Brain cell migration during normal development may offer insight on how cancer cells spread

SEATTLE – By shedding new light on how cells migrate in the developing brain, researchers at Fred Hutchinson Cancer Research Center also may have found a new mechanism by which other types of cells, including cancer cells, travel within the body. The findings by Jonathan Cooper, Ph.D., member and director of the Hutchinson Center's Basic Sciences Division, and Yves Jossin, Ph.D., a research fellow in Cooper's laboratory, published online April 24 in Nature Neuroscience, could lead to a better understanding of neurological development and, possibly, cancer metastasis.

During normal development cells divide, arrange themselves in appropriate patterns, and specialize to form discrete tissues and organs. For the body to develop properly, cells must coordinate their migratory patterns and the process by which they differentiate, or evolve from less-specialized cells into more-specialized cell types. A lack of such coordination leads to disordered development and, in some cases, cancer.

Jossin and Cooper set out to analyze how cells migrate in the cerebral cortex of the developing brain. The cerebral cortex, gray matter of the cerebrum, is the brain's command and control center where cognition and planning occur, and it is particularly well developed in humans.

The cerebral cortex is composed of horizontal layers of nerve cells, or neurons, which are specialized for different functions and connected vertically into circuits. If some neurons are in the wrong layers, the wiring can be defective and neurological disorders including epilepsy, autism and schizophrenia may result.

In the fetus, the cortex grows "from the inside out" via the sequential addition of new neurons, which move from the inside, pass between neurons in previously established intermediate layers, and form new layers on the outside. How the migrations are regulated remains unclear despite years of study.

Jossin and Cooper now report the discovery of signals that control a particular stage in a cortical neuron's journey. New neurons initially move in a straight line, from the inside to the outside, until they reach a layer called the intermediate zone. This zone contains relatively few neurons but many connecting fibers, or axons. When new neurons reach this layer, they lose their way and start wandering – up, down, left and right, frequently changing direction. When, seemingly by chance, they emerge from the intermediate zone, they realign with their original direction of movement and speed ahead through layers of differentiated neurons towards the outer surface of the cortex.

The researchers aimed to determine how neurons get back on track after they emerge from the chaos of the intermediate zone. They identified a signaling protein, called Reelin, which is made by cells in the outermost layer of the cortex. It has been known for years that mutations in the Reelin gene cause profound cortical layering abnormalities in rodents and people, but it has been unclear which stage of neuron migration goes awry when Reelin is absent.

The new study shows that new neurons respond to Reelin as they emerge from the intermediate zone. "This is remarkable because the top layer of the cortex, where Reelin is made, is widely separated from the top of the intermediate zone, where it acts, so the Reelin protein must be diffuse," Cooper said. "It is also remarkable that Reelin seems not to be a direction signal itself. Rather, Reelin triggers changes in the membranes of the migrating neurons that allow the cells to respond to direction signals."

The researchers show that a membrane protein called N-cadherin increases on the surface of neurons when the neurons encounter Reelin. The surface increase in N-cadherin allows the cell to choose the appropriate direction for its next stage of migration. "This represents a new and surprising function for N-cadherin," Jossin said, "because normally this protein acts as a cellular stabilizer and not as an orchestrator of migration."

For example, elsewhere in the cortex, N-cadherin forms tight adhesions between adjacent cells and prevents them from moving. Indeed, the general role for cadherins in the body is to stabilize sheets of cells and organize tissues by holding cells together.

"The new role for N-cadherin in orienting migrating cells is quite unexpected and suggests that cadherins on the surface of other types of normal or cancer cells may also be involved in helping them move rather than stay in place," Jossin said. "This finding could provide new clues to how normal and cancerous cells migrate within the body," he said.

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This research was funded in part by the National Institutes of Health and a Marie Curie Fellowship from the European Union.

At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world.www.fhcrc.org

Contact: Kristen Woodward
kwoodwar@fhcrc.org
206-667-5095
Fred Hutchinson Cancer Research Center

Nanoparticles May Enhance Circulating Tumor Cell Detection

ATLANTA – Tiny gold particles can help doctors detect tumor cells circulating in the blood of patients with head and neck cancer, researchers at Emory and Georgia Tech have found.

The detection of circulating tumor cells (CTCs) is an emerging technique that can allow oncologists to monitor patients with cancer for metastasis or to evaluate the progress of their treatment. The gold particles, which are embedded with dyes allowing their detection by laser spectroscopy, could enhance this technique’s specificity by reducing the number of false positives.

The results are published online in the journal Cancer Research.

Gold-based nanoparticles can detect circulating tumor cells. Download/view larger image.

One challenge with detecting CTCs is separating out signals from white blood cells, which are similarly sized as tumor cells and can stick to the same antibodies normally used to identify tumor cells. Commercially available devices trap CTCs using antibody-coated magnetic beads, and technicians must stain the trapped cells with several antibodies to avoid falsely identifying white blood cells as tumor cells.

Emory and Georgia Tech researchers show that polymer-coated and dye-studded gold particles, directly linked to a growth factor peptide rather than an antibody, can detect circulating tumor cells in the blood of patients with head and neck cancer.

“The key technological advance here is our finding that polymer-coated gold nanoparticles that are conjugated with low molecular weight peptides such as EGF are much less sticky than particles conjugated to whole antibodies,” says Shuming Nie, PhD, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “This effect has led to a major improvement in discriminating tumor cells from non-tumor cells in the blood.”

The particles are linked to EGF (epithelial growth factor), whose counterpart EGFR (epithelial growth factor receptor) is over-produced on the surfaces of several types of tumor cells.

Upon laser illumination, the particles display a sharp fingerprint-like pattern that is specific to the dye, because the gold enhances the signal coming from the dyes. This suggests that several types of nanoparticles could be combined to gain more information about the growth characteristics of the tumor cells. In addition, measuring CTC levels may be sensitive enough to distinguish patients with localized disease from those with metastatic disease.

“Nanoparticles could be instrumental in modifying the process so that circulating tumor cells can be detected without separating the tumor cells from normal blood cells,” Nie says. “We’ve demonstrated that one tumor cell out of approximately one to ten million normal cells can be detected this way.”

In collaboration with oncologists at Winship Cancer Institute, researchers used nanoparticles to test for CTCs in blood samples from 19 patients with head and neck cancer. Of these patients, 17 had positive signals for CTCs in their blood. The two with low signals were verified to have no circulating cells by a different technique.

“Although the results have not been compared or validated with current CTC detection methods, our ‘one-tube’ SERS technology could be faster and lower in costs than other detection methods,” says Dong Moon Shin, MD, professor of hematology and oncology and otolaryngology, associate director of academic development for Winship Cancer Institute and director of the Winship Cancer Institute Chemoprevention Program. “We need to validate this pilot study by continuing with larger groups of patients and comparing with other tests.”

http://cancerres.aacrjournals.org/content/early/2011/01/03/0008-5472.CAN-10-3069.abstract

Writer: Quinn Eastman

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The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focusing on teaching, research, health care and public service.

Learn more about Emory’s health sciences:
Blog: http://emoryhealthblog.com
Twitter: @emoryhealthsci
Web: http://emoryhealthsciences.org

New York- Presbyterian Hospital/Columbia University Medical Center research into robotic surgery for kidney cancer

New research helps optimize benefits of robotic approach

NEW YORK (July 28, 2008) -- Clinical research at NewYork-Presbyterian Hospital/Columbia University Medical Center is helping bring the advantages of robotic surgery, including reduced pain and quicker recovery, to kidney cancer patients.

Using the latest-generation da Vinci® S Surgical System by Intuitive Surgical, surgeons operate through several small incisions in the abdomen. Surgeons then remove only the cancerous tissue from the kidney, and repair the remaining normal kidney tissue, all using robotic arms guided by video taken by a camera controlled by a separate robotic arm.

The stereoscopic view provides enhanced visibility, and the nimble robotic mechanism makes for easy cutting and suturing, according to Drs. Ketan Badani and Jaime Landman, who make up the robotic kidney surgery team at NewYork-Presbyterian/Columbia.

"With robotics, there is a much greater opportunity for complex reconstruction of the kidney than can typically be achieved with a standard laparoscopic approach," notes Dr. Badani, director of robotic urologic surgery at NewYork-Presbyterian Hospital/Columbia University Medical Center and assistant professor of urology at Columbia University College of Physicians and Surgeons.

"This means that, hopefully, we will have an opportunity not only to reduce the need for kidney cancer patients to require a kidney transplant, but also reduce their need for dialysis later in life," adds Dr. Landman, director of minimally invasive urologic surgery at NewYork-Presbyterian Hospital/Columbia University Medical Center and associate professor of urology at Columbia University College of Physicians and Surgeons.

