Mushroom bodies (red), which are the center of learning and memory in the brain, from two adult fruit flies. Normally, new neurons do not appear in the adult mushroom body. UC Berkeley biologists altered neural stem cells to allow them to persist for at least a month in the adult brain, and to give rise to newborn nerve cells (green) that send out axons to other areas of the mushroom body, just like normal neurons. (Credit: Sarah Siegrist/UC Berkeley)
U. C. Berkeley, March 30, 2010 — University of California, Berkeley, biologists have found a signal that keeps stem cells alive in the adult brain, providing a focus for scientists looking for ways to re-grow or re-seed stem cells in the brain to allow injured areas to repair themselves.
The researchers discovered in fruit flies that keeping the insulin receptor revved up in the brain prevents the die-off of neural stem cells that occurs when most regions of the brain mature into their adult forms. Whether the same technique will work in humans is unknown, but the UC Berkeley team hopes to find out.
“This work doesn’t point the way to taking an adult who has already lost stem cells and bringing them back mysteriously, but it suggests what mechanisms might be operating to get rid of them in the first place,” said Iswar K. Hariharan, UC Berkeley professor of molecular and cell biology. “Plus, if you were able to introduce neural stem cells into an adult brain, this suggests what kinds of mechanisms you might need to have in place to keep them alive.”
Hariharan noted that other researchers have gotten neural stem cells to persist by blocking genes that cause them to die. Yet this alone does not produce healthy, normal-looking neural stem cells that can make mature neurons. The UC Berkeley team’s new finding shows that it also is necessary to provide an insulin-like signal. If stopping neural stem cell death is analogous to taking your foot off the brake, then providing an insulin-like signal is like stepping on the gas, he said. Both are essential.
Hariharan, post-doctoral researcher Sarah E. Siegrist and their colleagues published their findings in the online version of the journal Current Biology. Their report will appear in the journal’s April 13 print edition.
Most areas of the adult mammalian brain and fruit fly brain are devoid of neural stem cells, the only cells able to generate full-fledged neurons. Presumably, Hariharan said, the lack of neural stem cells is why the injured brain is unable to replace dead neurons.
In the new study, Siegrist showed that the stem cells present in the pupal stage of fruit flies are gone in the adult brain because they die off, rather than merely mature into neurons. The stem cells that persisted the longest were in the mushroom body, a region of the fly brain responsible for memory and learning that, in some ways, is like the hippocampus in humans.
In subsequent experiments, she attempted to prevent the death of neural stem cells in fruit flies by genetically blocking a process called programmed cell death (apoptosis). While this allowed the stem cells to survive longer, the cells were small and did not make many neurons. In fact, Siegrist said, they showed signs of impaired growth, suggestive of insulin withdrawal.
She then tried various genetic manipulations to mimic an insulin-type signal, this time using mutant fruit flies with their apoptosis genes also blocked. Amazingly, the neural stem cells persisted for at least a month and even generated many mature, apparently normal, nerve cells.
“These neural stem cells seem to behave properly, they express the proteins that you expect neural stem cells to express, they look like their normal counterparts, and most importantly, they spin off cells which become normal mature nerve cells that put out processes (axons) that, in some cases, seem to go where normal processes go,” Siegrist said. “We don’t know whether these cells function normally or whether they are electrically active. At least it is encouraging that we can get nerve cells made in a part of the (fruit fly) brain that normally cannot make nerve cells in the adult brain.”
“Sarah had to do two manipulations together to keep these neural stem cells alive, and neither worked alone,” Hariharan said. “One was to keep the insulin signal on, and one was to block programmed cell death. Each improved things a little bit, but when you did the two together, the neural stem cells survived for a month, at which time they were throwing off mature neurons or normal looking neurons that sent out processes.”
Siegrist plans to continue her search through mutant fruit flies to find other genes that improve survival in the mushroom body and allow stem cells in other areas of the fly brain to persist. She also plans collaborations to explore similar mechanisms in mammals, to see if analogous manipulations could keep neural stem cells alive in the mammalian brain.
