Study Of Hypoxia And New Gene Reveals Early-Stage Action Of P53 Tumor Suppressor Gene

Philadelphia, PA – Researchers have known for a decade that the p53 tumor suppressor gene is important for killing cells as they proliferate under low-oxygen conditions inside tumors. As tumors grow they outstrip their oxygen supply. If a cell has a normal p53 gene, the p53 protein will eliminate cancerous cells, keeping tumor growth at bay. Under conditions of stress to the cell – such as radiation or chemotherapy and hypoxia – p53 normally eliminates tumors.

Hypoxia, however, induces p53 to mutate: The less oxygen, the more mutations in the p53 gene, so cancer cells are not killed; instead, they proliferate. A team led by Wafik El-Deiry, MD, PhD, Associate Professor, Departments of Medicine, Genetics, and Pharmacology with the Abramson Cancer Center of the University of Pennsylvania, discovered a gene related to p53 called Bnip3L that can also cause cell death. The gene is turned on by p53 and a second transcription factor called hypoxia inducible factor, or HIF. The team silenced Bnip3L in cells with normal p53 and exposed cells to low oxygen conditions. In cell culture and in an animal model with implanted tumor cells, the researchers showed that tumors with silenced Bnip3L grew more aggressively in low oxygen conditions than cells and tumors with intact Bnip3L. El-Deiry and first author Peiwen Fei, MD, PhD, a post-doctoral fellow, report their findings in the December issue of Cancer Cell.

"From this, we predict in humans that another reason for tumor growth is the silencing of Bnip3L," says El-Deiry. "We think one of the ways that p53 suppresses tumors at their earliest stages is by turning on Bnip3L, and that's new. There is no information at present about how p53 works in the earliest stages of tumor growth, especially as the growth begins to outstrip the supply of nutrients and oxygen."

Understanding how cells die after they are starved for oxygen is important for fighting cancer as well as other diseases. "Down the road we would like to find strategies to turn Bnip3L back on to restore the ability to die under hypoxia now that we know how it happens in the first place," says El-Deiry

Nanotubes Help Advance Brain Tumor Research

 The potential of carbon nanotubes to diagnose and treat brain tumors is being explored through a partnership between NASA's Jet Propulsion Laboratory, Pasadena, Calif., and City of Hope, a leading cancer research and treatment center in Duarte, Calif.

Nanotechnology may help revolutionize medicine in the future with its promise to play a role in selective cancer therapy. City of Hope researchers hope to boost the brain's own immune response against tumors by delivering cancer-fighting agents via nanotubes. A nanotube is about 50,000 times narrower than a human hair, but it length can extend up to several centimeters.

If nanotube technology can be effectively applied to brain tumors, it might also be used to treat stroke, trauma, neurodegenerative disorders and other disease processes in the brain, said Dr. Behnam Badie, City of Hope's director of neurosurgery and of its brain tumor program.

"I'm very optimistic of how this nanotechnology will work out," he said. "We are hoping to begin testing in humans in about five years, and we have ideas about where to go next."

The Nano and Micro Systems Group at JPL, which has been researching nanotubes since about 2000, creates these tiny, cylindrical multi-walled carbon tubes for City of Hope.

City of Hope researchers, who began their quest in 2006, found good results: The nanotubes, which they used on mice, were non-toxic in brain cells, did not change cell reproduction and were capable of carrying DNA and siRNA, two types of molecules that encode genetic information.

JPL's Nano and Micro Systems Group grows the nanotubes on silicon strips a few square millimeters in area. The growth process forms them into hollow tubes as if by rolling sheets of graphite-like carbon.

Carbon nanotubes are extremely strong, flexible, heat-resistant, and have very sharp tips. Consequently, JPL uses nanotubes as field-emission cathodes -- vehicles that help produce electrons -- for various space applications such as x-ray and mass spectroscopy instruments, vacuum microelectronics and high-frequency communications.

"Nanotubes are important for miniaturizing spectroscopic instruments for space applications, developing extreme environment electronics, as well as for remote sensing," said Harish Manohara, the technical group supervisor for JPL's Nano and Micro Systems Group.

Nanotubes are a fairly new innovation, so they are not yet routinely used in current NASA missions, he added. However, they may be used in gas-analysis or mineralogical instruments for future missions to Mars, Venus and the Jupiter system.

JPL's collaboration with City of Hope began last year, after Manohara, Badie and Dr. Babak Kateb, City of Hope's former director of research and development in the brain tumor program, discussed using nanostructures to better diagnose and treat brain cancer. Badie said his team's nanomedical research continues, and the next goal will be to functionalize and attach inhibitory RNA to the nanotubes and deliver it to specific areas of the brain.

The JPL and City of Hope teams published the results of the study earlier this year in the journal NeuroImage.

Badie says that JPL's contribution to City of Hope's nanomedicine research has been invaluable.

"The fact that we can get pristine and really clean nanotubes from Manohara's department is unique," he said. "The fact that we are both collaborating for biological purposes is also really unique."

The collaboration between JPL and City of Hope is conducted under NASA's Innovative Partnership Program, designed to bring benefits of the space program to the public.

Crossing Blood-Brain Barrier: Scientists Develop Drug Delivery System For Brain Cancers, Other Diseases

Scientists have developed a new drug delivery system that is capable of crossing the blood-brain barrier to reach and kill cancer cells in the brain, according to research presented at the 20th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Geneva on 22 October.

Following successful preclinical studies, the technology is being evaluated in two phase I clinical trials in patients with malignant glioma and brain metastases.

The blood-brain barrier is formed by a network of closely sealed endothelial cells in the brain's capillaries, and it expresses a high level of proteins that pump foreign molecules away from the brain, while allowing others (such as glucose and insulin) that are necessary to the functioning of the brain cells to cross the barrier. This makes it very difficult for molecules, including anti-cancer drugs, to cross the blood-brain barrier and reach tumour cells in the brain.

Currently, less than five per cent of drugs (made up of very small molecules) are able to cross the barrier; one example is temozolomide, which is the only chemotherapy available for treating brain tumours such as glioblastoma multiforme and progressive anaplastic astrocytoma. These tumours have a poor prognosis and continue to grow, even after treatment with temozolomide. Therefore, new therapies for these hard-to-treat brain tumours are needed urgently.

In four related presentations to the symposium, scientists from Canada, the USA and France described how they are investigating a new drug delivery technology that provides a non-invasive and flexible way of transporting different drugs (for example, antibodies, proteins, peptides, siRNA, small molecules, etc.) across the blood-brain barrier and into the central nervous system.

The drug being evaluated in the four abstracts is called ANG1005. It is made up of one molecule of a peptide called Angiopep-2 joined together with three molecules of paclitaxel, a taxane chemotherapy drug.