In a recent issue of the Journal of Endourology, Dr. Badani described a new technique for port placement -- the location of the small incision through which the robot operates -- that maximizes range of motion for the robot's camera arm and working arm. The approach was shown to be successful in more than 50 cases, and has been adopted for use by medical centers worldwide.

Robotic surgery, most widely used for prostate cancer surgery, is beginning to be more widely available for other conditions. In addition to kidney cancer, Dr. Badani and Dr. Mitchell Benson (George F. Cahill Professor and Chairman of the Department of Urology at Columbia University College of Physicians and Surgeons and urologist-in-chief at NewYork-Presbyterian Hospital/Columbia University Medical Center), have established robotic surgery for bladder cancer, and they cite work being undertaken in pelvic floor reconstruction and repair of vaginal wall prolapse.

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Columbia University Medical Center

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians & Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States. For more information, please visit www.cumc.columbia.edu.

NewYork-Presbyterian Hospital

NewYork-Presbyterian Hospital, based in New York City, is the nation's largest not-for-profit, non-sectarian hospital, with 2,242 beds. The Hospital has nearly 2 million patient visits in a year, including more than 230,000 visits to its emergency departments -- more than any other area hospital. NewYork-Presbyterian provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine at five major centers: NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children's Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/Allen Pavilion and NewYork-Presbyterian Hospital/Westchester Division. One of the largest and most comprehensive health-care institutions in the world, the Hospital is committed to excellence in patient care, research, education and community service. It ranks sixth in U.S.News & World Report's guide to "America's Best Hospitals," ranks first on New York magazine's "Best Hospitals" survey, has the greatest number of physicians listed in New York magazine's "Best Doctors" issue, and is included among Solucient's top 15 major teaching hospitals. The Hospital's mortality rates are among the lowest for heart attack and heart failure in the country, according to a 2007 U.S. Department of Health and Human Services (HHS) report card. The Hospital has academic affiliations with two of the nation's leading medical colleges: Weill Cornell Medical College and Columbia University College of Physicians and Surgeons. For more information, visit www.nyp.org.

Blackwell Publishing : Prostate Cancer Patients Undergoing Hormone Therapy May Experience Cognitive Effects

A recent review of the literature has found that hormone deprivation therapy, a commonly used treatment for prostate cancer, may have subtle adverse effects on cognition in patients--such as in the ability to recall and concentrate. Published in the September 1, 2008 issue of CANCER, a peer-reviewed journal of the American Cancer Society, the study indicates that clinicians and patients should be aware of these potential effects and watch closely for their appearance.

For years, hormone deprivation therapy, also known as androgen depletion therapy, has been used as an effective treatment for prostate cancer because hormones such as testosterone drive the growth of prostate cancer cells. The most common way to achieve androgen depletion is through chemical castration with drugs such as leuprolide and goserelin. Androgen depletion therapy has traditionally been reserved for advanced cases of prostate cancer, but increasing numbers of men with earlier stages of the disease are also undergoing the treatment.

Prostate cancer patients who are prescribed these drugs often stay on them for the duration of their life, and researchers have been documenting the potential adverse effects associated with their use. Men may experience hot flashes, osteoporosis, anemia, fatigue, loss of libido, erectile dysfunction, risk of diabetes, risk of cardiovascular disease, emotional distress and other effects. Research also indicates that androgen depletion may impact cognitive functioning, which can affect a patient’s decision-making skills and quality of life.

Unfortunately, only a handful of relatively small studies have investigated the impact of androgen depletion on cognitive functioning, and some of these studies have reported contradictory results. Dr. Christian Nelson, a psychologist at Memorial Sloan-Kettering Cancer Center in New York City and his colleagues recently conducted the first review of these studies and summarized their overall results.

After performing a systematic literature search of studies in animals and humans, Dr. Nelson’s team found that testosterone and its derivatives may impact cognition via several mechanisms in the brain. For example, testosterone can modulate brain chemicals called neurotransmitters and stimulate the connections between neurons. Also, studies that have examined the impact of androgen depletion therapy in prostate cancer patients indicate that between 47 percent and 69 percent of men being treated decline in at least one cognitive area, most commonly in processes dependent on spatial ability and in high-order capacities such as the ability to multi-task.

The findings indicate that larger, more thorough studies that include brain imaging techniques are needed to better understand the nature and extent of the cognitive effects of androgen depletion.

In addition, researchers are exploring the effectiveness of using androgen depletion therapy in men with rising levels of prostate specific antigen, a potential precursor to prostate cancer. The authors concluded that “as the use of androgen depletion therapy increases, clinicians should become aware of this relationship [with cognitive decline], and inform and monitor patients for this possible side effect of treatment.”

Article: “The cognitive effects of hormone therapy in men with prostate cancer: a review.” Christian J. Nelson, Jennifer S. Lee, Maria C. Gamboa, and Andrew J. Roth. CANCER; Published Online: July 28, 2008 (DOI: 10.1002/cncr.23658); Print Issue Date: September 1, 2008.

Contact: Esther Napolitano, Media Relations Manager at Memorial Sloan-Kettering Cancer Center’s Department of Public Affairs. 212-639-3573, napolite@mskcc.org.

Blackwell Publishing : Hip Bone Density Helps Predict Breast Cancer Risk

Measuring a woman’s bone mineral density can provide additional information that may help more accurately determine a woman’s risk of developing breast cancer. That is the conclusion of a new study published in the September 1, 2008 issue of CANCER, a peer-reviewed journal of the American Cancer Society. The study’s results suggest that incorporating bone mineral density tests with current risk assessments might significantly improve physicians’ ability to predict breast cancer risk in older, postmenopausal women.

Bone mineral density testing is done to diagnose osteoporosis and help assess the risk of fractures. Low bone mineral density is linked to higher risk of fractures, while normal density is linked to lower risk of fractures. It is possible that over a woman’s lifetime, hormonal and other factors that lead to higher bone mineral density can also lead to higher risk of breast cancer. Studies have found an association between higher bone mineral density and higher breast cancer risk, and bone mineral density tests have been proposed as a potential addition to breast cancer risk models. This study, supported by Eli Lilly & Company, is the first to investigate the relationships among bone mineral density, traditional breast cancer risk assessment tool results, and breast cancer incidence among the same group of postmenopausal women.

To investigate these relationships, Dr. Zhao Chen of the University of Arizona Mel and Enid Zuckerman College of Public Health and her colleagues studied approximately 10,000 post-menopausal women (average age 63) taking part in the Women’s Health Initiative, a study conducted in 40 clinical centers throughout the United States and supported by the National Heart, Lung and Blood Institute of the National Institutes of Health. The researchers assessed the women’s initial bone mineral density level as well as their score on the Gail risk model, a well known and commonly used tool that estimates five year and lifetime risk of invasive breast cancer for women 35 years of age or older. They then followed the women for an average of approximately 8 years, noting which women developed breast cancer.

As expected, the study found that women with a high Gail score had a 35 percent increased risk of developing breast cancer compared to women with a lower Gail score. But the study also found a 25 percent increase in the risk of developing the disease with each unit increase in total hip bone mineral density t-score. While the two scores were independent of each other, women who had the highest scores on both assessments had a much higher risk in breast cancer.

The findings suggest that adding bone mineral density to currently used risk assessment tools may significantly improve the prediction of breast cancer risk. “Future studies should investigate whether incorporating bone mineral density and Gail score with other risk factors, such as breast density, can further improve the identification of women at high risk for developing breast cancer,” the authors wrote. This study also suggests that bone mineral density is a potential alternative for predicting breast cancer risk in postmenopausal women if Gail score is not available. Additional studies are needed to determine if the results from this investigation are applicable to a broader group of women, including minorities. The findings do not change the use of bone mineral density testing to diagnose osteoporosis or the need to treat osteoporosis in order to reduce the risk of fractures.

Article: “Hip bone density predicts breast cancer risk independently of Gail score - results from the Women’s Health Initiative.” Zhao Chen, Leslie Arendell, Mikel Aickin, Jane Cauley, Cora E. Lewis, and Rowan Chlebowski. CANCER; Published Online: July 28, 2008 (DOI: 10.1002/cncr.23674); Print Issue Date: September 1, 2008.

Contact: Lorraine Varela - University of Arizona Mel and Enid Zuckerman College of Public Health. (520) 626-7083, varelal@coph.arizona.edu.

Cedars-Sinai Medical Center : Erectile dysfunction drugs allowed more chemotherapy to reach brain tumors in laboratory study

The drugs blocked an enzyme and opened blood vessels to tumors but not normal brain

LOS ANGELES (July 28, 2008) – In a study using laboratory animals, researchers found that medications commonly prescribed for erectile dysfunction opened a mechanism called the blood-brain tumor barrier and increased delivery of cancer-fighting drugs to malignant brain tumors.