“In fruit flies, pathways downstream of the insulin receptor are important in keeping these neural stem cells alive,” Siegrist said. “Mammals have the same genes downstream of their insulin receptors, so we may find the same response to insulin or insulin-like growth factors in mammals.”
Other coauthors are former UC Berkeley undergraduate Najm Haque, now a technician in Hariharan’s lab; Chun-Hong Chen of the National Health Research Institutes in Zhunan Town, Taiwan; and Bruce A. Hay of the California Institute of Technology (Caltech) in Pasadena, Calif.
The research is funded by the National Institutes of Health and the Damon Runyon Cancer Research Foundation.
Adapted from materials provided by University of California – Berkeley.
- 1. Sarah E. Siegrist, Najm S. Haque, Chun-Hong Chen, Bruce A. Hay, and Iswar K. Hariharan. Inactivation of Both foxo and reaper Promotes Long-Term Adult Neurogenesis in Drosophila. Current Biology, 2010; DOI: 10.1016/j.cub.2010.01.060
ASU School of Life Sciences’ undergraduate Jenny Koehl and microbiologist Shelley Haydel investigate the chemistry and killing power of clays with antibacterial activity. (Credit: Jacob Mayfield/ASU)
Arizona State University, March 30, 2010 — Alternative approaches to medicine are stock-in-trade in the ASU laboratory of microbiologist Shelley Haydel.
So when ASU senior Jenny Koehl joined Haydel’s investigative team seeking firsthand knowledge of how basic research is done, how drugs are tested and potential cures produced, she found it and much more.
With the guidance of Tanya Cunningham, a graduate student mentor, Koehl has helped advance understanding about the antibacterial activity of clay minerals and their ability to kill what the best antibiotics on the market can’t touch.
Haydel’s group, part of the School of Life Sciences, in the College of Liberals Arts and Sciences, and the Biodesign Institute at ASU, did the work in collaboration with Jack Summers, an inorganic chemist at Western Carolina University. They uncovered two factors that control the antibacterial activity. Their article “pH-dependent metal ion toxicity influences the antibacterial activity of two natural mineral mixtures” was published March 1 in the journal PLoS ONE, published by the Public Library of Science.
“This work sets a baseline from which to look for potential mechanisms of antibacterial action,” said Cunningham, lead author, who is now a research technician with the Fred Hutchinson Cancer Research Center in Seattle.
“We need helpful alternatives, natural approaches to antibacterial cures, because there is bacterial resistance to drugs,” Koehl said. “Knowing the mechanisms of action will help us develop our own topical treatments.”
Clay has had a role in human health as ancient as man. However, specific identification of the mechanisms underlying this antibacterial activity has been elusive, until now.
The Haydel-Summers collaborative has added clarity to these distinctly muddy waters by screening more than 50 mineral mixtures (and aqueous extractions from them, known as leachates) marketed as health and cosmetic products using pathogens Escherichia coli, Salmonella enterica serovar Typhimurium, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa. Only two mineral mixtures of significantly different compositions (and their leachates) were discovered to possess antibacterial traits.
Clay minerals often are recognized as the slimy slurry of minerals that slicks rivers’ banks. Understanding clay’s structure is integral to answering questions about the mechanisms behind its antibacterial activity. Negatively charged surfaces attract positively charged elements, such as iron, copper, silver and other metals. In turn, water is absorbed between layers of the crystal structure creating a cation sandwich with aqueous filling or interlayer.
Antibacterial activity in leachates, extracted from the mineral mixtures, confirm that the antibacterial activity is chemically-based, rather than a result of physical interactions with microbes.
Because of the tendency of clay to attract multivalent ions, particularly metals, the scientists next examined the leachates’ chemistry and antibacterial activity in the presence of chelators, which bind metals. The researchers also used thiourea, a hydroxyl radical scavenger, at various pH levels. Chelation of the minerals with ethylenediaminetetraacetic acid (EDTA) or desferrioxamine eliminated or reduced toxicity, respectively.