Dr Reinhard Gabathuler, author of one of the abstracts and chief scientific officer at Angiochem Inc (Montreal, Canada) – the company that is developing the Angiopep technology and ANG1005 – explained: "Unlike invasive or pharmacological approaches to deliver drugs to the brain, the Angiopep technology utilises the physiological approach by making use of the receptors on the surface of the blood-brain barrier that are responsible for actively transporting necessary molecules across the barrier to the brain. The family of Angiopeps (including Angiopep-2) has been designed to interact with a specific receptor, Low Density Lipoprotein Receptor Related Protein-1 (LRP-1). This receptor has many functions, binds over 30 ligands [molecules] of various sizes, and is highly expressed at the blood-brain barrier."

In laboratory-based tests of ANG1005 on mice and rats, Dr Gabathuler, other scientists in the company and collaborators in the US and Canada found that the drug was transported rapidly across the blood-brain barrier and into the functional part of the brain, the parenchyma.

"In contrast to free paclitaxel, which is normally prevented from reaching the brain by the P-glycoprotein efflux pump, ANG1005 is efficiently transported across the blood-brain barrier, with approximately 100-fold higher transport rate compared to free paclitaxel and 10-fold higher transport rate than temozolomide," he said.

In addition, the drug resulted in a significant, 27% increase of survival of mice with glioblastoma tumours and a shrinking of glioblastoma tumours in rats.

A second study, led by Dr Francis Bichat, head of the scientific platform at Oncodesign (Dijon, France), evaluated the anti-cancer properties of the drug in cancer cell lines and mice, as well as investigating its toxicity and what happened to the drug in mice.

He found that ANG1005 had the same anti-cancer properties as did free paclitaxel (paclitaxel on its own) in cancer cell lines. Speaking before the conference, he said: "The anti-tumour activity of paclitaxel was maintained with ANG1005 compared with free paclitaxel. There was no loss of activity." He also found a significant inhibition of brain tumour growth in rats when they were treated with ANG1005, whereas tumours in rats that were treated with paclitaxel did not have their growth inhibited. "This is probably because free paclitaxel is not able to enter the brain," he said.

"The most interesting finding from this study is the potency of ANG1005 to bypass the blood-brain barrier and to allow paclitaxel into the brain where it shows anti-tumour activity," said Dr Bichat.

The success of these pre-clinical studies enabled Angiochem Inc to start two phase I clinical trials at cancer centres in the US: one in patients with advanced cancer and brain metastases, and the second in patients with recurrent malignant glioma.

These trials are still being conducted, but, as of 23 September 2008, 22 patients with advanced solid tumours (including breast cancer, melanoma, liver cancer and 15 patients with brain metastases) have been treated with ANG1005 in the first trial. The drug is given by intravenous infusion for one hour, every 21 days. At doses up to 500 mg/m2 the drug appears to be safe and well tolerated and no patient has discontinued due to adverse side-effects. The researchers are continuing to increase the dose.

Dr Jean-Paul Castaigne, president and chief executive officer of Angiochem Inc, who presented the clinical trials results, said: "To date, the safety and tolerability of ANG1005 has been excellent in patients with advanced solid tumours and brain metastases."

In the second trial in patients with recurrent malignant glioma, 12 patients had been treated by 23 September 2008 – eight with glioblastoma multiforme, one with anaplastic astrocytoma and three with anaplastic oligondendrocytoma.

Dr Castaigne said: "We have demonstrated that the drug is safe and tolerable up to and including doses of 75 mg/m2 and we are currently evaluating doses of 105 mg/m2. No patient has discontinued due to drug-related adverse side-effects. So far, all patients (with the exception of one) dosed up to 50 mg/m2 have had their disease progress following two cycles of treatment at six weeks. However, it should be noted that 50 mg/m2 of ANG1005 has an equivalent paclitaxel dose of only about 25 mg/m2, which is still quite low for appreciable cytotoxic effects."

He continued: "To date, treatment options for patients with recurrent malignant glioma are limited and prognosis is bleak because of the brain's highly evolved physiological structure. Results from both these trials show that Angiopep conjugates may provide a potentially safe and effective way to treat gliomas and other currently unmanageable diseases of the central nervous system. The Angiopep technology is well tolerated, since most of the side-effects observed to date with ANG1005 are caused by paclitaxel, the active drug component."

Both trials will be reporting their most important results by the end of 2008, and researchers are planning a continuation of the trial in patients with brain cancer in 2009.

Dr Castaigne said: "Angiochem's intention is to continue the early development of ANG1005 until proof-of-efficacy is obtained in either progressive malignant gliomas or brain metastases. We will seek to find a partner with significant oncology experience to carry forward the later development stages and marketing of ANG1005.

"Although other technologies have demonstrated abilities to cross the blood-brain barrier, we believe that the Angiopep technology is the furthest developed of the physiological approach and has significant advantages. ANG1005 is the company's first compound in clinical development using the Angiopep technology. We have been successful in conjugating other chemotherapeutics (e.g. doxorubicin and etoposide) to our technology; preclinical data have demonstrated success in delivering these compounds into the brain and retaining cytotoxic activities. Angiochem is also focusing considerable effort on the conjugation and delivery of other drug classes (including monoclonal antibodies, proteins, peptides, siRNA, etc.) to treat other CNS disorders."

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

Novel Glioblastoma Mouse Model Developed

Researchers at the Salk Institute for Biological Studies have developed a versatile mouse model of glioblastoma—the most common and deadly brain cancer in humans—that closely resembles the development and progression of human brain tumors that arise naturally.

"Mouse models of human cancer have taught us a great deal about the basic principles of cancer biology," says Inder Verma, Ph.D., a professor in the Laboratory of Genetics. "By definition, however, they are just that: approximations that simulate a disease but never fully capture the molecular complexity underlying disease in humans."

Trying to mimic randomly occurring mutations that lie at the heart of all tumors, the Salk researchers used modified viruses to shuttle cancer-causing oncogenes into a handful of cells in adult mice. Their strategy, described in the Jan. 4, 2009 online issue of the journal Nature Medicine, could not only prove a very useful method to faithfully reproduce different types of tumors but also to elucidate the nature of elusive cancer stem cells.

The most frequently used mouse cancer model relies on xenografts: Human tumor tissue or cancer cell lines are transplanted in immuno-compromised mice, which quickly develop tumors. "These tumors are very reproducible, but this approach ignores the fact that the immune system can make or break cancer," says first author Tomotoshi Marumoto, Ph.D., a former postdoctoral researcher in the Verma lab and now an assistant professor at the Kobe Medical Center Hospital in Kobe, Japan. Other animal models either express oncogenes in a tissue-specific manner or shut down the expression of tumor suppressor genes in the whole tissue. "But we know that tumors generally develop from a single cell or a small number of cells of a specific cell type, which is one of the major determinants of the characteristics of tumor cells," explains postdoctoral researcher and co-author Dinorah Friedmann-Morvinski.