The experiments were conducted at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute and published in Brain Research.

Viagra (sildenafil) and Levitra (vardenafil) are known as PDE5 inhibitors because they block an enzyme, phosphodiesterase5, which interrupts a series of biochemical events that cause the decreased blood flow of erectile dysfunction. This laboratory rat study, published online ahead of print in the journal, found that similar biochemical interactions in the small vessels of the brain play a major role in the blood-brain tumor barrier, which impedes delivery of anti-tumor drugs into brain tumors. PDE5 inhibitors were found to open the barrier and increase drug transport in this early animal study.

Although the normal blood-brain barrier, which regulates access to the brain from the bloodstream, shares many characteristics with the blood-brain tumor barrier, the signaling mechanism blocked by PDE5 inhibitors is unique to the blood-brain tumor barrier. This allows the PDE5 inhibitors to selectively increase drug transport to malignant brain tumors without affecting normal brain tissue.

According to the researchers, these findings may have significant implications in improving drug delivery to brain tumors in patients.

"This is the first study to show that oral administration of PDE5 inhibitors increases the rate of transport of compounds across the blood-brain tumor barrier and improves the effectiveness of the anti-tumor drug adriamycin in the treatment of brain tumors in a rat model. We chose adriamycin for this study because it is one of the most effective drugs against brain tumor cell lines in the laboratory but it has very little effect in animals and humans because it is unable to cross the blood-brain tumor barrier. The combination of vardenafil and adriamycin resulted in longer survival and smaller tumor size," said neurosurgeon Keith L. Black, M.D., chairman of the Department of Neurosurgery at Cedars-Sinai Medical Center and director of the Maxine Dunitz Neurosurgical Institute.

Black, the article's first and corresponding author, has been recognized for his earlier groundbreaking work to break through the blood-brain tumor barrier with natural and synthetic bradykinin, a peptide that temporarily opens the barrier and increases anti-cancer drug delivery into certain tumors by more than 1,000 percent. In 2000, he received the Javits Neuroscience Investigator Award from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, for his blood-brain barrier research.

In the current studies, the blood-brain tumor barrier-opening effects of PDE5 lasted considerably longer than those of bradykinin and allowed greater transport across the barrier into tumor tissues. Because vardenafil was found to be more effective than sildenafil in increasing blood-brain tumor barrier permeability and transport, vardenafil was used in a survival study of 29 tumor-bearing rats. Those treated with saline (control) survived 32 days on average while those treated with vardenafil alone survived about 35 days and those treated with adriamycin alone survived about 42 days. When vardenafil was combined with adriamycin, rats survived an average 53 days.

Although the researchers exposed the laboratory animals to doses of sildenafil and vardenafil that are comparable to the dose range approved for erectile dysfunction in humans, there were no detectable side effects in the rats, and neither drug increased transport of tracers into normal brain tissue.

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Funding for the studies was provided by the National Institute of Neurological Disorders and Stroke (the Javits Award), the Maxine Dunitz Neurosurgical Institute and the Ruth and Lawrence Harvey Chair in Neuroscience, held by Black.

Citation: Brain Research, "PDE5 Inhibitors Enhance Tumor Permeability and Efficacy of Chemotherapy in a Rat Brain Tumor Model," available online ahead of print.

American Cancer Society : Prostate cancer patients undergoing hormone therapy may experience cognitive effects

A recent review of the literature has found that hormone deprivation therapy, a commonly used treatment for prostate cancer, may have subtle adverse effects on cognition in patients-- such as in the ability to recall and concentrate. Published in the September 1, 2008 issue of CANCER, a peer-reviewed journal of the American Cancer Society, the study indicates that clinicians and patients should be aware of these potential effects and watch closely for their appearance.

For years, hormone deprivation therapy, also known as androgen depletion therapy, has been used as an effective treatment for prostate cancer because hormones such as testosterone drive the growth of prostate cancer cells. The most common way to achieve androgen depletion is through chemical castration with drugs such as leuprolide and goserelin. Androgen depletion therapy has traditionally been reserved for advanced cases of prostate cancer, but increasing numbers of men with earlier stages of the disease are also undergoing the treatment.

Prostate cancer patients who are prescribed these drugs often stay on them for the duration of their life, and researchers have been documenting the potential adverse effects associated with their use. Men may experience hot flashes, osteoporosis, anemia, fatigue, loss of libido, erectile dysfunction, risk of diabetes, risk of cardiovascular disease, emotional distress, and other effects. Research also indicates that androgen depletion may impact cognitive functioning, which can affect a patient's decision-making skills and quality of life.

Unfortunately, only a handful of relatively small studies have investigated the impact of androgen depletion on cognitive functioning, and some of these studies have reported contradictory results. Dr. Christian Nelson, a psychologist at Memorial Sloan-Kettering Cancer Center in New York City and his colleagues recently conducted the first review of these studies and summarized their overall results.

After performing a systematic literature search of studies in animals and humans, Dr. Nelson's team found that testosterone and its derivatives may impact cognition via several mechanisms in the brain. For example, testosterone can modulate brain chemicals called neurotransmitters and stimulate the connections between neurons. Also, studies that have examined the impact of androgen depletion therapy in prostate cancer patients indicate that between 47% and 69% of men being treated decline in at least one cognitive area, most commonly in processes dependent on spatial ability and in high-order capacities such as the ability to multi-task.

The findings indicate that larger, more thorough studies that include brain imaging techniques are needed to better understand the nature and extent of the cognitive effects of androgen depletion.

In addition, researchers are exploring the effectiveness of using androgen depletion therapy in men with rising levels of prostate specific antigen, a potential precursor to prostate cancer. The authors concluded that "as the use of androgen depletion therapy increases, clinicians should become aware of this relationship [with cognitive decline], and inform and monitor patients for this possible side effect of treatment."

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Article: "The cognitive effects of hormone therapy in men with prostate cancer: a review." Christian J. Nelson, Jennifer S. Lee, Maria C. Gamboa, and Andrew J. Roth. CANCER; Published Online: July 28, 2008 (DOI: 10.1002/cncr.23658); Print Issue Date: September 1, 2008.

American Cancer Society : Hip bone density helps predict breast cancer risk

Measuring a woman's bone mineral density can provide additional information that may help more accurately determine a woman's risk of developing breast cancer. That is the conclusion of a new study published in the September 1, 2008 issue of CANCER, a peer-reviewed journal of the American Cancer Society. The study's results suggest that incorporating bone mineral density tests with current risk assessments might significantly improve physicians' ability to predict breast cancer risk in older, postmenopausal women.

Bone mineral density testing is done to diagnose osteoporosis and help assess the risk of fractures. Low bone mineral density is linked to higher risk of fractures, while normal density is linked to lower risk of fractures. It is possible that over a woman's lifetime, hormonal and other factors that lead to higher bone mineral density (and lower risk of fractures) can also lead to higher risk of breast cancer. Studies have found an association between higher bone mineral density and higher breast cancer risk, and bone mineral density tests have been proposed as a potential addition to breast cancer risk models. This study, supported by Eli Lilly & Company, is the first to investigate the relationships among bone mineral density, traditional breast cancer risk assessment tool results, and breast cancer incidence among the same group of postmenopausal women.

To investigate these relationships, Dr. Zhao Chen of the University of Arizona Mel and Enid Zuckerman College of Public Health and her colleagues studied approximately 10,000 post-menopausal women (average age 63) taking part in the Women's Health Initiative, a study conducted in 40 clinical centers throughout the United States and supported by the National Heart, Lung and Blood Institute of the National Institutes of Health. The researchers assessed the women's initial bone mineral density level as well as their score on the Gail risk model, a well known and commonly used tool that estimates five year and lifetime risk of invasive breast cancer for women 35 years of age or older. They then followed the women for an average of approximately 8 years, noting which women developed breast cancer.

As expected, the study found that women with a high Gail score had a 35 percent increased risk of developing breast cancer compared to women with a lower Gail score. But the study also found a 25 percent increase in the risk of developing the disease with each unit increase in total hip bone mineral density t-score. While the two scores were independent of each other, women who had the highest scores on both assessments had a much higher risk in breast cancer.

The findings suggest that adding bone mineral density to currently used risk assessment tools may significantly improve the prediction of breast cancer risk. "Future studies should investigate whether incorporating bone mineral density and Gail score with other risk factors, such as breast density, can further improve the identification of women at high risk for developing breast cancer," the authors wrote. This study also suggests that bone mineral density is a potential alternative for predicting breast cancer risk in postmenopausal women if Gail score is not available. Additional studies are needed to determine if the results from this investigation are applicable to a broader group of women, including minorities. The findings do not change the use of bone mineral density testing to diagnose osteoporosis or the need to treat osteoporosis in order to reduce the risk of fractures.