Further testing of the mineral leachates confirmed that there are higher concentrations of chemically-accessible metal ions in leachates from antibacterial samples than from non-bactericidal mineral samples.
In addition, acidic conditions were found to increase the availability of metal ions and their toxicity. Overall, these findings suggest a role of an acid soluble metal species, particularly iron or other sequestered metal cations, in mineral toxicity.
However, whatever advances the study puts forward also present researchers with further challenges. Acidity may complicate development of topical treatments, if neutral pH, least damaging to skin and tissue, also reduces the mineral’s antibacterial action.
Another complicating factor, accentuated by the PLoS ONE study, is that chemical environments under which any particular clay can emerge can greatly influence its toxicity, adsorptive qualities and, according to their findings, its antibacterial effects.
“Because natural mineral mixtures can be variable, both mineralogically and chemically, we must continue to define specific chemical properties that influence the antibacterial effectiveness,” Haydel said. “Our goal is to understand the details, so we can, in the future, perhaps generate mineral mixtures that mimic the chemical compositions and environment, so that the antibacterial activity can be controlled and ensured.”
This work is about eliminating the unknowns,” Koehl said. “We have more analysis to do, looking at the leachate composition, the action of the chelators and activity of the iron scavengers.”
Koehl, who is working with Haydel as part of the School of Life Sciences Undergraduate Research (SOLUR) program, said of her experience: “Science is like an obstacle course. I’ve learned that when you come across problems in the laboratory, you have to be creative to work them out. This process has helped me be more critical, to be a thinking scientist, because I’ve had to analyze my own experiments and figure them out. This isn’t just something that someone handed to me on paper in a classroom.”
Studies are moving forward in other laboratories to develop structured clays for slow-release topical medical treatments, but there may be chemical schemes that come from Haydel’s research, supported by the National Institutes of Health, that enhance their effectiveness.
“This study has given me an idea of how things move from idea to shelf,” Koehl said. “One day, when I am a pharmacist, maybe I’ll be selling this!”
Adapted from materials provided by Arizona State University.
- 1. Tanya M. Cunningham, Jennifer L. Koehl, Jack S. Summers, Shelley E. Haydel. pH-Dependent Metal Ion Toxicity Influences the Antibacterial Activity of Two Natural Mineral Mixtures. PLoS ONE, 2010; 5 (3): e9456 DOI: 10.1371/journal.pone.0009456
Adipogel forms a viscous droplet when isolated on a petri dish. After further processing, it can be used as a natural extracellular matrix to support new tissue growth. (Credit: N. Sharma)
ScienceDaily (Mar. 26, 2010) — It frequently happens in science that what you throw away turns out to be most valuable. It happened to Deepak Nagrath, but not for long.
The Rice assistant professor in chemical and biomolecular engineering was looking for ways to grow cells in a scaffold, and he discarded the sticky substance secreted by the cells.
“I thought it was contamination, so I threw the plates away,” said Nagrath, then a research associate at Harvard Medical School.
That substance, derived from adipose cells — aka body fat — turned out to be a natural extracellular matrix, the very thing he was looking for.
Nagrath, who joined Rice in 2009, and his co-authors have since built a biological scaffold that allows cells to grow and mature. He hopes the new material, when suffused with stem cells, will someday be injected into the human body, where it can repair tissues of many types without fear of rejection.
The research by Nagrath and his co-authors appeared last week in the Federation of American Societies for Experimental Biology (FASEB) Journal.
The basic idea is simple: Prompt fat cells to secrete what bioengineers call “basement membrane.” This membrane mimics the architecture tissues naturally use in cell growth, literally a framework to which cells attach while they form a network. When the cells have matured into the desired tissue, they secrete another substance that breaks down and destroys the scaffold.
Structures that support the growth of living cells into tissues are highly valuable to pharmaceutical companies for testing drugs in vitro. Companies commonly use Matrigel, a protein mixture secreted by mouse cancer cells, but for that reason it can’t be injected into patients.