To sidestep the shortcomings of currently used cancer models, the Salk team harnessed the power of lentiviral vectors to infect nondividing as well as dividing cells and ferry activated oncogenes into a small number of cells in adult, fully immunocompetent mice. After initial experiments confirmed that the approach was working, Marumoto injected lentiviruses carrying two well-known oncogenes, H-Ras and Akt, into three separate brain regions of mice lacking one copy of the gene encoding the tumor suppressor p53: the hippocampus, which is involved in learning and memory; the subventricular zone, which lines the brain's fluid-filled cavity; and the cortex, which governs abstract reasoning and symbolic thought in humans.

He specifically targeted astrocytes, star-shaped brain cells that are part of the brain's support system. They hold neurons in place, nourish them, digest cellular debris, and are suspected to be the origin of glioblastoma. Within a few months, massive tumors that displayed all the histological characteristics of glioblastoma multiforme preferentially developed in the hippocampus and the subventricular zone.

The ability of adult stem cells to divide and generate both new stem cells (called self-renewal) as well as specialized cell types (called differentiation) is the key to maintaining healthy tissues. The cancer-stem-cell hypothesis posits that cancers grow from stem cells in the same way healthy tissues do. Known as tumor-initiating cells with stem like properties these cells have many characteristics in common with normal stem cells in that they are self-replicating and capable of giving rise to populations of differentiated cells.

To test whether the induced glioblastomas contained bona fide cancer stem cells, Marumoto isolated cultured individual tumor cells in the lab. These cells behaved and looked just like neural stem cells. They formed tiny spheres—often called tumor spheres—and expressed proteins typically found in immature neural progenitor cells. When given the right chemical cues, these brain cancer stem cells matured into neurons and astrocytes.

"They displayed all the characteristics of cancer stem cells, and less than 100 and as few as 10 cells were enough to initiate a tumor when injected into immunodeficient mice," says Friedmann-Morvinski. Most xenograft models for brain tumors using tumor cell lines require at least 10,000 cells.

"These findings show that our cancer model will not only allow us to start understanding the biology of glioblastoma but will also allow us to answer many questions surrounding cancer stem cells," says Verma. Although the work described to date pertains to glioblastoma, Verma and his team are currently using this methodology to investigate lung, pancreatic, and pituitary cancers.

Authors who also contributed to the work include Ayumu Tashiro, Ph.D., at the Kavli Institute for Systems Neuroscience at the Medical Technical Research Center in Trondheim, Norway; Miriam Scadeng, Ph.D., at the UCSD Center for Functional MRI in La Jolla; Yasushi Soda, Ph.D.; and Fred H. Gage in the Laboratory of Genetics at the Salk Institute.

This work was supported by the National Institutes of Health and in part by the H. N. and Frances C. Berger Foundation.

Nearly A Century Later, New Findings Support Warburg Theory Of Cancer

German scientist Otto H. Warburg's theory on the origin of cancer earned him the Nobel Prize in 1931, but the biochemical basis for his theory remained elusive.

His theory that cancer starts from irreversible injury to cellular respiration eventually fell out of favor amid research pointing to genomic mutations as the cause of uncontrolled cell growth.

Seventy-eight years after Warburg received science's highest honor, researchers from Boston College and Washington University School of Medicine report new evidence in support of the original Warburg Theory of Cancer.

A descendant of German aristocrats, World War I cavalry officer and pioneering biochemist, Warburg first proposed in 1924 that the prime cause of cancer was injury to a cell caused by impairment to a cell's power plant – or energy metabolism – found in its mitochondria.

In contrast to healthy cells, which generate energy by the oxidative breakdown of a simple acid within the mitochondria, tumors and cancer cells generate energy through the non-oxidative breakdown of glucose, a process called glycolysis. Indeed, glycolysis is the biochemical hallmark of most, if not all, types of cancers. Because of this difference between healthy cells and cancer cells, Warburg argued, cancer should be interpreted as a type of mitochondrial disease.

In the years that followed, Warburg's theory inspired controversy and debate as researchers instead found that genetic mutations within cells caused malignant transformation and uncontrolled cell growth. Many researchers argued Warburg's findings really identified the effects, and not the causes, of cancer since no mitochondrial defects could be found that were consistently associated with malignant transformation in cancers.

Boston College biologists and colleagues at Washington University School of Medicine found new evidence to support Warburg's theory by examining mitochondrial lipids in a diverse group of mouse brain tumors, specifically a complex lipid known as cardiolipin (CL). They reported their findings in the December edition of the Journal of Lipid Research.

Abnormalities in cardiolipin can impair mitochondrial function and energy production. Boston College doctoral student Michael Kiebish and Professors Thomas N. Seyfried and Jeffrey Chuang compared the cardiolipin content in normal mouse brain mitochondria with CL content in several types of brain tumors taken from mice. Bioinformatic models were used to compare the lipid characteristics of the normal and the tumor mitochondria samples. Major abnormalities in cardiolipin content or composition were present in all types of tumors and closely associated with significant reductions in energy-generating activities.

The findings were consistent with the pivotal role of cardiolipin in maintaining the structural integrity of a cell's inner mitochondrial membrane, responsible for energy production. The results suggest that cardiolipin abnormalities "can underlie the irreversible respiratory injury in tumors and link mitochondrial lipid defects to the Warburg theory of cancer," according to the co-authors.

These findings can provide insight into new cancer therapies that could exploit the bioenergetic defects of tumor cells without harming normal body cells.

Seyfried, Chuang and Kiebish were joined by co-authors Xianlin Han and Hua Cheng from the Washington University School of Medicine, Department of Internal Medicine, in St. Louis.

Fruit Flies Soar As Lab Model, Drug Screen For The Deadliest Of Human Brain Cancers

Fruit flies and humans share most of their genes, including 70 percent of all known human disease genes. Taking advantage of this remarkable evolutionary conservation, researchers at the Salk Institute for Biological Studies transformed the fruit fly into a laboratory model for an innovative study of gliomas, the most common malignant brain tumors.

"Gliomas are a devastating disease but we still know very little about the underlying disease process," explains John B. Thomas, Ph.D., a professor in the Molecular Neurobiology Laboratory and senior author of the study, which is published in the current edition of thePublic Library of Science Genetics. "We can now use the power of Drosophila genetics to uncover genes that drive these tumors and identify novel therapeutic targets, which will speed up the development of effective drugs."

Better models for research into human gliomas are urgently needed. Last year alone, about 21,000 people in this country were diagnosed with brain and nervous system cancers, Senator Edward M. Kennedy the most famous among them. About 77 percent of malignant brain tumors are gliomas and their prognosis is usually bleak. While they rarely spread to elsewhere in the body, cancerous glial cells quickly infiltrate the brain and grow rapidly, which renders them largely incurable even with current therapies.

Gliomas originate in brain cells known as "glia" and are categorized into subtypes based on how aggressive they appear, with glioblastoma being the most common and most aggressive form of glioma. Their diversity is mirrored by the number of different signaling pathways involved in the generation of these tumors, yet aggressive gliomas all seem to have one thing in common: Most, if not all human glioblastomas carry mutations that activate the EGFR-Ras and PI-3K signaling pathways. Such mutations are also thought to play a key role in developing drug resistance.