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Article: "Hip bone density predicts breast cancer risk independently of Gail score - results from the Women's Health Initiative." Zhao Chen, Leslie Arendell, Mikel Aickin, Jane Cauley, Cora E. Lewis, and Rowan Chlebowski. CANCER; Published Online: July 28, 2008 (DOI:10.1002/cncr.23674); Print Issue Date: September 1, 2008.

Harvard Medical School Being a control freak aids dividing cells

Micromanagers may generate resentment in an office setting, but they get results in your body. New data indicate that a dividing cell takes micromanagement to the extreme, tagging more than 14,000 different sites on its proteins with phosphate, a molecule that typically serves as a signal for a variety of biological processes.

This preponderance of signals suggests that the cell may become a control freak during the division process, regulating each of its parts, no matter how obscure. It may take extreme measures to ensure that each "daughter" receives a full complement of cellular material. The new data—published online the week of July 28 in PNAS—open unexplored frontiers to developmental biologists, cancer researchers, and others who study cell growth and proliferation.

"There's a massive wave of phosphorylation in dividing cells, much bigger than anyone expected," says HMS associate professor of cell biology Steven Gygi, who is corresponding author on the study. "This discovery implies that we've severely underestimated the scope of regulation in cell division for decades, which has implications for our understanding of a wide-range of diseases and developmental defects linked to the cell cycle, from cancer to holes in the heart."

Traditionally, researchers probed cell division by zooming in on a particular gene or protein and tracing its interactions. But Gygi took a different approach. A leader in the emerging field of "proteomics," which involves looking at thousands of proteins at once, his team used an instrument called a mass spectrometer to essentially take a wide-angle shot of dividing cells, capturing information that narrow studies missed. The panoramic view revealed a surprising level of signaling activity throughout the cell.

"An enormous number of proteins—more than 1,000—became highly phosphorylated during cell division, some more than 10 times," says postdoctoral researcher Noah Dephoure, who ran the experiment.

In collaboration with Chunshui Zhou, a researcher in HMS professor of genetics Stephen Elledge's lab, Dephoure worked with human cells, dividing them into two dishes. (The cells used are HeLa cells, which, while derived from a tumor, are used for many experiments because they thrive in culture. It's possible that some of the signaling events reported here are unique to these cells.) The first dish received nutrients with "heavy" carbon atoms—more massive than their "light" counterparts, which are abundant in nature. The second dish received normal nutrients, plus a toxic chemical to freeze the cells mid-division.

Dephoure and Zhou mixed all the cells together, killed them, chopped their constituent proteins—which were preserved—into small pieces called peptides, and fed these into a mass spectrometer. The instrument distinguished between otherwise identical peptides, based on the presence of "heavy" or "light" atoms, generating a ratio for each peptide. Dephoure paid particular attention to the ratios for peptides containing phosphate groups and uncovered major differences between the two populations of cells.

The dividing cells harbored a staggering number of regulated phosphate groups in unexpected places.

Gygi hypothesizes that the cell uses phosphorylation to break down every last protein complex before dividing. "Maybe the cell does something akin to putting Humpty Dumpty back together again at the end," he says.

"The massive number of phosphorylation changes in cell division strongly suggests that it involves a massive reorganization of the cell," adds HMS Department of Systems Biology chair Marc Kirschner, who was not involved in the study.

"Or the cell might phosphorylate everything to ensure that it hits a few key targets critical for proper division," says Dephoure. Under this scenario, extraneous phosphorylation may cloud the picture.

Armed with the team's list of proteins and phosphorylation sites, labs can conduct additional experiments to resolve this debate. They can investigate particular phosphorylation events and determine which ones contribute to successful regulation of cell division. Some may present therapeutic targets for patients with cell cycle diseases such as cancer.

"This study demonstrates how much a broad systematic approach to protein modification can facilitate experiments in the cell cycle field," says Kirschner. "We will be reaping results from this study for years ahead."

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This research is funded by the National Institutes of Health, the Spanish Ministry of Education and Science, and Howard Hughes Medical Institute.

Fred Hutchinson Cancer Research Center : A new biomarker for early cancer detection? Research reveals that 'microRNA' may fit the bill

Scientists at Fred Hutchinson Cancer Research Center have discovered that microRNAs – molecular workhorses that regulate gene expression – are released by cancer cells and circulate in the blood, which gives them the potential to become a new class of biomarkers to detect cancer at its earliest stages. Muneesh Tewari, M.D., Ph.D., and colleagues describe their findings in the July 28 issue of the Proceedings of the National Academy of Sciences.

MicroRNAs, which act as brakes on different parts of a cell, keeping genes in check, have some advantages over protein-based early-detection systems, including that they can be detected potentially in smaller quantities and that the technology exists to rapidly develop microRNA-based early-detection tests, said Tewari, an assistant member in the Hutchinson Center's Human Biology and Clinical Research divisions. His work is focused on understanding why the brakes fail – allowing unchecked cell growth – in prostate and ovarian cancer.

"Current technology for developing tests to measure microRNAs in clinical samples is quite advanced, whereas the bottleneck for developing protein-based biomarkers is the slow process of generating assays for measuring specific proteins," he said.

The next steps, now that a proof of principle has been established, are to identify specific microRNAs that can signal the presence of a variety of solid-tumor cancers at an early stage, and to further develop the technology to detect the microRNAs in minute quantities.

For the study, Tewari and colleagues tested blood from mice and humans with advanced prostate cancers, as well as that from healthy controls. They measured microRNAs made by the tumors in both cases and controls, and they could distinguish which individuals had cancer based on blood microRNA measurement.

"This research shows that microRNAs, which weren't previously thought of as markers of cancer in the blood, are a worthwhile class of molecules to study for the purpose of early cancer detection," Tewari said.

The research that led to the surprising finding of microRNAs in plasma and serum resulted from a combination of observations and a hunch, he said.

MicroRNAs play a key role in a wide range of normal cell processes, including embryonic development and cell differentiation. The tiny regulatory molecules modulate the activity of specific messenger-RNA targets, which in turn give rise to proteins. Humans have 30,000 genes that can make messenger RNAs. There are more than 500 known microRNAs encoded by the human genome and each is thought to target up to hundreds of messenger RNAs.

That microRNAs existed in humans is in itself a recent discovery. Tewari's group initially was studying their role in cancer development and maintenance because microRNAs are often dysregulated in cancer. During the course of those experiments, the scientists found that microRNAs circulate outside of cells and are remarkably stable.

"We were surprised to discover that there are microRNAs in plasma and serum that are not associated with cells and that are not being degraded by enzymes in the blood that would degrade regular RNA," Tewari said. It isn't fully known how the microRNAs are protected from degradation or how they get into the blood.

This in turn led the researchers into a new direction of determining whether cancer-associated microRNAs could be found. Earlier studies in model organisms such as worms and flies showed that some microRNAs have specific expression in certain kinds of cells and not anywhere else.

The paper details the step-by-step approach that led to discovering microRNAs in plasma and serum components of blood, that microRNAs remain stable even after incubation at room temperature for 24 hours and after eight freeze/thaw cycles, and finally that tumor-derived microRNAs enter the circulation at levels sufficient to be measured as biomarkers for cancer.

"The results presented here establish the foundation and rationale to motivate future global investigations of microRNAs as circulating cancer biomarkers for a variety of common cancers," the authors wrote.

The availability of existing, powerful tools to characterize and measure microRNAs, such as polymerase-chain reaction technology for DNA amplification, "suggests that the discovery-validation pipeline for microRNA biomarkers will be more efficient than traditional proteomic biomarker discovery-validation pipelines, which typically encounter bottlenecks at the point of antibody and quantitative assay development for validation of biomarker candidates," the authors wrote.

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In addition to those from the Hutchinson Center, scientists from the Institute for Systems Biology in Seattle, the Department of Urology at the University of Washington School of Medicine and the Department of Veterans Affairs Puget Sound Health Care System contributed to the research. The National Cancer Institute, the Pacific Ovarian Cancer Research Consortium Specialized Program of Research Excellence, the Pacific Northwest Prostate Specialized Program of Research Excellence, the Core Center of Excellence in Hematology and the Paul Allen Foundation for Medical Research funded the research.

Note to editors/reporters: Contact Dean Forbes at Fred Hutchinson Cancer Research Center to schedule interviews with Dr. Tewari and to obtain an embargoed proof copy of the paper "Circulating microRNAs as stable blood-based markers for cancer detection."

At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc.org.

Journal of Experimental Medicine Researchers tap into a new and potentially better source of platelets for transfusion

Clot-forming blood cells, or platelets, can drop to dangerously low levels in diseases such as anemia and in patients undergoing chemotherapy. To replace these critical cells, doctors filter platelets from donated blood, but this approach can increase the risk of transmitting blood infections and cause other side effects in patients who need frequent transfusions.