“Fat is one thing that is in excess in the body. We can always lose it,” Nagrath said. The substance derived from the secretions, called Adipogel, has proven effective for growing hepatocytes, the primary liver cells often used for pharmaceutical testing.
“My approach is to force the cells to secrete a natural matrix,” he said. That matrix is a honey-like gel that retains the natural growth factors, cytokines (substances that carry signals between cells) and hormones in the original tissue.
Nagrath’s strategy for growing cells isn’t the only approach being pursued, even at Rice: Another method reported last week in Nature Nanotechnology uses magnetic levitation to grow three-dimensional cell cultures.
But Nagrath is convinced his strategy is ultimately the most practical for rebuilding tissue in vivo, and not only because it may cost significantly less than Matrigel. “The short-term goal is to use this as a feeder layer for human embryonic stem cells. It’s very hard to maintain them in the pluripotent state, where they keep dividing and are self-renewing,” he said.
Once that goal is achieved, Adipogel may be just the ticket for transplanting cells to repair organs. “You can use this matrix as an adipogenic scaffold for stem cells and transplant it into the body where an organ is damaged. Then, we hope, these cells and the Adipogel can take over and improve their functionality.”
Nagrath’s co-authors are Nripen S. Sharma, a research associate at Rutgers University, and Martin Yarmush, the Helen Andrus Benedict Professor of Surgery and Bioengineering at Harvard Medical School.
The National Institutes of Health and the Shriners Hospitals for Children supported their research.
Adapted from materials provided by Rice University.
- 1. Sharma et al. Adipocyte-derived basement membrane extract with biological activity: applications in hepatocyte functional augmentation in vitro. The FASEB Journal, 2010; DOI: 10.1096/fj.09-135095
University of Utah Health Sciences, March 30, 2010 — Treating virulent influenza, sepsis, and other potentially deadly infections long has focused on looking for ways to kill viruses and bacteria. But new research from the University of Utah and Utah State University shows that modulating the body’s own overeager inflammatory response to infection may help save more lives.
In a study published March 17 in Science Translational Medicine, researchers led by U of U cardiologist Dean Y. Li, M.D., Ph.D., professor of internal medicine and director of the Molecular Medicine Program, shows that protecting blood vessels from hyper-inflammatory response to infection reduced mortality rates in mouse models of avian flu and sepsis by as much as 50 percent. Specifically, the researchers identified a protein signaling pathway, Robo4, that when activated prevents inflammation from weakening blood vessels, which causes them to leak and can result in life-threatening organ damage.
The findings raise the possibility of new broad-range therapies that could be rapidly implemented by public health agencies to fight both viral and bacterial infections, such as pandemic influenza and sepsis, and even potentially deadly human-made biological agents that could cause widespread illness and death, according to Li. Such therapies would be given along with antibiotics, antivirals, and other drugs.
“By blocking the ill effects of inflammation on the host or patient by stabilizing blood vessels, we have identified an entirely different strategy to treat these infections,” Li said. “In essence, we’ve shown that rather than attacking the pathogen, we can target the host to help it to fight infections.”
While this study proves the concept of controlling the effects of inflammation to fight the effects of serious infection, developing therapies for people will take years.
Inflammation is a powerful weapon in the body’s immune system; without this inflammation, patients would not be able to fight infection. But it’s also a double-edged sword. When Biochemical mediators, called cytokines, are released in massive quantities as part of the inflammatory response, they can destabilize blood vessels, resulting in leakage, tissue edema (swelling), and in extreme cases, organ failure and death. For example, a severe infection such as that of the 1918 pandemic flu, can cause life-threatening lung damage when alveoli become inflamed and fill with fluid, a condition known as lung edema. Similarly, sepsis can damage organs such as the kidneys by weakening blood vessels and allowing fluid to leak into the kidney tissue, impairing its vital functions.