"Fruit flies possess homologs of many relevant human genes including EGFR, Ras, and PI-3K," explains postdoctoral researcher and first author Renee Read, who spearheaded the project. "We developed the Drosophila model to figure out how these genes specifically regulate brain tumor pathogenesis and to discover new ways to attack these tumors."

When Read activated both signaling pathways specifically in glia in genetically engineered fruit flies, she found that, just as in the mammalian brain, activation of the EGFR-Ras and PI-3K pathways gave rise to rapidly dividing, invasive cells that created tumor-like growths in the fly brain, mimicking the human disease.

"Once I had verified that the fly tumors share key aspects with human gliomas, I could use the model to screen for new genes that are involved in disease process and compare them to the genes that were found as part of The Cancer Genome Atlas' glioblastoma initiative," explains Read.

Glioblastoma is one of the first cancers studied by The Cancer Genome Atlas research network, whose goal is to accelerate understanding of the molecular basis of cancer through the application of modern genome characterization technologies such as large-scale genome sequencing.

Like most cancers, gliomas arise from changes in a person's DNA that accumulate over a lifetime but sorting changes with wide-ranging impacts from innocent bystanders has been a challenge. "While these initiatives give us big lists of altered genes they don't tell us much about which ones are really important," says Read. "Addressing this question in mouse models or patient studies is extremely expensive and time-consuming. In flies, I can test hundreds of genes every week."

The Salk researchers are now using their fly model to search for genes and drugs that might block EGFR/PI-3K-associated brain tumors. The drug tests are being done in collaboration with co-authors professor Webster Cavenee, Ph.D., and associate professor Frank Furnari, Ph.D., both experts in human brain tumor biology at the Ludwig Institute for Cancer Research at the University of California, San Diego.

The researchers are hoping that through their combined efforts new discoveries from the fly model can be rapidly translated into mouse and human brain tumor studies and lead to development of new therapies for this deadly cancer.

The work was supported by the National Institutes for Neurological Disorders and Stroke and the American Brain Tumor Association.

Marker For Severity In Adult Brain Cancer Identified

Researchers at UT Southwestern Medical Center have identified a new biological indicator that may help identify which brain-cancer patients have the most aggressive forms of the disease.

The researchers found that an inflammation-related molecule called RIP1 is commonly found in high levels in glioblastoma, the most common primary malignant brain tumor in adults. The protein RIP1 is a component of the complex NF-kB signaling network — a family of proteins that play a key role in inflammation-induced cancer.

The study, available online and published in the April issue of Cancer Research, could provide a new target for therapeutic drugs for glioblastoma patients who have a high level of RIP1 in their tumors coupled with NF-kB activation.

“This is the first report of high RIP1 levels being associated with any type of cancer,” said Dr. Amyn Habib, assistant professor of neurology at UT Southwestern and the study’s senior author. “Our data suggests that increased expression of RIP1 could serve as a marker to identify patients who have a significantly worse prognosis and who will likely be resistant to chemotherapy.”

Glioblastoma multiforme (GBM), a cancer of the supportive tissue of the brain, is resistant to treatment. GBM can infiltrate the brain extensively and sometimes become large before turning symptomatic. The median survival of patients with GBM is about 15 months after diagnosis, even with radiation and chemotherapy treatments.

In the study, researchers examined tumor tissues from 92 patients to determine the distribution of RIP1 in each. They found that the most malignant form of the tumors, which also are the most common, had highest levels of RIP1.

One of the next steps is to determine whether these patients may respond better to drugs targeting the NF-kB network. There are many drugs currently available that target these proteins.

Another significant finding of the study is the protein RIP1 regulates the function of p53, a tumor suppressor gene that inhibits the growth of tumors.

“RIP1 activates NF-kB and then that increases the expression of a gene called mdm2, which inhibits the p53 gene,” Dr. Habib said. “Inhibition of p53 allows cells with damaged DNA to proliferate and potentially to become cancerous.”

Dr. Habib cautioned that the results are preliminary and more research is needed to investigate possible therapeutic strategies.

“We’ve found a correlation,” Dr. Habib said. “If RIP1 is increased, patients do worse; however, we don’t know whether this molecule has some causal role in pathogenesis.”

Other UT Southwestern researchers involved in the study were co-lead author Dr. Seongmi Park, postdoctoral fellow in radiation oncology; co-lead author Dr. Kimmo Hatanpaa, assistant professor of pathology; Dr. Yang Xie, assistant professor of clinical sciences; Dr. Bruce Mickey, professor of neurological surgery and of otolaryngology — head and neck surgery; Dr. Christopher Madden, assistant professor of neurological surgery; Dr. Jack Raisanen, associate professor of pathology; Dr. Guanghua Xiao, assistant professor of clinical sciences; Dr. Debabrata Saha, assistant professor of radiation oncology; Dr. David Boothman, professor of pharmacology and radiation oncology; Dr. Dawen Zhao, assistant professor of radiology; and Dr. Robert Bachoo, assistant professor of neurology. Drs. Boothman, Habib, Xie and Bachoo are also affiliated with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

The research was partly funded by a grant from the Department of Energy.

Scorpion Venom With Nanoparticles Slows Spread Of Brain Cancer

 By combining nanoparticles with a scorpion venom compound already being investigated for treating brain cancer, University of Washington researchers found they could cut the spread of cancerous cells by 98 percent, compared to 45 percent for the scorpion venom alone.

"People talk about the treatment being more effective with nanoparticles but they don't know how much, maybe 5 percent or 10 percent," said Miqin Zhang, professor of materials science and engineering. "This was quite a surprise to us." She is lead author of a study recently published in the journalSmall.

For more than a decade scientists have looked at using chlorotoxin, a small peptide isolated from scorpion venom, to target and treat cancer cells.

Chlorotoxin binds to a surface protein overexpressed by many types of tumors, including brain cancer. Previous research by Zhang's group combined chlorotoxin with nanometer-scale particles of iron oxide, which fluoresce at that size, for both magnetic resonance and optical imaging.

Chlorotoxin also disrupts the spread of invasive tumors -- specifically, it slows cell invasion, the ability of the cancerous cell to penetrate the protective matrix surrounding the cell and travel to a different area of the body to start a new cancer. The MMP-2 on the cell's surface, which is the binding site for chlorotoxin, is hyperactive in highly invasive tumors such as brain cancer. Researchers believe MMP-2 helps the cancerous cell break through the protective matrix to invade new regions of the body. But when chlorotoxin binds to MMP-2, both get drawn into the cancerous cell.

Other researchers are currently conducting human trials using chlorotoxin to slow cancer's spread.

