Dr. Luis Parada, chairman of developmental biology and senior author of a study in the Aug. 14 issue of the journal Neuron

Researchers at UT Southwestern Medical Center have discovered in mice that the brain must create new nerve cells for either exercise or antidepressants to reduce depression-like behavior.

ScienceDaily, August 30, 2008 — In addition, the researchers found that antidepressants and exercise use the same biochemical pathway to exert their effects.

These results might help explain some unknown mechanisms of antidepressants and provide a new direction for developing drugs to treat depression, said Dr. Luis Parada, chairman of developmental biology and senior author of a study in the Aug. 14 issue of the journal Neuron.

In animals, it was already known that long-term treatment with antidepressants causes new nerve cells to be generated in a part of the brain called the dentate gyrus. Exercise, which can also relieve the symptoms of depression, stimulates the generation of new nerve cells in the same area.

“We would never claim that what we study in mice directly relates to how antidepressants work in humans, but there are interesting features in parallel,” Dr. Parada said. “The study unifies different observations that point to the brain’s dentate gyrus region and to creation of nerve cells as being important in depression.”

Antidepressants act very quickly to increase levels of natural compounds, called neurotransmitters, which nerve cells use to communicate. It takes several weeks to several months, however, for the patients who respond to such treatments to feel less depressed. Dr. Parada said this implies that some other long-term mechanism is also at work.

The current study was designed to test several phenomena that have long been observed in animal studies but have not been studied together to see if they are linked, Dr. Parada said.

The researchers focused on a molecule called TrkB, or Track-B, which is found on the surface of nerve cells and responds to several growth factors to cause new nerves to grow in the dentate gyrus.

They genetically engineered mice to lack TrkB specifically in the stem cells that give rise to new neurons, then gave them antidepressants for several weeks or allowed them to run on wheels. When the mice were tested for depressive behavior, the tests revealed that neither the antidepressants nor the exercise had helped them, and the animals also had not grown new nerve cells in the dentate gyrus.

“At least in mice, this result directly links antidepressants and voluntary exercise with TrkB-mediated creation of nerve cells,” Dr. Parada said.

The results also showed that antidepressants required TrkB to stimulate the growth of new nerve cells.

Matching the timeframe for medicated patients to feel less depressed, it takes several weeks for new nerve cells to grow, Dr. Parada said. This parallel effect, he said, may mean that antidepressants need to stimulate growth of new cells in the dentate gyrus in order to achieve their full effect.

“We can get biochemical, physiological, behavioral and anatomical results in animal models,” Dr. Parada said. “These all resonate with the human condition, so perhaps you have a physiological relevancy.

“There could be a way to stimulate growth of nerve cells to fight depression, for example.”

Other UT Southwestern researchers involved in the study were lead author Yun Li, graduate student in developmental biology; Bryan Luikart, former graduate student in developmental biology; Dr. Shari Birnbaum, assistant professor of psychiatry; Jian Chen, student research assistant in developmental biology; Dr. Chang-Hyuk Kwon, instructor of developmental biology; Dr. Steven Kernie, associate professor of pediatrics; and Dr. Rhonda Bassel-Duby, associate professor of molecular biology.

The work was supported by the National Institute of Neurological Disorders and Stroke.

ScienceDaily (Aug. 29, 2008) — Researchers at Barrow Neurological Institute at St. Joseph’s Hospital and Medical Center recently participated in a pilot study with the Montreal Neurological Institute that suggests a certain type of MRI scanning can detect when a patient is failing brain tumor treatment before symptoms appear. The results of the study pave the way for a proactive treatment approach.

The study followed patients with recurring malignant brain tumors who were receiving chemotherapy. Patients received scans through an imaging device called MR spectroscopy to identify metabolic changes.

The scanning technique suggested that the use of metabolic imaging identifies chemical changes earlier than structural imaging such as a conventional MRI and CT scans. This approach allowed researchers to determine if the tumors were responding to treatment early by assessing metabolic changes in a brain tumor, which are easy to detect and appear before structural changes or symptoms. The result may give patients more time to try another treatment.

“The study has shown for the first time that metabolic response to brain tumor treatment can be detected earlier and faster by metabolic imaging instead of through structural imaging or assessment of the neurological status of a patient,” says Mark C. Preul, M.D., Newsome Chair of Neurosurgery Research at St. Joseph’s.

The imaging can be done often, poses no radiation hazard and is non-invasive.

“Frequent use of this type of imaging may be a useful tool to follow a patient’s response to chemotherapy for malignant brain tumors,” says Dr. Preul. “It gives us the ability to identify treatment failure early and more time to alter a patient’s treatment plan before the disease progresses.”