Although it will take much more work to determine if Robo4 can be manipulated to block inflammation in sepsis, influenza, and other infections, the protein’s signaling pathway appears to be ideal for stabilizing the endothelial cells that line blood vessels, according to Guy A. Zimmerman, M.D., a U of U professor of internal medicine who investigates inflammation and sepsis. “For this reason, the Robo4 pathway may be more effective and less likely to have negative side-effects than some of the approaches and drugs that have been tried in the past,” said Zimmerman, a co-author on the study.
Targeting the pathogens that cause influenza and sepsis has been the primary strategy to fight those infections. While this has been successful, it also has limitations because pathogens can evolve quickly to develop resistance to antibiotics and antiviral medications. A second approach has been to dampen a patient’s immune system response to infection. However, past approaches led to poor outcomes in patients, in part because they sometimes increased the sick individual’s susceptibility to a second, “opportunistic” infection.
Protecting the host from its own inflammatory response to infection offers a potential strategy to reduce the mortality rate from many different types of serious infections. In the mouse models of this study, the mortality rate for some sepsis and avian flu infections approached 90 percent when left untreated. By protecting blood vessels through activating Robo4, mortality was reduced in some cases to almost half.
Dale L. Barnard, Ph.D., a virus specialist and research associate professor at the Institute for Antiviral Research in the Department of Animal, Dairy and Veterinary Sciences at Utah State University, said the study opens a potentially exciting approach to treating virulent viral-caused infections such as pandemic H1N1 and the highly infectious avian flu. “It may be even a more effective approach if it were to be used in combination with antiviral drug therapy, perhaps allowing the antiviral drug to be used at concentrations below those which would induce drug resistance or allow the drug to be administered for shorter periods of time,” said Barnard, also a co-author on the study.
Li’s study of Robo4 as an agent for mitigating the effects of inflammation grew from his research into blood vessel formation. In 2003, he cloned Robo4 and showed that it inhibits uncontrolled blood vessel growth, thereby stabilizing vessels and preventing leakage. Robo4 is activated by another protein, called Slit.
Adapted from materials provided by University of Utah Health Sciences.
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University of Utah Health Sciences (2010, March 19). Targeting blood vessels, immune system may offer way to stop infection-caused inflammation. ScienceDaily. Retrieved March 30, 2010, from http://www.sciencedaily.com /releases/2010/03/100317161958.htm
SUNY Downstate Medical Center, March 30, 2010 — It is well known that the onset of puberty marks the end of the optimal period for learning language and certain spatial skills, such as computer/video game operation. Recent work published in the journal Science by Sheryl Smith, PhD, professor of physiology and pharmacology, and colleagues at SUNY Downstate Medical Center in Brooklyn shows that a novel brain receptor, alpha4-beta-delta, emerges at puberty in the hippocampus, part of the brain that controls learning and memory.
Before puberty, expression of this receptor is low and learning is optimal. However, at puberty, increases in this receptor reduce brain excitability and impair spatial learning. Dr. Smith has demonstrated that this learning deficit can be reversed by a stress steroid that diminishes the harmful effects of the alpha4-beta-delta receptors, thereby facilitating learning.
“These findings suggest that intrinsic brain mechanisms alter learning during adolescence, but that mild stress may be one factor that can reverse this decline in learning proficiency during the teenage years,” says Dr. Smith. “They also suggest that different strategies for learning and motivation may be helpful in middle school. And it is within the realm of possibility that a drug could be developed that would increase learning ability post-puberty, one that might be especially useful for adolescents with learning disabilities.”
In 2007, Dr. Smith and colleagues demonstrated that a hormone normally released in response to stress, THP, actually reverses its effect at puberty, when it increases activity of the hippocampus. While in adults this hormone acts like at tranquilizer, in adolescents it has the opposite effect, an action that may help to explain mood swings in teenagers.