Zhang's group investigated chlorotoxin action when it is attached to nanoparticles and found the resultant complex doubles the therapy's effect compared to chlorotoxin alone. Adding nanoparticles often improves a therapy, partly because the combination lasts longer in the body and so has a better chance of reaching the tumor. Combining also boosts the effect because therapeutic molecules clump around each nanoparticle. In the newly published study an average of 10 chlorotoxin molecules were attached to each nanoparticle. Each clump thus offers many therapeutic molecules that can simultaneously latch on to many MMP-2 proteins.

Experiments were performed using mouse brain-cancer cells that were grown in the lab. The imaging results confirm that adding nanoparticles means more of the MMP-2 ends up safely tucked away inside the cell, thus preventing MMP-2 from helping the cancer spread.

Further images showed that the cells containing nanoparticles plus chlorotoxin were unable to elongate, whereas cells containing only nanoparticles or only chlorotoxin could stretch out. This suggests that the nanoparticle-plus-chlorotoxin disabled the machinery on the cell's surface that allows cells to change shape, yet another step required for a tumor cell to slip through the body.

"We hypothesized the mechanism and we have all the data to prove our hypothesis," Zhang said. Further experiments will involve testing on mice.

So far most cancer research has combined nanoparticles either with chemotherapy that kills cancer cells, or therapy seeking to disrupt the genetic activity of a cancerous cell. This is the first time that nanoparticles have been combined with a therapy that physically stops cancer's spread.

Slowing the spread of cancer would be especially useful for treating highly invasive tumors such as brain cancer. MMP-2 also shows signs of being overactive in cancers of the breast, colon, skin, lung, prostate and ovaries, and researchers believe that the technique could slow the spread of these other tumors.

Co-authors are Omid Veiseh, Jonathan Gunn, Forrest Kievit, Conroy Sun and Chen Fang of the UW and Jerry Lee of the National Cancer Institute and Johns Hopkins University. The research was funded by the National Institutes of Health and fellowships from the National Cancer Institute and Ford Motor Company.

New Imaging Analysis Predicts Brain Tumor Survival

As early as one week after beginning treatment for brain tumors, a new imaging analysis method was able to predict which patients would live longer, researchers from the University of Michigan Comprehensive Cancer Center have found.

The method uses a standard magnetic resonance imaging, or MRI, protocol to monitor changes over time in tumor blood volume within individual voxels of the image, rather than a composite view of average change within the tumor. This parametric response map allowed researchers to see specific areas in which tumor blood volume increased or decreased, that may have canceled each other out when looking at the changes as an average.

"What we have potentially is a generalized analytical approach that we can use to quantify treatment intervention in patients," says study author Brian Ross, Ph.D., professor of radiology and biological chemistry at the U-M Medical School and co-director of the Molecular Imaging Program at the U-M Comprehensive Cancer Center.

The researchers looked at 44 people with high-grade glioma, a type of brain tumor, who were treated with chemotherapy and radiation. Each participant underwent MRIs before treatment, and one week and three weeks after starting treatment. The researchers then looked at the relative cerebral blood volume and the relative cerebral blood flow of the tumor to analyze voxel-wise changes among the serial scans.

Looking at standard comparisons using averages, the scans indicated no change one week and three weeks into treatment. But, using the parametric response map approach, the researchers were able to show changes in the tumor's blood volume and blood flow after one week that corresponded to the patient's overall survival.

"We're seeing treatment response earlier into the treatment, and responses that couldn't be detected at all looking at average changes. We could detect this after just one week, which is amazing for brain tumors," says study author Craig Galbán, Ph.D., assistant professor of radiology at the U-M Medical School.

High grade gliomas have a high mortality rate, with people surviving only an average of 12 months after diagnosis. Typically, patients receive six to seven weeks of treatment, followed by a traditional MRI scan six weeks after completing therapy to determine if the tumor shrank. If the cancer did not respond to the treatment, a new approach may be tried.

The researchers believe this approach might also be useful with other imaging techniques such as PET and CT scans.

Brain cancer statistics: 21,810 Americans will be diagnosed with brain cancer this year and 13,070 will die from the disease, according to the American Cancer Society.

Additional authors include Thomas Chenevert, Ph.D.; Charles Meyer, Ph.D.; Christina Tsien, M.D., Theodore Lawrence, M.D., Ph.D.; Daniel Hamstra, M.D., Ph.D.; Larry Junck, M.D.; Pia Sundgren, M.D., Ph.D.; Timothy D. Johnson, Ph.D.; David Ross; and Alnawaz Rehemtulla, Ph.D.

Funding was provided by the National Institutes of Health.

The University of Michigan has filed a patent application on this technology.

Most Common Brain Cancer May Originate In Neural Stem Cells

University of Michigan scientists have found that a deficiency in a key tumor suppressor gene in the brain leads to the most common type of adult brain cancer. The study, conducted in mice that mimic human cancer, points the way to more effective future treatments and a way to screen for the disease early.

Appearing June 2 in Cancer Cell, the U-M team's findings in mice show for the first time that:

• Glioblastoma, the type of cancer that afflicts U.S. Sen. Edward Kennedy and is diagnosed in about 10,000 Americans each year, may originate in neural stem cells located in a brain region known as the subventricular zone, or SVZ.
• In mice, neural stem cells that normally live in this niche give rise to more specialized nerve cells that migrate out of the niche. Cancer could begin with a single genetic mutation in the p53 gene, which makes stem cells migrate out of the niche like their specialized progenies.

Much research on cancer has focused on the p53 gene, known as the "guardian of the genome" because it initiates a wave of other gene actions that normally thwart cancer.

Implications

The finding of a specific zone of origin could lead to treatments that may improve the dire median survival rate of 12 months for this type of brain cancer, says Yuan Zhu, Ph.D., the study's senior author and assistant professor in the departments of internal medicine and cell and developmental biology at the U-M Medical School.

"We have to pay more attention to the stem cell niche" in both early detection and treatment, says Zhu. If glioblastoma originates in neural stem cells in the subventricular zone in humans as it does in mice, the study suggests that doctors need to direct treatments there, as well as to the tumor, to eliminate the source of the cancer and keep it from returning, Zhu says.

The findings in mice also may lead in time to effective early screening tests for glioblastoma. The U-M scientists show that the expression of mutant p53 protein is a marker for glioma cells in all stages of the disease.

"Now, if we believe that the SVZ is the location of the cells of origin, with enhanced resolution we could detect tumor cells there," says Zhu. If it's possible to detect the disease early, the chances of treatment success should improve.

The link between neural stem cells and this aggressive type of cancer is a warning sign for scientists to proceed carefully with new treatments for neurodegenerative diseases such as Parkinson's disease, where the hope is to use neural stem cells to help regenerate lost nerve function, says Zhu.

"Our results in mice show that these neural stem cells in the brain have high potential to accumulate genetic lesions and to become a cellular target for cancerous cells," he says. " To some degree, the cancerous cells in early stages are not much different from normal stem cells, but aberrantly combine the key features of neural stem cells (self-renewal) and specialized progenies (migration). We have to understand these stem cells more extensively before we can harness them to treat disease."