To get around these problems, scientists have been trying to generate platelets from embryonic stem cell lines. But stem cells also give rise to other types of cells, which tend to quickly outnumber the platelets. The Japanese group solved this problem with a simple refinement—they started with a stem cell population that was already committed to becoming platelets.

Another problem with making platelets from stem cells is that the resulting platelets often fail to form clots properly. This defect can be caused by the presence of enzymes that shear adhesive proteins from the cells' surface, preventing them from sticking to one another or to blood vessel walls. The researchers found these enzymes in their laboratory cultures and showed that blocking them restored platelet function when the cells were infused into injured mice. The scientists now plan to test whether the same approach will work in humans.

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University of North Carolina School of Medicine Study provides clues to preventing and treating cancer spread

Isn't it odd that cancer cells from one organ, such as the skin, can travel and take root in a totally different organ, like the lung?

What's more, why is it that certain cancers prefer to spread, or metastasize, to certain places? Prostate cancer usually moves to bone; colon cancer, to the liver.

To answer these questions, Dr. Hendrik van Deventer, assistant professor of medicine at the University of North Carolina at Chapel Hill and a member of the UNC Lineberger Comprehensive Cancer Center, turned to a century-old idea of cancer spread: English surgeon Stephen Paget's "seed and soil."

The idea is that the spread of cancer isn't just about the tumor itself (the seed), but also the environment where it grows (the soil). Other scientists have shown that cells from bone marrow can migrate and change the environment so that it is receptive to incoming cancer cells. These cells do so by forming small neighborhoods or niches within distant organs. Thus, biologists refer to these areas as "premetastic niches."

Van Deventer and his colleagues wanted to know what mysterious non-tumor cell could change a normal organ so cancer cells would invade. If scientists could discover the identity of that normal cell, maybe they could devise treatments to stop metastases.

In a study published in the July issue of The American Journal of Pathology, van Deventer showed for the first time that that cell could be a fibrocyte – cells that travel around the body, rushing to the site of an injury to aid in healing when needed. The study also suggests ways to develop treatments to prevent metastases using already available medications.

"This study shows it's possible for fibrocytes to form the premetastatic niche. But it stops short of proving they positively are the cells," van Deventer said.

The UNC researcher's work with fibrocytes began when he wanted to figure out why "knockout mice" that are missing the cell receptor CCR5 get fewer cancer metastases than normal mice. CCR5 helps control the migration of cells through the body. He injected these knockout mice with all types of cells from normal mice, to try to make the mice form more metastases of melanoma (skin cancer).

The only cells that did it were those that appeared to be fibrocytes.

When van Deventer injected the mice with just 60,000 of these cells, the rate of metastases nearly doubled. "That's a big effect for a relatively small number of cells," he said.

Though cancer researchers don't usually study fibrocytes, it makes sense to van Deventer that fibrocytes could form the premetastatic niche. In healthy humans, fibrocytes travel through the bloodstream to areas of injury. Once there, they produce changes that are good for wounds. Unfortunately, these same changes can help cancers grow. It is not yet clear if fibrocytes are causing these problems in cancer patients. However, "there is some clinical data that suggests that these cells are increased in patients with metastatic cancer," he said.

The experiment also showed that injection of these cells induced MMP9, an enzyme that is known to promote cancer. The researchers considered this good news, since drugs are available that block MMP enzymes and have proven beneficial in treating cancer.

Still, many basic questions remain to be answered. How do cancers promote the formation of the premetastatic niche? Do they change the behavior of these circulating cells or simply increase their number? Are some patients at higher risk for metastasis because their environment changes their fibrocytes? Is some of the benefit of our cancer treatments lost because of inadvertent changes to these cells?

"These are daunting questions, but ones that would have pleased Dr. Paget," van Deventer said. "This paper gives us a place to start looking for the answers."

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Other authors of the study, all from UNC Lineberger, are research specialist Qing Ping Wu; professional fellow Daniel T. Bergstralh, Ph.D.; research associate Beckley K. Davis, Ph.D.; postdoctoral fellow Brian P. O'Connor, Ph.D., distinguished professor of microbiology and immunology Jenny P. Y. Ting, Ph.D.; and distinguished associate professor of medicine and of microbiology and immunology, Jonathan S. Serody, M.D., Ph.D.

The study was funded by the National Cancer Institute, part of the National Institutes of Health.

Van Deventer can be reached at (919) 966-3835 or hvand@med.unc.edu.

School of Medicine contact: Leslie Lang, (919) 966-9366, llang@med.unc.edu
Lineberger Center contact: Dianne Shaw, (919) 966-7834, dgs@med.unc.edu
News Services contact: Patric Lane, (919) 962-8596, patric_lane@unc.edu

Radiological Society of North America Minimally invasive treatment improves male fertility

A minimally invasive treatment for a common cause of male infertility can significantly improve a couple's chances for pregnancy, according to a new study published in the August issue of Radiology. The study, conducted at the University of Bonn in Germany, also found that the level of sperm motility prior to treatment is a key predictor of success.

"Venous embolization, a simple treatment using a catheter through the groin, can help to improve sperm function in infertile men," said lead author Sebastian Flacke, M.D., Ph.D., now an associate professor of radiology at the Tufts University School of Medicine, director of noninvasive cardiovascular imaging and vice chair for research and development in the department of radiology at the Lahey Clinic in Burlington, Mass. "With the patients' improved sperm function, more than one-quarter of their healthy partners were able to become pregnant."

Normally, blood flows to the testicles and returns to the heart via a network of tiny veins that have a series of one-way valves to prevent the blood from flowing backward to the testicles. If the valves that regulate the blood flow from these veins become defective, blood does not properly circulate out of the testicles, causing swelling and a network of tangled blood vessels in the scrotum called a varicocele, or varicose vein.

Varicoceles are relatively common, affecting approximately 10 percent to 15 percent of the adult male population in the U.S. According to the National Institutes of Health, most cases occur in young men between the ages of 15 and 25. Many varicoceles cause no symptoms and are harmless. But sometimes a varicocele can cause pain, shrinkage or fertility problems.

The traditional treatment for problematic varicoceles has been open surgery, but recently varicocele embolization has emerged as a minimally invasive outpatient alternative. In the procedure, an interventional radiologist inserts a small catheter through a nick in the skin at the groin and uses x-ray guidance to steer it into the varicocele. A tiny platinum coil and a few milliliters of an agent to ensure the occlusion of the gonadic vein are then inserted through the catheter. Recovery time is minimal, and patients typically can return to work the next day.

Dr. Flacke and colleagues set out to identify predictors of pregnancy after embolization of varicoceles in infertile men. The study included 223 infertile men, ages 18-50, with at least one varicocele. All of the men had healthy partners with whom they were trying to achieve a pregnancy.

In the study, 226 of the patients' 228 varicoceles were successfully treated with embolization. A semen analysis performed on 173 patients three months after the procedure showed that, on average, sperm motility and sperm count had significantly improved. Six months later, 45 couples, or 26 percent, reported a pregnancy. A high level of sperm motility before the procedure was identified as the only significant pre-treatment factor associated with increasing the odds of successful post-treatment pregnancy.

"Embolization of varicoceles in infertile men may be considered a useful adjunct to in-vitro fertilization," Dr. Flacke said.

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"Embolization of Varicoceles: Pre-treatment Sperm Motility Predicts Later Pregnancy in Partners of Infertile Men." Collaborating with Dr. Flacke were Michael Schuster, M.D., Attila Kovacs, M.D., Marcus von Falkenhausen, M.D., Holger M. Strunk, M.D., Gerhard Haidl, M.D., and Hans Schild, M.D. Journal attribution requested.

Radiology is edited by Herbert Y. Kressel, M.D., Harvard Medical School, Boston, Mass., and owned and published by the Radiological Society of North America, Inc. (RSNA.org/radiologyjnl)

The Radiological Society of North America (RSNA) is an association of more than 41,000 radiologists, radiation oncologists, medical physicists and related scientists committed to excellence in patient care through education and research. (RSNA.org)

For patient-friendly information on embolization, visit RadiologyInfo.org.

Massachusetts Institute of Technology researchers offer glimpse of rare mutant cells

Imaging system may help understand origins of cancer

MIT biological engineers have developed a new imaging system that allows them to see cells that have undergone a specific mutation.

The work, which could help scientists understand how precancerous mutations arise, marks the first time researchers have been able to pinpoint the number and location of mutant cells—cells with a particular mutation—in intact tissue. In this case, the researchers worked with mouse pancreatic cells.

"Understanding where mutations come from is fundamental to understanding the origins of cancer," said Bevin Engelward, associate professor of biological engineering and member of MIT's Center for Environmental Health Sciences, and an author of a paper on the work appearing in this week's online edition of the Proceedings of the National Academy of Science.