- 1. Hui Shen, Nicole Sabaliauskas, Ang Sherpa, André A. Fenton, Armin Stelzer, Chiye Aoki, and Sheryl S. Smith. A Critical Role for Alpha4-Beta-Delta GABA-A Receptors in Shaping Learning Deficits at Puberty in Mice. Science, 19 March 2010 327: 1515-1518 DOI: 10.1126/science.1184245
ScienceDaily (Mar. 30, 2010) — Short bursts of physical activity can ease fibromyalgia symptoms. Researchers writing in BioMed Central’s open access journal Arthritis Research & Therapy have shown that encouraging patients to undertake ‘Lifestyle Physical Activity’ (LPA) can markedly increase the average number of steps taken per day and produce clinically relevant reductions in perceived disability and pain.
Kevin Fontaine, from Johns Hopkins University School of Medicine, worked with a team of researchers at the Johns Hopkins Bayview Medical Center campus to investigate the effects of 30 minutes of LPA, five to seven days a week, on physical function, pain and other measures of disability in 84 fibromyalgia patients. He said, “Fibromyalgia is estimated to occur in 2% of the U.S. general population, affecting about eight times more women than men. Although exercise has been shown to be beneficial, the symptoms often create obstacles that deter many from exercising consistently enough to derive benefits.”
LPA involves moderate-intensity physical activity based around everyday life such as taking the stairs instead of using an elevator, gardening and walking. In this study, participants were taught to perform LPA intense enough to cause heavy breathing, but not so heavily that they could not hold a conversation. During subsequent sessions participants were taught self-monitoring of LPA, goal setting, dealing with symptom flares, problem solving strategies to overcome barriers to being more physically active, as well as instruction in finding new ways to integrate short bouts of LPA into their daily lives.
At the end of the study, the participants randomized to LPA increased their average daily steps by 54%. Compared to the controls, the LPA group also reported significantly less perceived functional deficits and less pain. Speaking about these results, Fontaine said, “The nature of fibromyalgia’s symptoms, the body pain and fatigue, make it hard for people with this malady to participate in traditional exercise. We’ve shown that LPA can help them to get at least a little more physically active, and that this seems to help improve their symptoms.”
ScienceDaily (Mar. 30, 2010) — Microglia are the cells responsible for immune surveillance in the brain, and they initiate protective inflammatory reactions in response to tissue damage and infection. An international team under the leadership of LMU neuroscientist Professor Jochen Herms has now shown that these cells may actually make a significant contribution to the loss of neurons associated with Alzheimer’s disease.
About 1.2 million people are thought to suffer from this form of progressive dementia in Germany, and this figure is expected to double as the average age of the population continues to increase. Their new findings lead Professor Herms and his team to believe that, as the disease develops, stressed nerve cells secrete a chemical messenger that attracts microglia. The ensuing inflammatory reactions ultimately result in the elimination of the neurons.
This implies that chemical signalling between nerve cells and microglia plays an important role in mediating neuron loss during the course of the disease. “We may be able to make use of these results to develop novel agents that can slow the rate of neuron loss by interrupting communications between the two cell types,” says Herms. It is estimated that as many as 18 million people currently suffer from Alzheimer’s disease worldwide, and the numbers are rising. This form of progressive dementia is due to an inexorable loss of nerve cells from the brain that is associated with the formation of insoluble protein aggregates, called beta-amyloid plaques and tangles.
Large numbers of microglia gather in the vicinity of these plaques. Microglia serve as immune “policemen” that use their long processes to monitor their surroundings for signs of tissue damage. In accordance with this role, it has been thought that they congregate near plaques in order to degrade them.
Using two-photon microscopy, Professor Herms and his colleagues at the LMU’s Center for Neuropathology were able to look directly into the brains of genetically modified mice that develop many of the symptoms characteristic of Alzheimer’s disease in humans. The mice had also been engineered to make fluorescent forms of proteins that are specific for neurons and microglia, and the imaging technique enabled the researchers to monitor the fate of identifiable neurons and microglia over periods of weeks and months.
This approach made it possible, for the first time, to visualize the loss of nerve cells in the brains of living mice. Nerve loss was found to be preceded by the activation of microglia.