As a result of the pilot study, Barrow researchers are planning to conduct a second study that will use imaging in the same way to monitor the effects of brain tumor treatment. They are also developing imaging modalities that will show how brain tumors change their shape and metabolism with treatment.

Adapted from materials provided by St. Joseph’s Hospital and Medical Center, via EurekAlert!, a service of AAAS.

Opening from less invasive brain surgery.

Dr. Edward Duckworth is part of a new generation of neurosurgeons who are making brain surgery a lot easier on patients.

At Loyola University Hospital, Duckworth is using less-invasive techniques to remove tumors, to repair life-threatening aneurysms and to dramatically reduce seizures in epilepsy patients.

Rather than removing large sections of the skull or face, Duckworth is reaching the brain through much smaller openings. And in certain cases, he goes through the nose to get to the brain.

“It’s not necessary to expose a large surface of the brain in order to access a small abnormality,” said Duckworth, an assistant professor, neurological surgery, at Loyola University Chicago Stritch School of Medicine.

Less-invasive brain surgery can result in decreased pain and shorter hospital stays. It also makes patients less apprehensive, Duckworth said.


ScienceDaily — Viruses genetically designed to kill cancer cells offer a promising strategy for treating incurable brain tumors such as glioblastoma, but the body’s natural defenses often eliminate the viruses before they can eliminate the tumor.

The findings of an animal study by researchers at the Ohio State University Comprehensive Cancer Center help explain why this happens and could improve this therapy for brain cancer patients.

The research, published in the June 10 issue of the journal Molecular Therapy, shows that as the viruses destroy the tumor cells, they cause the cells to make proteins that stimulate the growth of new blood vessels to the tumor. These vessels transport immune cells that eradicate the viruses and actually stimulate regrowth of the tumor.

“This study points to an important side effect of oncolytic viral therapy that may limit its efficacy,” says principal investigator Balveen Kaur, a researcher with Ohio State’s Comprehensive Cancer Center and the Dardinger Laboratory for Neuro-oncology and Neurosciences.

“Knowing this, we can now work on designing a combination therapy that will inhibit this effect and enhance the action of the viral therapy.”

The researchers also discovered that, in infected tumor cells, the viruses changed the activity levels of three genes linked to blood-vessel growth in gliomas.

One of these genes, CYR61, was nine times more active in virus-treated tumor cells than in uninfected tumors. The researchers also showed that the higher the dose of virus used, the greater the gene’s activity.

For this study, Kaur and her colleagues implanted human glioma cells into rodents with a working immune system, then injected the resulting tumors of some with a cancer-killing, or oncolytic, virus called hrR3. The treated animals lived 17 days compared with 14 days for the untreated controls. The virus-treated tumors had roughly five times more blood vessels in them than the untreated tumors.

Treated tumors also showed changes in gene activity for three of 11 genes thought to play a role in blood-vessel development in gliomas. Of these, CYR61 showing an 8.9-fold increase in activity 12 hours after treatment.

Last, the researchers verified the virus-caused increase in CYR61 gene activity using several different glioma cell lines and glioma cells from patients, and several strains of active, replicating oncolytic viruses.

“In all cases, we observed a rise in CYR61 gene activity, which indicates that this change in gene activity may represent a host response to the viral infection,” Kaur says. Non-replicating viruses had no affect on the gene’s activity.

Kaur and her colleagues are now studying why cells turn on this gene when infected with oncolytic viruses and whether the protein that results from this gene activation might serve as a biomarker reflecting patients’ response to oncolytic virus therapy.

“Measuring a patient’s response to viral infection is currently not feasible,” Kaur says, “so if this were to work, it would be a significant advance.”

Funding from the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, the American Association for Neurological Surgeons/Congress of Neurological Surgeons and the American Brain Tumor Association supported this research.

Adapted from materials provided by Ohio State University Medical Center, via EurekAlert!, a service of AAAS.

As a brain tumor grows, it can increase pressure inside the skull. Brain tissue surrounding the tumor may become inflamed and swell, further increasing pressure. The tumor can also distort delicate brain structure.

Sophisticated 3-D computer models help Mayo neurosurgeons plan the safest way to a brain tumor.

A patient may see several Mayo Clinic specialists from the brain tumor treatment team, who work together to provide the high-quality, integrated care for which Mayo Clinic is known. Generally, a neurologist who has expertise and additional training in neuro-oncology, will coordinate the care team. In addition, the neuro-oncologist will counsel the patient about neurologic issues.