Peter So, professor of biological and mechanical engineering, Engelward and members of their laboratories developed technologies that made it possible to detect clusters of cells that appeared to be descended from the same progenitor cell.

Unexpectedly, more than 90 percent of the cells harboring mutations were within clusters. That offers evidence that the majority of mutations are inherited from another cell, rather than arising spontaneously in individual cells.

Since the type of mutation being studied (in this case a recombination event) occurs at a rate on par with other types of mutations, "it is as if we are peering in at the very general process of mutation formation, persistence and clonal expansion," said Engelward.

"We think this raises the possibility that mutations resulting from cell division are a tremendous factor in increasing the mutagenic load," she said.

The higher the mutagenic load, the more likely it is that cancer will develop.

Engelward and So started working together several years ago after a faculty retreat for MIT's newly formed Biological Engineering Division. So was developing a new type of microscopy, known as two-photon imaging, and the researchers wondered whether it could be used to locate and image rare types of cells.

The team genetically engineered a strain of mice in which DNA would fluoresce if a mutation occurred in a particular sequence. That allowed them to use So's newly developed high-resolution, high-throughput microscopy technique to detect individual cells that carry the mutation.

"The problem drove the development of a new imaging technology, which now can be used for lots of things," said Engelward.

Lead author of the paper is Dominika Wiktor-Brown, a postdoctoral associate in biological engineering. Other authors of the paper are Hyuk-Sang Kwon, a research affiliate in the Department of Mechanical Engineering, and Yoon Sung Nam, a graduate student in biological engineering.

The work was truly a team effort between many people with very different areas of expertise, said Engelward. "The Department of Biological Engineering and the Center for Environmental Health Sciences are key in helping to bridge people across disciplines," she said.

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The research was funded by the National Institutes of Health, the Department of Energy and the Singapore-MIT Alliance.

Georgia Institute of Technology : Using Magenetic Nanoparticles to Combat Cancer

Scientists at Georgia Tech have developed a potential new treatment against cancer that attaches magnetic nanoparticles to cancer cells, allowing them to be captured and carried out of the body. The treatment, which has been tested in the laboratory and will now be looked at in survival studies, is detailed online in the Journal of the American Chemical Society.

Magnetic Nanoparticles Capture Ovarian Cancer CellsFLV = 1.77 MB

"We've been able to use magnetic nanoparticles to capture free-floating cancer cells and then take them out of the body,” said John McDonald, chair of the School of Biology at Georgia Tech and chief research scientist at the Ovarian Cancer Institute. “This technology may be of special importance in the treatment of ovarian cancer where the malignancy is typically spread by free-floating cancer cells released from the primary tumor into the abdominal cavity.” The idea came to the research team from the work of Ken Scarberry, a Ph.D. student in Tech’s School of Chemistry and Biochemistry. Scarberry originally conceived of the idea as a means of extracting viruses and virally infected cells when his advisor, Chemistry professor John Zhang, had another idea. He asked if the technology could be applied to cancer. Scarberry suggested it might be an effective means of preventing cancer cells from spreading. They began by testing the therapy on mice. After giving the cancer cells in the mice a fluorescent green tag and staining the magnetic nanoparticles red, they were able to apply a magnet and move the green cancer cells to the abdominal region. “If the therapy is able to pass further tests that show it can prevent the cancer from spreading from the original tumor,” Scarberry said, “it could be an important tool in cancer treatment.” This technology holds more promise than solely using antibodies to fight cancer because there seems to be less potential for the body to develop an immune response due to the unique peptide-targeting strategy, and the composition of the magnetic nanoparticles. "If you modify the nanoparticle and target it directly to the tumor cells using a small peptide, you are less likely to generate an undesirable immune response and more accurately target the cells of interest,” said Research Scientist Erin Dickerson. In addition to testing magnetic nanoparticles, the research team is collaborating with other groups at Georgia Tech to determine how peptide-directed gold nanoparticles and nanohydrogels might also be used in fighting cancer.

Lifespan : New research from Rhode Island Hospital may help predict outcomes for stomach cancer patients

Study identifies possible markers for cancer prognosis

Researchers at Rhode Island Hospital have identified two potential molecular markers that may predict outcomes for patients with stomach cancer, one of the most common and fatal cancers worldwide.
According to the study, published in the July 1 issue of Clinical Cancer Research, patients who had poor outcomes following surgery for stomach cancer also had extremely low amounts of two proteins, known as gastrokine 1 and 2 (GKN1 and GKN2), which are produced by normal stomach cells.
The study's findings confirm previous research showing that once stomach cells become cancerous, they manufacture very low amounts of GKN1 and GKN2. However, this is the first known study to link these low protein levels with outcomes following stomach cancer surgery. Researchers say this discovery could eventually help physicians better determine and individualize therapy for stomach cancer, including which patients should be offered chemotherapy and other treatments in addition to surgery.
"Unfortunately, stomach cancer is difficult to cure unless it's discovered early, but because the early stage of the disease has very few symptoms, the cancer is usually advanced by the time it's diagnosed," says lead author Steven Moss, MD, a gastroenterologist with Rhode Island Hospital and an associate professor of medicine at The Warren Alpert Medical School of Brown University.
"That's what makes our findings so significant, because if the potential markers identified in our study can help predict a patient's prognosis, we can decide right away which course of action to take and hopefully help patients live longer and more comfortably," he adds.
According to the National Cancer Institute, approximately 760,000 cases of stomach cancer are diagnosed worldwide each year. Microscopically, stomach cancers can be subdivided into those which appear "diffuse" (a more aggressive form of cancer that can occur throughout the stomach and is more likely to spread) or "intestinal" (resembling the cells normally found only in the small or large intestines). Stomach cancers of both types are often triggered by a chronic infection brought on by Helicobacter pylori (H. pylori), a common bacterium that causes stomach inflammation and ulcers. Surgery is the most common treatment for stomach cancer and can include partial or full removal of the stomach. The five-year relative survival rate of patients with stomach cancer is 24 percent.
Moss, an expert on H.pylori, and colleagues initially set out to learn more about what the bacterium does to normal stomach cells. They focused on GKN1 and GKN2 because these proteins are also suppressed by stomach infections caused by H. pylori.
After looking at tissue samples from more than 150 stomach cancer patients who underwent surgery, the researchers discovered a near total suppression of GKN1 and GKN2 in the majority of patients. This was particularly evident in those patients with the diffuse variant of stomach cancer. More than three-quarters of these patients had extremely low levels of GKN1 and 85 percent had nearly nonexistent levels of GKN2.
Furthermore, in those patients with the intestinal variant of stomach cancer, very low levels of GKN 1 or GKN 2 at the time of surgery were associated with a significantly worse outcome. The median survival was about two years in these patients compared to a survival of more than 10 years for patients with normal levels of GKN1 or GKN2.
Researchers do not yet know the exact function of GKN1 and GKN2. They say further studies are needed to demonstrate the mechanisms responsible for the loss of GKN1 and GKN2 in this patient popoulation as well as the clinical biomarker potential of these two proteins.
The study included tissue samples from 155 patients with stomach cancer (81 men and 74 women) who underwent surgery at Rhode Island Hospital and The Miriam Hospital, both in Providence, R.I. The average age at surgery was 72 years. All four stages of cancer were represented in the study, including 37 patients with Stage I, 44 patients with Stage II, 34 patients with Stage III, and 40 patients with Stage IV. More than 61 patients were being treated for the intestinal variant of stomach cancer while 90 patients had the diffuse variant.
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The study was funded by research grants from the National Institutes of Health.
Study co-authors were Murray Resnick, Edmond Sabo, John Gao, Patricia A. Meitner, and Rose Tavares from Rhode Island Hospital and Alpert Medical School; John Rommel and Anna Rubin from Alpert Medical School; Jin-Woo Lee from Inha University Hospital, South Korea; and Bruce R. Westley and Felicity E.B. May from the Northern Institute for Cancer Research at University of Newscastle upon Tyne, United Kingdom.
Founded in 1863, Rhode Island Hospital (www.rhodeislandhospital.org) is a private, not-for-profit hospital and is the largest teaching hospital of The Warren Alpert Medical School of Brown University. A major trauma center for southeastern New England, the hospital is dedicated to being on the cutting edge of medicine and research. Rhode Island Hospital ranks among the country's leading independent hospitals that receive funding from the National Institutes of Health, with research awards of nearly $27 million annually. Many of its physicians are recognized as leaders in their respective fields of cancer, cardiology, diabetes, orthopedics, neurology and minimally invasive surgery. The hospital's pediatrics division, Hasbro Children's Hospital, has pioneered numerous procedures and is at the forefront of fetal surgery, orthopedics and pediatric neurosurgery. Rhode Island Hospital is a founding member of the Lifespan health system.