“We assume that the sick nerve cells near plaques secrete a chemical messenger that induces the microglia to home in on them,” says Herms. “The best candidate for the messenger responsible is the chemokine fractalikine, which docks onto a receptor protein on the surface of the microglial cells.”
Indeed, when this receptor was genetically eliminated, nerve cell loss was prevented. These results demonstrate that microglia are not only involved in the removal of the amyloid aggregates typical of Alzheimer’s disease, they also contribute actively to the catastrophic loss of nerve cells. In this picture, the communication channel between nerve cell and microglia that is mediated by the fractalkine receptor plays a crucial role in the pathology of Alzheimer’s disease.
“The new findings could possibly lead to new therapeutic approaches to preventing neuron loss,” says Herms.
Adapted from materials provided by Ludwig-Maximilians-Universitaet Muenchen (LMU).
- 1. Fuhrmann et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nature Neuroscience, 2010; DOI: 10.1038/nn.2511
ScienceDaily (Mar. 30, 2010) — Trends indicate that survival is improving in patients with metastatic breast cancer, especially in those patients whose tumours are described as being HER2 (human epidermal growth factor receptor-2) positive, a surgical oncologist said on March 26 at the seventh European Breast Cancer Conference.
Dr Marie Sundquist, from the Department of Surgery, County Hospital, Kalmar, Sweden, said that the median survival times for five-year intervals of 557 metastatic breast cancer patients in Kalmar, Sweden, increased steadily, from 10 months for the 1985 to 1990 period, to 22 months for the 2000 to 2004 period.
She reported the findings of a retrospective analysis of follow-up data of breast cancer patients who were diagnosed in hospitals in Kalmar County since 1985. “A strength of our work is that we have studied a consecutive population in a defined geographical area for a continuous period of 25 years,” Dr Sundquist will tell the conference.
Dr Sundquist tolddelegates that for 288 patients with grade III tumours, the most aggressive type of breast cancer, the median survival time increased from 10 months for the 1985 to1990 period to 17 months for the 2000 to 2004 period. The increased use of the chemotherapy drugs called anthracyclines and taxanes led to the improved survival outcomes in this group of patients with the aggressive form of metastatic breast cancer, she said.
Some breast cancer cells have receptors, which allow certain types of hormones or proteins to attach to the cancer cell. Breast cancer hormone-receptor status can affect the individual patient’s treatment options as well as overall prognosis. Analysis of the data by HER2 positive status revealed that HER2 positive patients with metastatic breast cancer had improved survival rates. Prior to the year 2000, 40 HER2 positive patients had a median survival of 14 months compared to 21 months for 40 HER2 positive patients diagnosed with breast cancer from the year 2000 onwards.
Dr Sundquist said: “There is no doubt that trastuzumab (Herceptin), which targets the HER2 gene, is the most important reason for the improved survival in this group of patients, and use of the chemotherapy drugs known as anthracyclines also contributed.
“In the group of HER2 positive patients that had the most aggressive type of breast cancer (grade III), 45% of those patients that received trastuzumab had survived more than three years and 30% more than five years,” Dr Sundquist added.
“Patients whose breast tumours have spread outside of the breast and armpit areas are essentially incurable. However, some patients live even decades with a good quality of life despite an initially widespread tumour burden, while others fail to respond to any therapy. To explore and try to understand these mechanisms would make it easier to tailor the treatment for each individual patient,” Dr Sundquist said.
A new era of breast cancer treatment started with the gene-targeted therapy of trastuzumab. Since then, a number of similar targeted therapies including antibodies or inhibitors of specific genes have been developed. This will open new avenues in the treatment of all metastatic breast cancers and also of primary breast cancer.
“These new targeted therapies will, at least in the beginning after their development, be very costly for healthcare systems. On the other hand they will make it possible for many women to lead almost normal lives, work and contribute to society for an increased number of years,” she concluded.
The researchers intend to follow up their work by performing genetic analyses of the tumours with different responsiveness to specific treatments. “Health care systems will need to provide tools for the routine clinical assessment of a number of genes related to treatment response,” she added.