Because new treatments develop continually, several options may be available for patients at different points in their treatment. The pros and cons of each option are discussed in detail during treatment planning. Mayo Clinic’s goal is to improve the duration and quality of survival. Every effort is made to tailor the treatment program to the needs of the patient and family.

When appropriate, the patient’s case history may be presented and discussed with a multidisciplinary tumor team, comprised of specialists in neurosurgery, medical oncology, neurology, radiation oncology, neuroradiology and neuropathology. This collaborative team helps identify the best treatment plan.

Most brain tumor care, aside from surgery, is delivered on an outpatient basis.

During chemotherapy and radiation therapy, blood counts and blood chemistry are closely monitored. During phases of active therapy (which can last up to a year or more) MRI scans of the brain are obtained at regular intervals to monitor tumor growth or shrinkage. These scans are also conducted for several years after active therapy has been completed to watch for signs of tumor recurrence and allow for immediate intervention, if necessary.

Quality of Life

Quality of life is as important as quantity of life in Mayo’s treatment plans. As cancer treatments become more successful, enabling patients to live longer, patients face greater risks of long-term adverse effects of treatment. The most significant adverse effects are cognitive problems. Mayo specialists, including world-renowned neuropsychologists and experts in brain rehabilitation, help patients with these issues. Almost all clinical trials at Mayo and the North Central Cancer Treatment Group incorporate quality of life measures.

Whenever possible, the brain tumor treatment team tries to integrate care from the patient’s local physician and oncologists to offer the most comprehensive management. Mayo specialists work with local physicians to administer some therapy closer to home for patients who live a significant distance from Mayo Clinic.

Treatment Options


Surgery is the initial therapy for nearly all patients with brain tumors and can cure most benign tumors, including meningiomas. The goal of surgery is to remove as much of the tumor as possible while minimizing damage to healthy tissue.

Some tumors can be removed completely; others can be removed only partially or not at all. Partial removal helps relieve symptoms by reducing pressure on the brain and reducing the size of the tumor to be treated by radiation or chemotherapy.

After the tumor has been removed, Mayo Clinic pathologists immediately evaluate the tissue and report results directly to the surgeon in the operating room. Direct, face-to-face contact with the pathologist during the surgery allows the surgeon to verify that the tumor has been fully removed and may reduce the need for an additional operation.

If a tumor cannot be surgically removed, the physician may do only a biopsy. A small piece of the tumor is removed so a pathologist can examine it under a microscope to determine its cell makeup. The finding helps determine the proper treatment.

Patients diagnosed with brain tumors often can be scheduled for surgery the next day, if desired. Surgeons provide patients with information to help them decide which treatment is best for them.

Surgical removal demands great skill. Mayo’s neurosurgeons operate on hundreds of patients each year, using the latest technological advances. Mayo surgeons were pioneers in developing computer-assisted neurosurgery, which allows surgeons to precisely map the brain and more accurately and aggressively treat brain tumors.

Another technology available at Mayo is intraoperative MRI, which provides the neurosurgeon with real-time data on tumor volume and location.

Mayo Clinic neurosurgeons also use awake brain surgery on tumors that infiltrate brain regions which control functions like speech and movement. The surgery is performed with the patient awake during segments of the operation. The patient’s responses to questions allow the surgeon and attending team to more precisely identify critical brain regions and minimize injury during tumor removal.

Lasers are sometimes used to remove tumors. In some cases, tumors can be removed using minimally invasive techniques. Innovative techniques such as gene therapy also are available under research protocols.

Radiation Therapy

Radiotherapy is an essential component of treatment for many patients with brain tumors. It can cure some patients and prolongs survival for most. Radiation is often the primary treatment for patients with metastatic brain tumors.

External-Beam Radiation

This traditional form of radiation therapy delivers radiation from outside the body. The radiation usually involves treatments five days a week; the length of time depends on the type of tumor. External beam radiation is less precise, but allows a wider area of tissue around the tumor to be treated.

Fractionated Stereotactic Radiotherapy (FSR)

This technique minimizes damage to normal tissue by carefully targeting radiation. The treatment involves many smaller treatments rather than one big “shot” of radiation. Normal brain tissues and cranial nerves can tolerate many smaller treatments but cannot tolerate single large treatments. FSR also offers the biological benefit of fractionation, which is to exploit the different sensitivities of normal versus cancer tissue. These advantages are helpful when treating lesions near structures such as the optic nerves, which cannot tolerate high levels of radiation.

For this procedure, the patient is fitted with a plastic mask that aids in targeting the radiation and locating the tumor during treatment. The patient lies on a table and X-rays are taken to determine correct positioning. The treatment is given in several smaller units called arcs. The number of treatments depends on the size and location of the tumor.