Weizmann Institute of Science In two complementary studies,

Weizmann Institute scientists have developed a new method for reconstructing a cell’s 'family tree,' and have applied this technique to trace the history of the development of cancer. So far, the scientists have been able to calculate the age of the tumor and characterize its growth pattern. The scientists believe cell lineage studies of cancer can eventually lead us to the root of cancer.

Weizmann Institute Scientists’ New Technique Gets to the Root of Cancer
In two complementary studies, Weizmann Institute scientists have developed a new method for reconstructing a cell’s 'family tree,' and have applied this technique to trace the history of the development of cancer.
The quest to understand a cell’s path of descent, called a cell lineage tree, is shared by many branches of biology and medicine as gleaning such knowledge is key to answering many fundamental questions, such as whether neurons in our brain can regenerate, or whether new eggs are created in adult females.
So far, only tree lineages of tiny organisms, such as worms, which possess only a thousand cells, or 'branches,' have been determined. Now, Prof. Ehud Shapiro of the Institute’s Biological Chemistry, and Computer Science and Applied Mathematics Departments, together with Doctoral students Dan Frumkin and Adam Wasserstrom have developed a novel way to reconstruct, in principle, trees for larger organisms, including humans. The human body is made of about 100 trillion cells, all of which are descendants of a single cell – the fertilized egg (zygote). Cells that have undergone a small number of cell divisions are relatively close descendants (akin to branches representing children and grandchildren etc., on a family tree), while some cells may have undergone hundreds or even thousands of divisions ('distant cell generations'). Knowing the number of cell divisions since the zygote, known as the depth of cells, would enable scientists to address questions about the behavior of the body under physiological and pathological conditions.
Until now, estimates of cell depth were based on theoretical calculations and assumptions, but Shapiro provides a practical way of determining cell depth precisely. The concept behind their new method is simple: Previous research indicated that each time a cell divides, harmless mutations are introduced, and that 'cell relatives' of distant generations tend to acquire more mutations, drifting away from the original DNA sequence of the zygote. Inspired by this, the team developed a non-invasive, accurate and systematic way, involving DNA amplification and computer simulations, to quantitatively estimate cell depth on the basis of the number of mutations in microsatellites (repetitive DNA sequences), and has applied it to several cell lineages in mice.
According to the team’s estimates, as reported in PLoS Computational Biology, the average depth of B cells – a type of immune cell – is related to mouse age, suggesting a rate of one cell division per day. In contrast, various types of adult stem cells underwent fewer divisions, supporting the notion that they are relatively quiescent.
Shapiro and Frumkin, in collaboration with Prof. Gideon Rechavi from the Sheba Medical Center and others then decided to apply this method to reconstruct, for the first time, the family tree of a cancer cell. 'Despite several decades of scientific research, basic properties of the growth and spread of tumor cells remain controversial. This is surprising, since cancer is primarily a disturbance of cell growth and survival, and an aberrant growth pattern is perhaps the only property that is shared by all cancers. However, because the initiation and much of the subsequent development of tumors occurs prior to diagnosis, studying the growth and spread of tumors seems to require retrospective techniques and these have not been forthcoming,' explains Shapiro.
Therefore, by reconstructing a cancer cell lineage tree and performing an analysis of mutations accumulated in the cells, scientists would be able to trace back and reveal several aspects of the tumor’s developmental history. Shapiro: 'We intend to apply this method to study key questions in human cancers, including when and where does a tumor initiate? The progression from pre-malignant to malignant states. At what stage does metastasis occur? Can the depth of tumor cells serve as a prognostic marker for cancer severity? And does chemotherapy target a subset of cells characterized by distinct lineage features (e.g. greater depth)?'
So far, their findings, featuring on the cover of the July 15th issue of Cancer Research, show that cancer cells (extracted from tissue sections of a mouse lymphoma by laser micro-dissection) had almost double the number of branched generations (i.e., had divided almost twice as many times) compared to adjacent normal lung cells in the same amount of time. They were also able to calculate the age of the tumor and characterize its growth pattern. Further analysis was sufficient to corroborate the long-standing hypothesis on the single-cell origin of cancer.
The scientists believe cell lineage studies of cancer can greatly enhance our understanding of, and eventually lead us to the root of cancer.
Prof. Ehud Shapiro's research is supported by the Clore Center for Biological Physics; the Arie and Ida Crown Memorial Charitable Fund; the Cymerman - Jakubskind Prize; the Fusfeld Research Fund; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; the Henry Gutwirth Fund for Research; Ms. Sally Leafman Appelbaum, Scottsdale, AZ; the Carolito Stiftung, Switzerland; the Louis Chor Memorial Trust Fund; and the estate of Fannie Sherr, New York, NY.Prof. Shapiro is the incumbent of the Harry Weinrebe Chair of Computer Science and Biology
The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
Weizmann Institute news releases are posted on the World Wide Web at http://wis-wander.weizmann.ac.il, and are also available at http://www.eurekalert.org.

American Association for Cancer Researchers discover link between organ transplantation and increased cancer risk

Researchers have determined a novel mechanism through which organ transplantation often leads to cancer, and their findings suggest that targeted therapies may reduce or prevent that risk.
In the July 15, 2008, issue of Cancer Research, researchers at Harvard Medical School found in animal and laboratory experiments that the anti-rejection, immunosuppressive drug cyclosporine ramps up expression of vascular endothelial growth factor (VEGF), which signals the growth of new blood vessels that can feed tumors.
They also found that simultaneously administering an anti-VEGF therapy with cyclosporine in mice repressed this tumor growth. Several inhibitors of VEGF are already in use in human cancer therapy.
The findings could offer some good news for the 15 to 20 percent of transplant patients who develop cancer within a decade of receiving new organs, according to the study's senior investigator, Soumitro Pal, Ph.D., an assistant professor at Harvard Medical School's Transplantation Research Center at Children's Hospital in Boston.
"It may be that anti-VEGF agents given judiciously after transplantation can reduce future cancer occurrence," he said.
VEGF expression is markedly increased in patients post-transplantation, and this can aid in the development of a blood supply to a transplanted organ, helping it survive and thrive. "But once the organ has stabilized, it may be possible to lower the level of VEGF expression to prevent tumor growth," he said. "We would need to figure out how to balance benefit and risk to keep cancer at bay."
Tumors that develop after transplantation may have three potential sources: they may have pre-existed or could have been a recurrence of previous cancer – and in both of these cases, a patient's pre-transplant immune system might have kept these cancers in check – or cancer-causing viruses could have come from the donor organ. Physicians have long observed that immunosuppressive agents, such as the class of calcineurin inhibitors that includes cyclosporine, appear to promote cancer development, often in organs that are not transplanted, but the cause of this was unclear. The Harvard team tested the ability of cyclosporine to promote growth of pre-existing tumors in mice implanted with human renal (kidney) cancer cells. Mice treated with the agent formed tumors faster than untreated mice, but anti-VEGF therapy substantially reduced that excessive growth.
Digging deeper into the biological pathway of VEGF activation, the scientists found that cyclosporine activates two of the three forms of the common protein catalyst, protein kinase C, which leads to increased expression of VEGF.
"We think PKC-mediated VEGF transcriptional activation is a key component in the progression of cyclosporine-induced post-transplantation cancer," Pal said. "It is likely not the whole story, but this gives us a clue that we might be able to use existing or novel therapies to reduce cancer risk in transplanted patients."
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The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and 80 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication and its sixth major journal, Cancer Prevention Research, is dedicated exclusively to cancer prevention, from preclinical research to clinical trials. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.

Cedars-Sinai Medical Center Brain cancer study: Magnitude of post-vaccine immune response linked to clinical outcomes

Stronger immune response correlates with longer survival, giving researchers a new tool for evaluating effectiveness of experimental therapies

LOS ANGELES (STRICTLY EMBARGOED UNTIL JULY 15, 2008 AT 12:01 A.M. EDT) – Researchers conducting a clinical trial of a dendritic cell vaccine designed to fight malignant brain tumors called glioblastoma multiforme (GBM) have found a correlation between the "intensity" of a patient's immune response and clinical outcome, according to an article in the July 15 issue of the journal Cancer Research.

While other studies have suggested a link, this is believed to be the first to show direct and continual proportionality between the strength of anti-tumor responses and clinical benefits in cancer patients. This also may be the first documentation of a definite immune response/patient outcome correlation that can be credited to tumor-altering therapeutic interventions.

"Fifty-three percent of patients in our study exhibited a significant vaccine-enhanced immune response. Compared to non-responders or those with limited responses, the vaccine responders had significantly longer times to tumor progression and longer survival," said Keith L. Black, M.D., chairman of Cedars-Sinai's Department of Neurosurgery and director of the Maxine Dunitz Neurosurgical Institute. Black is one of the article's authors.