Context

Glioblastoma, also called glioblastoma multiforme, is notoriously hard to treat. It returns in most cases despite virtually all current therapies, which include surgery, radiation and chemotherapy. Survival rates have not improved for two decades, a fact that the new insights into p53 may help explain.

The results found in mice add specific new insights to an unfolding picture of how genes go awry to result in brain cancer. Scientists recently learned that certain genes and pathways of cell action are altered in glioblastoma. One of these key alterations involves mutations in genes that are players in the p53 pathway. But until now, scientists have not known what cell type initiates the cancer, or precisely how a deficiency in p53-mediated pathways works with other mutations to transform brain cells into cancerous ones.

In the last six years, studies have shown that stem cell-like cells are involved in a number of cancers, including glioblastoma. But the new study specifically reveals that glioblastoma begins in neural stem cells that have a p53 mutation. These cells then give rise to mutated, fast-multiplying cells down the line of cell differentiation – a class called transit-amplifying progenitor cells.

"We found that the cells with p53 mutations are highly plastic. If a treatment blocks one path of action, they may learn other ways to grow," Zhu says. That helps explain why glioblastoma multiforme returns in drug-resistant forms.

Research details

Zhu's team conducted a series of experiments using mice engineered to have a p53 mutation in the central nervous system. They found that a majority developed malignant brain tumors, and that a mutant form of p53 was present in the tumor cells, a phenomenon that is commonly found in human glioblastoma.

"Then we asked, does mutant p53 have any role in tumor initiation and progression? If so, we can use this as a marker for brain cancer in brain cells," says Yuan Wang, the study's first author and a U-M Ph.D. student in cell and developmental biology. The team found that mutant p53 was detectable in a minority of highly proliferative neural stem cells of p53-deficient mice two months after birth, and that the expansion of the mutant-p53-expressing cell population with features of transit-amplifying cells underlies the tumor initiation. The evidence supports the idea that mutant p53 can be a useful marker to trace the glioma cells at all stages.

What's next

Before any treatments based on these discoveries can benefit people, scientists will need to do more animal studies and verify the animal findings in human studies.

Zhu and his team plan to continue experiments in mice to see if p53 function can be restored in tumor cells. They are also examining whether inhibiting neural stem cells in the SVZ has promise as a potential therapy. Given the plasticity of these cancer-initiating cells, targeting a single signaling pathway may not be sufficient, says Zhu. This trait adds to the complexity of cancer therapy.

Besides Zhu and Wang, other authors are Jiong Yang, Huarui Zheng, Gerald J. Tomasek, Peng Zhang, U-M Department of Internal Medicine, Division of Molecular Medicine and Genetics and Department of Cell and Developmental Biology; Paul E. McKeever, U-M Department of Pathology; and Eva Y-H. P. Lee, University of California, Irvine.

How Cancers Spread To The Brain

Research has shown for the first time how cancers that spread to the brain establish themselves and begin to grow.

The Oxford University study, published in the journal PLoS One, has identified the mechanism that metastatic cancer cells use to anchor themselves to blood vessels in the brain. This could allow new drugs to be developed to stop cancers from spreading and growing in the brain.

Metastasis is the process where cancer breaks out from where a tumour has initially grown and spreads to other parts of the body. It is usually the reason why cancer is fatal.

Brain metastases are the most common malignant tumours of the central nervous system, outnumbering by ten times those that originate in the brain. Once such cancers have reached the brain the prognosis is not good: the median survival is 9 months with maximal treatment. Over 20% of all cancer patients will eventually develop metastatic cancer in the central nervous system.

‘Metastasis to the brain is essentially terminal, and very little is known about the process by which it occurs,’ says Dr W Shawn Carbonell, a post-doctoral research scientist at the MRC/CRUK Gray Institute for Radiation Oncology and Biology at the University of Oxford. ‘But by quickly remedying our lack of knowledge, we hope to be able to come up with new and better ways of treating such cancers.’ 

The Oxford University team, led by Professor Ruth Muschel at the Gray Institute for Radiation Oncology and Biology with funding from Cancer Research UK, the Medical Research Council and the US National Institutes of Health, set out to answer the question: how do tumour cells grow in the brain. They looked at a comprehensive range of cancer cell types from humans and mice – breast cancer cell lines, melanoma cells and a lymphoma cell line – and examined how the cells establish themselves in the brain in laboratory studies.

The researchers found that the metastatic cancer cells start to grow on the walls of blood vessels in the brain in over 95% of cases, and not on the nerve cells. The researchers suggest that by ‘co-opting’ the vascular networks in the brain, the cancer cells can get all the nutrients and oxygen they need to start growing without having to grow new blood vessels of their own first. In addition the cancer cells require the brain blood vessels to invade into the brain for further cancer growth.

The team also discovered that a particular protein called an integrin on the outside surface of the cancer cells is necessary for them to stick to the blood vessels. Removal of the integrin stopped the cancer cells from attaching and starting to grow. This discovery is promising, as it may be possible to develop drugs to target the integrin and stop brain metastasis.

'Our research describes a novel mechanism which explains how tumour cells metastasize to the brain. The dependency of early brain metastases on the host blood vessels might provide a target for new drug therapies,' says Professor Muschel.

Dr Helen George, Cancer Research UK's head of science information, says: ‘This is an important part of the puzzle. Our research shows that cancer cells which spread to the brain latch on to blood vessels, paving the way for new and much-needed treatments to tackle cancers that have spread to the brain, in the future.’

Nanoparticles Cross Blood-Brain Barrier To Enable 'Brain Tumor Painting'

Brain cancer is among the deadliest of cancers. It's also one of the hardest to treat. Imaging results are often imprecise because brain cancers are extremely invasive. Surgeons must saw through the skull and safely remove as much of the tumor as they can. Then doctors use radiation or chemotherapy to destroy cancerous cells in the surrounding tissue

Researchers at the University of Washington have been able to illuminate brain tumors by injecting fluorescent nanoparticles into the bloodstream that safely cross the blood-brain barrier -- an almost impenetrable barrier that protects the brain from infection. The nanoparticles remained in mouse tumors for up to five days and did not show any evidence of damaging the blood-brain barrier, according to results published this week in the journal Cancer Research.

Results showed the nanoparticles improved the contrast in both MRI and optical imaging, which is used during surgery.

"Brain cancers are very invasive, different from the other cancers. They will invade the surrounding tissue and there is no clear boundary between the tumor tissue and the normal brain tissue," said lead author Miqin Zhang, a UW professor of materials science and engineering.

Being unable to distinguish a boundary complicates the surgery. Severe cognitive problems are a common side effect.

"If we can inject these nanoparticles with infrared dye, they will increase the contrast between the tumor tissue and the normal tissue," Zhang said. "So during the surgery, the surgeons can see the boundary more precisely.

"We call it 'brain tumor illumination or brain tumor painting,'" she said. "The tumor will light up."

