. This carrying process is made via the vacuoles, which can roughly be described as blisters or bags consisting of cell membranes. The process is similar to what was behind last year’s Nobel Prize in physiology or medicine, the discovery that describes how cellular vesicles move things from the interior of the cell to its surface.
Cell membranes collapsed
When cancer cells were filled with a large amount of vacuoles, the cell membranes, the outer wall of the cell, collapsed and the cell simply exploded and necrotized.
“This is an entirely new mechanism for cancer treatment. A possible medicine based on this principle would therefore attack the glioblastoma in an entirely new way. This principle may also work for other cancer diseases, we have not really explored this yet,” says Patrik Ernfors, professor of tissue biology at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.
Researchers made mice that had human glioblastoma cells transplanted ingest the substance for five days. The average survival was about 30 days for the control group that did not receive the substance. Of those who received the substance six of eight mice were still alive after 80 days. The study was then considered of such interest that the scientific journal wanted to publish the article immediately.
“We now want to try to take this discovery in basic research through preclinical development and all the way to the clinic. The goal is to get into a phase 1 trial,” says Patrik Ernfors.
Breast cancer spreads to brain by masquerading as neurons
Often, several years can pass between the time a breast cancer patient successfully goes into remission and a related brain tumor develops. During that time, the breast cancer cells somehow hide, escaping detection as they grow and develop. Now City of Hope researchers have found out how.
Breast cancer cells disguise themselves as neurons, becoming “cellular chameleons,” the scientists found. This allows them to slip undetected into the brain and, from there, develop into tumors.
The discovery is being heralded as “a tremendous advance in breast cancer research.”
Although breast cancer is a very curable disease – with more than 95 percent of women with early-stage disease surviving after five years – breast cancer that metastasizes to the brain is difficult to fight. In fact, only about 20 percent of patients survive a year after diagnosis.
"There remains a paucity of public awareness about cancer’s relentless endgame," said Rahul Jandial, M.D., Ph.D., a City of Hope neurosurgeon who headed the breast-cancer-and-brain-tumor study, published online ahead of print this week in the Proceedings of the National Academy of Sciences.
"Cancer kills by spreading. In fact, 90 percent of all cancer mortality is from metastasis," Jandial said. "The most dreaded location for cancer to spread is the brain. As we have become better at keeping cancer at bay with drugs such as Herceptin, women are fortunately living longer. In this hard-fought life extension, brain metastases are being unmasked as the next battleground for extending the lives of women with breast cancer."
He added: “I have personally seen my neurosurgery clinic undergo a sharp rise in women with brain metastases years – and even decades – after their initial diagnosis.”
Jandial and other City of Hope scientists wanted to explore how breast cancer cells cross the blood-brain barrier – a separation of the blood circulating in the body from fluid in the brain – without being destroyed by the immune system.
“If, by chance, a malignant breast cancer cell swimming in the bloodstream crossed into the brain, how would it survive in a completely new, foreign habitat?” said Jandial in a recent interview with New Scientist.
Jandial and his team’s hypothesis: Given that the brain is rich in many brain-specific types of chemicals and proteins, perhaps breast cancer cells that could exploit these resources by assuming similar properties would be the most likely to flourish. These cancer cells could deceive the immune system by blending in with the neurons, neurotransmitters, other types of proteins, cells and chemicals.
Taking samples from brain tumors resulting from breast cancer, Jandial and his team found that the breast cancer cells were exploiting the brain’s most abundant chemical as a fuel source. This chemical, GABA, is a neurotransmitter used for communication between neurons.
When compared to cells from nonmetastatic breast cancer, the metastasized cells expressed a receptor for GABA, as well as for a protein that draws the transmitter into cells. This allowed the cancer cells to essentially masquerade as neurons.”Breast cancer cells can be cellular chameleons (or masquerade as neurons) and spread to the brain,” Jandial said.
Jandial says that further study is required to better understand the mechanisms that allow the cancer cells to achieve this disguise. He hopes that ultimately, unmasking these disguised invaders will result in new therapies.
Researchers Find Promising Therapeutic Target for Hard-To-Treat Brain Tumor
Specific protein found in nearly all high-grade meningiomas
Johns Hopkins researchers say they have found a specific protein in nearly 100 percent of high-grade meningiomas — the most common form of brain tumor — suggesting a new target for therapies for a cancer that does not respond to current chemotherapy.
Importantly, the investigators say, the protein — NY-ESO-1 — is already at the center of a clinical trial underway at the National Cancer Institute. That trial is designed to activate the immune systems of patients with other types of tumors that express the protein, training the body to attack the cancer and eradicate it.
“Typically there is a lag time before a laboratory finding like this leads to a clear path forward to help patients. But in this case, since there is already a clinical trial underway, we have a chance of helping people sooner rather than later,” says Gregory J. Riggins, M.D., Ph.D., a professor of neurosurgery at the Johns Hopkins University School of Medicine and the senior author of the study published online in the journal Cancer Immunology Research.
In the NCI trial, NY-ESO-1 is found in a much smaller percentage of tumors than Riggins and his team found in high-grade meningioma, suggesting that for the brain cancer, the target would be potentially more significant.