Stereotactic Radiosurgery

Gamma Knife Machine™

Stereotactic radiosurgery is effective for well-circumscribed lesions such as meningioma or limited brain metastases. Radiosurgery precisely targets the tumor with high doses of radiation, while sparing nearby normal tissue because there is a rapid fall-off of radiation at the edges of the area being treated.


Although chemotherapy provides only modest benefit for many patients with brain tumors, it plays an increasingly important role in pain relief. Chemotherapy benefits only a small number of patients with glioma over the long term.

Other Drugs

Corticosteroids are indispensable for controlling increased intracranial pressure and reducing tumor sizes. Unfortunately, the long-term use of these agents can result in substantial toxic effects. Anti-convulsant drugs are sometimes administered after surgery in patients who have had seizures.

Deep vein thrombosis or pulmonary emboli can occur in 20 percent to 30 percent of patients with primary brain tumors. Conventional therapy with heparin and warfarin is usually effective and well tolerated.

Clinical Trials

Mayo Clinic participates in numerous clinical trials for brain and nervous system tumors, including trials originating at Mayo Clinic and those sponsored by the National Cancer Institute through the North Central Cancer Treatment Group (NCCTG).

Brain Rehabilitation

Brain injury can lead to problems with thoughts, feelings and behaviors. Many people with brain injury find that returning to independent living, work or school presents challenges that they cannot cope with alone. Mayo Clinic rehabilitation specialists help people with brain injury live as independently as possible within their family and community.

Illustration of brain tumor scan. (Credit: Image courtesy of University of California – San Diego)

ScienceDaily — Doctors diagnose and prescribe treatment for brain tumors by studying, under a microscope, tumor tissue and cell samples obtained through invasive biopsy or surgery. Now, researchers at UCSD School of Medicine have shown that Magnetic Resonance Imaging (MRI) technology has the potential to non-invasively characterize tumors and determine which of them may be responsive to specific forms of treatment, based on their specific molecular properties.

“This approach reveals that, using existing imaging techniques, we can identify the molecular properties of tumors,” said Michael Kuo, M.D., assistant professor of interventional radiology at UCSD School of Medicine. Kuo and colleagues analyzed more than 2,000 genes that had previously been shown to have altered expression in Glioblastoma multiforme (GBM) tumors. They then mapped the correlations between gene expression and MRI features.

The researchers also identified characteristic imaging features associated with overall survival of patients with GBM, the most common and lethal type of primary brain tumor.

The researchers discovered five distinct MRI features that were significantly linked with particular gene expression patterns. For example, one specific characteristic seen in some images is associated with proliferation of the tumor, and another with growth and formation of new blood vessels within the tumor–both of which are susceptible to treatment with specific drugs.

These physiological changes seen in the images are caused by genetic programs, or patterns of gene activation within the tumor cells. Some of these programs are tightly associated with drug targets, so when they are detected, they could indicate which patients would respond to a particular anti-cancer therapy, according to the researchers.

“For the first time, we have shown that the activity of specific molecular programs in these tumors can be determined based on MRI scans alone,” said Kuo. “We were also able to link the MRI with a group of genes that appear to be involved in tumor cell invasion–a phenotype associated with a reduced rate of patient survival.”

Laboratory work that relies on tissue samples is routinely used to diagnose and guide treatment for GBM. However, the biological activity shown may depend on the portion of the tumor from which the tissue sample is obtained. The researchers have shown that MRI could be used to identify differences in gene expression programs within the same tumor.

“Gene expression results in the production of proteins, which largely determine a tumor’s characteristics and behavior. This non-invasive MRI method could, for example, detect which part of a tumor expresses genes related to blood vessel formation and growth or tumor cell invasion,” said Kuo. “Understanding the genetic activity could prove to be a very strong predictor of survival in patients, and help explain why some patients have better outcomes than others.”

Kuo also led an earlier study, published in Nature Biotechnology in May 2007, correlating CT images of cancerous tissue with gene expression patterns in liver tumors. “In the new study, we were able to take a different imaging technology, MRI, and apply it to a totally different tumor type,” he said, noting that the studies open up promising new avenues for non-invasive diagnoses and classification of cancer.

The new study will be published online by the Proceedings of the National Academy of Science.

Contributors to the paper include first author Maximilian Diehn, UCSD Department of Radiology and Department of Radiation Oncology at Stanford University School of Medicine; Christine Nardini and David S. Wang, UCSD Department of Radiology; Susan McGovern and Kenneth Aldape, Department of Neuropathology, University of Texas M.D. Anderson Cancer Center, Houston; Mahesh Jayaraman, Department of Radiology, Brown University; Yu Liang, UCSF Brain Tumor Research Center, and Soonmee Cha, Department of Radiology, UCSF Medical Center.