Nano-imaging could also help with early cancer detection, Zhang said. Current imaging techniques have a maximum resolution of 1 millimeter (1/25 of an inch). Nanoparticles could improve the resolution by a factor of 10 or more, allowing detection of smaller tumors and earlier treatment.

Until now, no nanoparticle used for imaging has been able to cross the blood-brain barrier and specifically bind to brain-tumor cells. With current techniques doctors inject dyes into the body and use drugs to temporarily open the blood-brain barrier, risking infection of the brain.

The UW team surmounted this challenge by building a nanoparticle that remains small in wet conditions. The particle was about 33 nanometers in diameter when wet, about a third the size of similar particles used in other parts of the body.

Crossing the blood-brain barrier depends on the size of the particle, its lipid, or fat, content, and the electric charge on the particle. Zhang and colleagues built a particle that can pass through the barrier and reach tumors. To specifically target tumor cells they used chlorotoxin, a small peptide isolated from scorpion venom that many groups, including Zhang's, are exploring for its tumor-targeting abilities. On the nanoparticle's surface Zhang placed a small fluorescent molecule for optical imaging, and binding sites that could be used for attaching other molecules.

Future research will evaluate this nanoparticle's potential for treating tumors, Zhang said. She and colleagues already showed that chlorotoxin combined with nanoparticles dramatically slows tumors' spread. They will see whether that ability could extend to brain cancer, the most common solid tumor to affect children.

Merely improving imaging, however, would improve patient outcomes.

"Precise imaging of brain tumors is phenomenally important. We know that patient survival for brain tumors is directly related to the amount of tumor that you can resect," said co-author Richard Ellenbogen, professor and chair of neurological surgery at the UW School of Medicine. "This is the next generation of cancer imaging," he said. "The last generation was CT, this generation was MRI, and this is the next generation of advances."

Other co-authors are Omid Veiseh, Conroy Sun, Chen Fang, Narayan Bhattarai, Jonathan Gunn of the UW's department of materials science and engineering; Forrest Kievit and Kim Du of UW bioengineering; Donghoon Lee of UW radiology; Barbara Pullar of the Fred Hutchinson Cancer Research Center; and Jim Olson of the Fred Hutchinson Cancer Research Center and Seattle Children's Hospital.

The research was funded by the National Institutes of Health, the Jordyn Dukelow Memorial Fund and the Seattle Children's Hospital Brain Tumor Research Endowment.

Nano-Bio Material Kills Cancer Cells, Leaves Healthy Cells In Unharmed

Scientists from the U.S. Department of Energy's (DOE) Argonne National Laboratory and the University of Chicago's Brain Tumor Center have developed a way to target brain cancer cells using inorganic titanium dioxide nanoparticles bonded to soft biological material.

Thousands of people die from malignant brain tumors every year, and the tumors are resistant to conventional therapies. This nano-bio technology may eventually provide an alternative form of therapy that targets only cancer cells and does not affect normal living tissue.

"It is a real example of how nano and biological interfacing can be used for biomedical application," said scientist Elena Rozhkova with Argonne's Center for Nanoscale Materials. "We chose brain cancer because of its difficulty in treatment and its unique receptors."

This new therapy relies on a two-pronged approach. Titanium dioxide is a versatile photoreactive nanomaterial that can be bonded with biomolecules. When linked to an antibody nanoparticles recognize and bind specifically to cancer cells. Focused visible light is shined onto the affected region, and the localized titanium dioxide reacts to the light by creating free oxygen radicals that interact with the mitochondria in the cancer cells. Mitochondria act as cellular energy plants, and when free radicals interfere with their biochemical pathways, mitochondria receive a signal to start cell death.

"The significance of this work lies in our ability to effectively target nanoparticles to specific cell surface receptors expressed on brain cancer cells," said Dr. Maciej S. Lesniak, Director of Neurosurgical Oncology at University of Chicago Brain Tumor Center. "In so doing, we have overcome a major limitation involving the application of nanoparticles in medicine, namely the potential of these agents to distribute throughout the body. We are now in a position to develop this exciting technology in preclinical models of brain tumors, with the hope of one day employing this new technology in patients."

X-ray fluorescence microscopy done at Argonne's Advanced Photon Source also showed that the tumors' invadopodia, actin-rich micron scale protrusions that allow the cancer to invade surrounding healthy cells, can be also attacked by the titanium dioxide.

So far, tests have been done only on cells in a laboratory setting, but animal testing is planned for the next phase. Results show an almost 100 percent cancer cell toxicity rate after six hours of illumination, and 80 percent after 48 hours.

Also, since the antibody only targets the cancer cells, surrounding healthy cells are not affected, unlike other cancer treatments such as chemotherapy and radiotherapy. Rozhkova said that a proof of concept is demonstrated, and other cancers can be treated as well using different targeting molecules, but research is in the early stages.

Funding for this research was through the Department of Energy's Office of Basic Energy Sciences, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Alliance for Cancer Gene Therapy, American Cancer Society and Brain Research Foundation.

Protein Link May Be Key to New Treatment for Aggressive Brain Tumor

Biomedical researchers at the University of Central Florida have found a protein that could hold the key to treating one of the most common and aggressive brain tumors in adults.

Glioblastoma multiforme (GBM), the type of malignant brain tumor that killed the late U.S. Sen. Edward Kennedy, is difficult to treat because it spreads cancerous cells to other parts of the brain very quickly. About 10,000 cases are diagnosed in the United States each year.

There is no cure, and treatments have limited success. They consist of surgically removing the tumor from the brain, followed by radiation therapy and chemotherapy. About half of the patients don't survive for more than a year after their diagnosis

That's why the role of the protein TRPC6 discovered at UCF is so promising.

"Collectively, our studies indicate that TRPC6 is a key mediator of tumor growth of GBM. It may be a promising therapeutic target in the treatment of human GBM," said Sic L. Chan, the UCF assistant professor of Neuroscience who led the team of scientists.

TRPC6 is a receptor channel protein found in most, if not all, cells in the body. It promotes cell growth during development of the central nervous system.

Chan and his team ran several experiments with cancerous brain tissue obtained from Florida Hospital in Orlando and Duke University Medical Center. They found that this protein is strongly expressed and functional in brain tumor cells. Further research found that they could stop the growth and spread of tumors by knocking down the expression of this protein.

It is the first time such findings have been made with this particular kind of brain tumor.

"This is very exciting, because our work will help patients in the future," said UCF research fellow Srinivasulu Chigurupati, who worked on the team. "Malignant gliomas remain one of the most devastating cancers despite recent advancements."

UCF's research findings are published in the Jan. 1, 2010, edition of the journal Cancer Research.

Others who contributed to the research include Raji Venkataraman, Daniel Barrera, Anusha Naganathan, Meenu Madan, Leena Paul, Jogi V. Pattisapu, George A. Kyriazis and Kiminobu Sugaya from UCF; Sergey Bushnev from Florida Hospital Cancer Institute; and Justin D. Lathia and Jeremy N. Rich from the Duke University Medical Center and the Department of Stem Cell Biology and Regenerative Medicine at the Cleveland Clinic.