Most low-grade meningiomas located in easy-to-reach locations can be treated successfully with surgery and radiation. But more atypical, higher-grade tumors are much more difficult to eradicate and are deadlier.
Riggins and his colleagues, including Gilson S. Baia, Ph.D., and Otavia L. Caballero, M.D., Ph.D., set out to find cancer antigens in meningioma. Cancer antigens are proteins expressed in tumors but not in healthy cells, making them good targets for chemical or immune system attack. They looked specifically at 37 cancer/testis (CT) genes, which are not found in normal cells in the body except in germ cells and cells cordoned off in the testicles or, in some cases, ovaries.
CT genes are activated, however, in various cancers. While they are seen as “foreign” by the body’s immune system, they are often locked behind the sophisticated defense system that cancers use to evade attack by immune cells. Finding a way to get the immune system to see these protein antigens, however, could allow for the body to recognize the invasion and go after the cancer cells. Various approaches are being used to do that, including vaccines and a system involving removing T-cells from the body and reprogramming them before returning them and setting them loose on the cancer cells.
The Johns Hopkins researchers took tissue from 18 different meningioma samples, removed the genetic material and protein and checked at what levels the 37 different genes were turned on. The gene that is the blueprint for the NY-ESO-1 protein was turned on more frequently than any other, in five of the 18 patient samples.
Then they analyzed NY-ESO-1 expression in a larger group of 110 meningioma tissue samples. They found NY-ESO-1 in 108 of them. The more expression in the sample, they also determined, the higher the tumor grade. The higher levels of NY-ESO-1 expressed also correlated with significantly lower disease-free and overall survival rates in the patients they came from.
The NCI trial originally began in melanoma patients. NY-ESO-1 is expressed in roughly one-third of melanomas as well as approximately one-third of breast, prostate, lung, ovarian, thyroid and bladder cancers, as well as sarcomas. Riggins and his team did not find the protein in glioblastoma, the deadliest form of brain cancer.
He calls the fact that the NCI trial could now include meningioma patients a “stroke of luck.”
“If that therapy did not exist, there would be a lot of work that would have to be done to convince people to pursue this,” Riggins says. “Our goal is to get something that works to the patients. This puts us well on our way.”
(Source: hopkinsmedicine.org)
New Therapy Improves Life Span in Melanoma Patients with Brain Metastases
In a retrospective study, Saint Louis University researchers have found that patients with melanoma brain metastases can be treated with large doses of interleukin-2 (HD IL-2), a therapy that triggers the body’s own immune system to destroy the cancer cells.
The study that was recently published in Chemotherapy Research and Practice, reviews cases of eight patients who underwent this therapy at Saint Louis University.
John Richart, M.D., associate professor of internal medicine at SLU and principal investigator of the study, first treated a patient with the disease using the HD IL-2 treatment in 1999.
"Traditionally, melanoma patients with brain metastases have not been considered for HD IL-2 because treatment was thought to be futile," Richart said. "Our study shows that having this condition does not exclude a patient from getting this treatment and can in fact improve the length of their life."
Melanoma is the most dangerous form of skin cancer that begins in the melanin-producing cells called melanocytes. In some melanoma patients, the cancer spreads to the brain, causing multiple tumors that are difficult to treat. According to the CDC, melanoma is the third most common cancer causing brain metastases in the U.S. Richart said the median overall survival of patients with melanoma brain metastases is approximately four months whereas in the study, the median overall survival for patients was 8.7 months.
During the treatment, patients are given an IV medication - a chemical the body naturally makes that stimulates the immune system to recognize and destroy melanoma cells - for a period of six days while they are admitted to the hospital and are closely monitored by doctors and nurses. A patient requires four such six-day admission cycles in order to complete the course of the treatment.
To be eligible for HD IL-2 treatment, melanoma patients with brain metastases have to be in healthy shape with good brain function - that is they cannot have brain lesions that are growing rapidly or show any symptoms of brain lesions. In the past, melanoma patients with brain metastases have been considered ineligible for this treatment because doctors thought that the treatment would cause life-threatening cerebral edema, a complication that causes excess accumulation of fluids in the brain, and neurotoxicity, or irreversible damage to the brain or the nervous system.
"In this review, we found that there were no episodes of treatment-related mortality. Our findings demonstrate that HD IL-2 can be considered as an option for patients with melanoma brain metastases," said Melinda Chu, M.D., a first year dermatology resident at SLU and first author of the study.
SLU is the only medical center in the region that provides this treatment.
"We need a highly skilled nursing staff for the HD-IL-2 program to be successful," Richart said. "Our nursing team at SLU is with each patient every step of the way, 24 hours a day. They help patients get through and continue the treatment."
Brain Cancer: Hunger for Amino Acids Makes It More Aggressive
An enzyme that facilitates the breakdown of specific amino acids makes brain cancers particularly aggressive. Scientists from the German Cancer Research Center (DKFZ) discovered this in an attempt to find new targets for therapies against this dangerous disease. They have reported their findings in the journal “Nature Medicine”.