The research was funded in part by the National Institutes of Health.

Adapted from materials provided by University of California – San Diego.

Enlarged Image for Glioma

Astrocytoma is the most common type of primary brain tumor.

Molecular Biologists Devise Strategy To Starve Brain Tumors

Brain tumor researchers have found that brain tumors arise from cancer stem cells living within tiny protective areas formed by blood vessels in the brain. Killing those cells is a promising strategy to eliminate tumors and prevents them from re-growing. The researchers have found that drugs that block new blood vessel formation can destroy the protected areas and stop cancer from developing.

Brain tumors are often deadly. Figuring out a way to wipe them out has been a mystery for scientists. But now, a new discovery may offer clues and hope for those with even the most hard-to-treat tumors.

In the last two months, Will Pappas has had three surgeries, chemo and radiation.

“You hold out hope that well, it’s just something little, and they can get it all. And then it wasn’t. Then you think, well, at least it’s not cancerous, and then it is,” Cayce Pappas, Will’s mom, says.

“It” is a brain tumor — the stubborn kind that’s hard to treat. In fact, doctors gave this seven-year-old only a 20 percent chance of surviving. Stories like Will’s have molecular biologists determined to find a way to destroy brain tumors.

“It’s what makes us all come to work in the morning,” Richard Gilbertson, a molecular biologist from St. Jude Children’s Hospital, says.

For years, researchers thought all cells inside a tumor were the same. But recently, they’ve discovered something different — a small group of cancer stem cells.

“They give rise to all the cells that make up the cancer,” Dr. Gilbertson explains.

Dr. Gilbertson’s research shows those cancer stem cells live close to blood vessels, which fuel them. In lab experiments, he’s proven drugs that target the blood vessels also destroy the cancer stem cells and can ultimately wipe out the tumor.

“So, if you can target those cells, you can have a devastating effect on the disease,” Dr. Gilbertson says. Drugs like Avastin and Tarceva are now being tested in humans to see if they can target the cancer stem cells. “It’s this tangible way of actually getting at the heart of the disease,” Dr. Gilbertson says.

Will is taking the drug Tarceva. His mom is hoping it will work a miracle.

“That would be amazing. We would jump at the opportunity to increase our odds. He’s still got a lot left to do,” Cayce says.

Dr. Gilbertson says other cancers, like those of the blood, breast and colon, also contain cancer stem cells and may be treated in a similar way in the future.

BACKGROUND: Researchers at St. Jude Children’s Hospital have found that brain tumors appear to arise from cancer stem cells that live inside tiny protective ‘niches’ formed by blood vessels in the brain. Breaking down these niches is a promising strategy for eliminating the tumors and preventing them from regrowing.

ABOUT CANCER STEM CELLS: Scientists previously believed that tumors are lumps of cancerous tissue that must be completely removed or destroyed to cure a patient. But over the last five years, cancer researchers have learned that not all cancer cells are created equal. In the same way that normal tissue in the body is generated from stem cells, so is cancer. CSCs are the ultimate source of the tumor, consistently supplying it with new cells. Researchers have identified the CSCs for acute myeloma leukemia, four types of brain cancer, and breast cancer. So it is possible that we need not kill all cancer cells to rid a patient of the disease. Targeting the CSCs specifically might be much more efficient.

To find a weakness for CSCs, neurobiologists at St. Jude compared them to noncancerous neural stem cells. These neural tissue generators are concentrated in regions rich in blood vessels. The vessels are lined with endothelial cells, which secrete chemical signals that help stem cells survive. CSCs, they discovered, required similar conditions to flourish: in over 70 human brain tumors, the CSCs were frequently located close to tiny vessels called capillaries. When the researchers injected mice with a mix of stem and endothelial cells from human brain tumors, those animals sprouted larger tumors than the mice that received stem cells alone.

NEW DRUG THERAPY: The new findings from St. Jude indicates that it is possible to kill the cancer by disrupting the shielded compartments in the small capillaries of the brain where CSCs reside. Anti-angiogenic drugs, such as Avastin, block the formation of new blood vessels. In tests with mice, those same drugs cause a significant drop in cancer stem cells and slow tumor growth. Human clinical trials are currently in progress at St. Jude to determine the effectiveness of Avastin and another anti-angiogenic drug in eliminating tumors and preventing their recurrence in children with brain cancers.