'Microtentacles' On Tumor Cells Appear to Play Role in How Breast Cancer Spreads

 Researchers at the University of Maryland Marlene and Stewart Greenebaum Cancer Center have discovered that "microtentacles," or extensions of the plasma membrane of breast cancer cells, appear to play a key role in how cancers spread to distant locations in the body. Targeting these microtentacles might prove to be a new way to prevent or slow the growth of these secondary cancers, the scientists say.

They report in an article to be published online March 15, 2010, in the journalOncogene that a protein called "tau" promotes the formation of these microtentacles on breast tumor cells which break away from primary cancers and circulate in the bloodstream. While twisted remnants of tau protein have been seen in the brain tissue of patients with Alzheimer's disease, this is the first report that tau could play a role in tumor metastasis by changing the shape of cancer cells. These tau-induced microtentacles can help the cells reattach to the walls of small blood vessels to create new pockets of cancer.

"Our study demonstrates that tau promotes the creation of microtentacles in breast tumor cells. These microtentacles increase the ability of circulating breast tumor cells to reattach in the small capillaries of the lung, where they can survive until they can seed new cancers," says the senior author, Stuart S. Martin, Ph.D., a researcher at the University of Maryland Greenebaum Cancer Center and associate professor of physiology at the University of Maryland School of Medicine. Michael A. Matrone, Ph.D., is the study's lead author.

Healthy cells are programmed to die -- a process called apoptosis -- after they break off of epithelial layers that cover internal organs in the body. They also can be crushed if they are forced through small capillaries. However, cancer cells are able to survive for weeks, months and even years in the body. Once they are trapped in small blood vessels, the cells can squeeze through microscopic gaps in the vessels' lining and spread to organs such as the brain, lung and liver.

"We hope that through our research, we will be able to identify drugs that will target the growth of these microtentacles and help to stop the spread of the original cancer. Drugs that reduce tau expression may hold potential to inhibit tumor metastasis," Dr. Martin says.

He notes that metastatic cancers are the leading cause of death in people with cancer, but methods used to treat primary tumors have limited success in treating metastatic cancer. In breast cancer, metastases can develop years after primary tumors are first discovered.

Tau is present in a subset of chemotherapy-resistant breast cancers and is also associated with poor prognosis, but Dr. Martin adds, "While tau expression has been studied in breast cancers for contributing to chemotherapy resistance, the protein's role in tumor cells circulating in the bloodstream hasn't been investigated. And that's the focus of our research."

In this recent study, the University of Maryland researchers analyzed breast tumor cells from 102 patients and found that 52 percent had tau in their metastatic tumors and 26 percent (27 patients) showed a significant increase in tau as their cancer progressed. Twenty-two of these patients even had tau in metastatic tumors despite having none in their primary tumors.

Dr. Martin says more studies are needed to determine if tau is a clear predictor of metastasis. Given the complex nature of tumors, there most likely are other factors involved in causing cancers to spread, he says.

"Metastasis is a very major concern for people diagnosed with cancer, and the discovery of these microtentacles and the role that tau plays in their formation is a very exciting development that holds great promise for developing new drugs," says E. Albert Reece, M.D., Ph.D., M.B.A., acting president of the University of Maryland, Baltimore, and dean of the University of Maryland School of Medicine.

The University of Maryland, Baltimore, has filed patents on the microtentacle discoveries of Dr. Martin's lab group and is looking to partner with biopharmaceutical companies on new drug development. The researchers identified these cell extensions while they were studying the effects of two drugs that prevent cell division, or mitosis. Most chemotherapy drugs target cell division, aiming to slow or stop tumor growth.

Dr. Martin says his team found that a popular chemotherapy drug, taxol, actually causes cancer cell microtentacles to grow longer and allows tumor cells to reattach faster, which may have important treatment implications for breast cancer patients. Their studies are continuing.

"We think more research is needed into how chemotherapies that slow down cell division affect metastasis. The timing of giving these drugs can be particularly important. If you treat people with taxol before surgery to shrink the primary tumor, levels of circulating tumor cells go up 1,000 to 10,000 fold, potentially increasing metastasis," he adds.

The study being published in Oncogene was funded by grants from the National Cancer Institute, the USA Medical Research and Materiel Command, and the Flight Attendants Medical Research Institute.

Brain Tumors: Tissue Stem Cell Turning Into Tumor Stem Cell

The "cradle" of new neurons in the adult brain is well known. It is what is called the subventricular zone, a tissue structure lining the lateral ventricles. This is where neural or brain stem cells reside, which are responsible for generating new neurons if needed. For many years now, the subventricular zone has been suspected to be the origin of specific malignant brain tumors called gliomas, the most deadly type of which is glioblastoma.

Scientists from the divisions of Professor Dr. Günther Schütz and Professor Dr. Peter Lichter at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have recently shown in mouse brains that brain stem cells in the subventricular zone are characterized by a specific molecule: Protein Tlx, a transcription factor, which stimulates the activity of various genes. In the adult animal, Tlx is expressed exclusively in brain stem cells. When the scientists switched off Tlx, there were no more detectable stem cells in the brain and the formation of new neurons ceased. Functioning of the stem cells thus appears to depend on the presence of this protein.

In their recent study, the teams headed by Günther Schütz and Peter Lichter, jointly with Professor Dr. Guido Reifenberger of Düsseldorf University, have now tested the opposite case: What happens if the production of Tlx is increased? Using a molecular-biological trick, the investigators induced an overproduction of Tlx by the brain stem cells of mice. As a result, cell division activity in the subventricular zone increased, the cells left their habitual environment called stem cell niche, and started forming glioblastoma-like tissue lesions. In another experiment in which the researchers additionally switched off the p53 protein as an important cancer brake, invasively growing glioblastomas arose from the cancer precursors.

Moreover, the scientists discovered that stem cells with increased Tlx production stimulate the formation of new vessels. This enables the cells to migrate into distant brain regions and, thus, to generate the typical coral-like growth of glioblastoma.

"We recognize brain stem cells specifically by their Tlx production. If we boost it, the tissue stem cell turns into a cancer stem cell from which malignant glioblastomas arise. Therefore, we are now able, for the first time, to hold brain stem cells directly responsible for the formation of brain tumor stem cells," Günther Schütz explains.

The researchers expect to be able to develop new therapies to treat glioblastoma on the basis of these results from fundamental cell biology research. Tlx seems to play its fatal role not only in mouse brains. Studying tumor tissue from glioblastoma patients, Lichter and Reifenberger discovered that the Tlx gene is often present in multiple copies and, thus, more Tlx protein is produced. "Apparently, human brain tumor stem cells also depend on Tlx. Therefore, we can now try to develop therapies that are directed very specifically against Tlx producing cells," said Schütz describing the next steps. The mice whose brain stem cells overproduce Tlx are an ideal model system for such investigations.