To fuel phases of fast and aggressive growth, tumors need higher-than-normal amounts of energy and the molecular building blocks needed to build new cellular components. Cancer cells therefore consume a lot of sugar (glucose A number of tumors are also able to catabolize the amino acid glutamine, an important building block of proteins. A key enzyme in amino acid decomposition is isocitrate dehydrogenase (IDH). Several years ago, scientists discovered mutations in the gene coding for IDH in numerous types of brain cancer. Very malignant brain tumors called primary glioblastomas carry an intact IDH gene, whereas those that grow more slowly usually have a defective form.
“The study of the IDH gene currently is one of the most important diagnostic criteria for differentiating glioblastomas from other brain cancers that grow more slowly,” says Dr. Bernhard Radlwimmer from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). “We wanted to find out what spurs the aggressive growth of glioblastomas.” In collaboration with scientists from other institutes including Heidelberg University Hospital, Dr. Martje Tönjes and Dr. Sebastian Barbus from Radlwimmer’s team compared gene activity profiles from several hundred brain tumors. They aimed to find out whether either altered or intact IDH show further, specific genetic characteristics that might help explain the aggressiveness of the disease.
The researchers found a significant difference between the two groups in the highly increased activity of the gene for the BCAT1 enzyme, which in normal brain tissue is responsible for breaking down so-called branched-chain amino acids. However, Radlwimmer’s team discovered, only those tumor cells whose IDH gene is not mutated produce BCAT1. “This is not surprising, because as IDH breaks down amino acids, it produces ketoglutarate – a molecule which BCAT1 needs. This explains why BCAT1 is produced only in tumor cells carrying intact IDH. The two enzymes seem to form a kind of functional unit in amino acid catabolism,” says Bernhard Radlwimmer.
Glioblastomas are particularly dreaded because they aggressively invade the healthy brain tissue that surrounds them. When the researchers used a pharmacological substance to block BCAT1’s effects, the tumor cells lost their invasive capacity. In addition, the cells released less of the glutamate neurotransmitter. High glutamate release is responsible for severe neurological symptoms such as epileptic seizures, which are frequently associated with the disease. When transferred to mice, glioblastoma cells in which the BCAT1 gene had been blocked no longer grew into tumors.
“Altogether, we can see that overexpression of BCAT1 contributes to the aggressiveness of glioblastoma cells,” Radlwimmer says. The study suggests that the two enzymes, BCAT1 and IDH, cooperate in the decomposition of branched-chain amino acids. These protein building blocks appear to act as a “food source” that increases the cancer cells’ aggressiveness. Branched-chain amino acids also play a significant role in metabolic diseases such as diabetes. This is the first time that scientists have been able to show the role of these amino acids in the growth of malignant tumors.
“The good news,” sums up Radlwimmer, “is that we have found another target for therapies in BCAT1. In collaboration with Bayer Healthcare, we have already started searching for agents that might be specifically directed against this enzyme.” The researchers also plan to investigate whether BCAT1 expression may serve as an additional marker to diagnose the malignancy of brain cancer.
The Living Lab: Navigating into cells
How do viruses attach to cells? How do proteins interact and mediate infection? How do molecular machines organize themselves in healthy cells? How do they differ in diseased cells? These are the types of questions National Institutes of Health researchers ask in the recently established Living Lab for Structural Biology, questions they strive to answer through the most sophisticated of imaging techniques.
The Living Lab is an innovative partnership between NIH and FEI, an Oregon-based instrumentation company that manufactures advanced microscopes. FEI brings to the table invaluable assistance in developing and customizing electron microscopes for biological applications. Using that cutting edge technology, scientists in the Living Lab, unencumbered by any pressure to patent or otherwise protect discoveries for commercial purposes, can proceed purely driven by scientific and biomedical puzzles. Success of the Living Lab, which is on the NIH campus in Bethesda, Md., will rest on that collaboration between the government and the private sector—and the idea that answering scientific questions and technical advancement go hand in hand.
“We want to navigate our way into cells and into viruses,” said Sriram Subramaniam, Ph. D., director of the NIH component of the Living Lab. “We would like to be able to describe the function of complex things, such as whole cells or infectious viruses, in terms of their molecular make-up, and try to figure out how they work.”
The Living Lab’s advanced imaging technology allows researchers to tackle previously unanswered questions in structural biology by creating three-dimensional shapes of various molecular machines. Visualizing tiny details is a step toward understanding the molecular origins of disease. “The prospects for studying structures of a broad spectrum of medically relevant complexes at minute resolutions has changed dramatically in recent years with advances in structural biology,” said Subramaniam. “Our goal with the Living Lab is to capture the synergy between all of these methods including the latest advances in cryo-electron microscopy to extend these advances to key scientific challenges in modern structural biology.”
Subramaniam, who earned his doctorate at Stanford University and did post-doctoral work at the Massachusetts Institute of Technology in chemistry and biology, directs the research activities of the Living Lab, in close consultation with other team members from FEI and from the National Institute of Diabetes and Digestive and Kidney Diseases.