The study also substantiates a finding previously reported by the researchers: Dendritic cell vaccination and chemotherapy work synergistically to improve treatment. Time to tumor progression increased significantly when vaccination was followed by chemotherapy, compared to vaccination alone.

"No other vaccine trial in cancer patients has shown the kind of progressive correlation between immune responses and clinical outcomes that we found," said Christopher J. Wheeler, Ph.D., research scientist at the MDNSI and the article's first and corresponding author. "We looked at whether the correlation was present after vaccination alone or after post-vaccine chemotherapy. It was evident only after post-vaccine chemotherapy. This leads us to believe that while T-cell activity may not result in net destruction of the tumor it is fundamentally changing the tumor into one that is predominantly comprised of chemosensitive cells rather than chemoresistant cells."

The findings also appear to give scientists a way to more quickly evaluate future vaccine-related research.

"The demonstration that the magnitude of immune response is directly related to survival of patients gives us a very good tool or 'surrogate marker' for clinical benefit. If we can improve the immune response of our vaccine, we can anticipate that the clinical benefit will be improved as well. This allows us to fine-tune our vaccine in more of a real-time way," said John S. Yu, M.D., director of Surgical Neuro-oncology at Cedars-Sinai, principal investigator of the clinical trial and senior author of the article.

This study centered on the immune responses of 32 patients enrolled in a Phase II clinical trial. Seventeen patients had a significant positive response after three vaccinations; 15 showed no such responsiveness. Average time to tumor progression (based on when tumor volume increased by about 25 percent on MRI scans) was about 308 days among responders, compared to 167 days for non-responders. Average length of survival (based on date of death or date of last contact with surviving patients) was about 642 days (about 21 months) among responders, compared to 430 days (about 14 months) for non-responders.

Forty-one percent of vaccine responders, compared to seven percent of non-responders, survived at least two years. All patients in the trial had longer time to progression and longer time of survival, on average, than patients undergoing standard treatment without vaccination, although their pre-vaccine disease courses were similar.

The vaccine was first used experimentally in patient treatment in May 1998, and numerous studies have been conducted to fine-tune the therapy and combine it with other cancer-killing treatments.

Upon founding the Maxine Dunitz Neurosurgical Institute in 1997, Black led the development of the dendritic cell vaccine because gliomas and other cancer cells are not readily detected or attacked by the immune system. Dendritic cells are the immune system's most powerful antigen-presenting cells – those responsible for helping the immune system recognize invaders.

When a tumor is surgically removed, proteins are collected, cultured and introduced in a Petri dish to dendritic cells taken from the patient's blood. The new, "educated" dendritic cells are then injected into the patient where they are intended to recognize and destroy lingering tumor cells. Patients receive three vaccinations at two-week intervals. A fourth vaccination is given six weeks after the third.

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Certain rights in the dendritic cell vaccine technology and corresponding intellectual property have been exclusively licensed by Cedars-Sinai to ImmunoCellular Therapeutics, Inc., including subsequently-developed versions of the vaccine investigated in this clinical study. Yu is chairman of the board of IMUC and Black maintains an ownership interest in the company.

Citation: Cancer Research, "Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients," July 15, 2008.

University of Texas M. D. Anderson Cancer Center : TG2 identified as potential therapeutic target in chemo-resistant ovarian cancer

M. D. Anderson team silences protein with siRNA, implicates TG2 in fourth cancer

HOUSTON, TX – Scientists from The University of Texas M. D. Anderson Cancer Center have found overexpression of tissue type transglutaminase (TG2) in ovarian cancer is associated with increased tumor cell growth and adhesion, resistance to chemotherapy and lower overall survival rates. When researchers targeted and silenced TG2 in animal models, cancer progression was reversed, suggesting the protein may also provide a novel therapeutic approach for late-stage ovarian cancer.

These findings in the July 15th issue of Cancer Research by a team of researchers led by Anil K. Sood, M.D., professor in the Departments of Gynecologic Oncology and Cancer Biology, and Kapil Mehta, Ph.D., professor in the Department of Experimental Therapeutics at M. D. Anderson, are among the first to explore TG2's functionality in ovarian cancer.

"TG2 appears to fuel different types of cancer through multiple molecular pathways, making it an important therapeutic target," said Mehta, whose lab also has connected TG2 overexpression to drug-resistant and metastatic melanoma, breast cancer and pancreatic cancer.

"Drug resistance and metastasis are major impediments to the successful treatment of ovarian cancer and until now we had little information about the role TG2 played in ovarian cancer," Sood said. "We began to see its story unfold as we translated this data from tissue samples to cell lines to animal models."

The American Cancer Society estimates 15,000 U.S. women will die from ovarian cancer this year. Most patients present with advanced stage disease that has spread beyond the primary tumor site. More than 70 percent of ovarian cancer patients will suffer a recurrence and eventually succumb to the disease.

Higher TG2, lower survival

The study, which examined 93 ovarian cancer samples of ranging stages, found that high levels of TG2 corresponded with significantly lower patient survival than those with low levels of TG2. Sixty-nine percent of high-stage ovarian cancers overexpressed TG2 compared with 30 percent of low-stage cancers. In-depth analysis demonstrated that tumors which overexpressed the protein tended to have an increased ability to invade healthy tissue and to survive or avoid the affects of chemotherapy.

"From this investigation it became clear that TG2 activates the survival pathway p13K/Akt in these tumors, explaining the adverse, resistant behavior we observed on a molecular level," said Sood. "We then focused on whether silencing TG2 would block these effects."

Researchers shut off TG2 with a small interfering RNA strand (TG2 siRNA) targeted to the protein, reducing the ability of the tumor cells to invade and killing them through programmed cell death, or apoptosis. "When exposed to this potent targeted therapy, ovarian cancer cells greatly reduced cancer cell proliferation and blood vessel development, while increasing apoptosis," said Sood.

Mouse model studies of chemotherapy-sensitive and chemotherapy-resistant models showed considerable antitumor activity both with TG2 siRNA alone and in combination with docetaxel chemotherapy. The combination therapy of TG2 siRNA with docetaxel reduced tumor weight by 86 percent, proving to have the greatest efficacy compared to control groups or those without chemotherapy.

"While it remains to be seen if these results will translate in humans, looking ahead long term, it will be an attractive option against advanced ovarian cancer," said co-author Gabriel Lopez-Berestein, M.D. professor in the Department of Experimental Therapeutics at M. D. Anderson.

TG2 fuels pancreatic cancer differently

Sood and Lopez-Berestein, have developed siRNA therapy by packaging the gene-silencing strips of RNA in a fatty nanoparticle called a liposome and delivering it intravenously. TG2 is the third protein they have targeted in preclinical research. Sood and Mehta are moving TG2 siRNA toward Phase I clinical trials for ovarian and pancreatic cancers.

TG2 acts through different pathways in other types of cancer, Mehta noted. For example, TG2 overexpression causes the degradation of the tumor-suppressing protein PTEN in pancreatic cancer, Mehta and colleagues reported in Clinical Cancer Research in April. With PTEN out of the picture, pancreatic cancer is protected from a separate type of cell death called autophagy. In a separate paper, they showed that silencing TG2 with the siRNA liposome reduced tumor size, slowed metastasis and enhanced the effect of gemcitabine chemotherapy.

"This aberrant protein is doing so many different things, you would have to develop a small-molecule drug to block each function," Mehta said. "Liposomal siRNA is exciting because it takes out TG2 completely, blocking everything that it does."

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Research was funded by grants from the National Cancer Institute, including M. D. Anderson's Specialized Program in Research Excellence in Ovarian Cancer grant, a program project development grant from the Ovarian Cancer Research Fund, Inc., and the Zarrow Foundation.

In addition to Sood, Mehta and Lopez-Berestein, authors include Jee Young Hwang, M.D., Lingegowda S. Mangala, Ph.D., co-first authors, and Yvonne G. Lin, M.D., William M. Merritt, M.D., Whitney A. Spannuth, M.D., Alpa M. Nick, M.D., Derek J. Fiterman, M.D., and Robert L. Coleman, M.D., all of M. D. Anderson's Department of Gynecologic Oncology; Jansina Y. Fok, also a co-first author, and Pablo E. Vivas-Mejia, Ph.D., both of the Department of Experimental Therapeutics; and Michael T. Deavers, M.D., of M. D. Anderson's Department of Pathology. Hwang is also with the Department of Obstetrics and Gynecology, Dongguk University of College of Medicine, Kyung-ju, Korea.

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 39 Comprehensive Cancer Centers designated by the National Cancer Institute. For five of the past eight years, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News and World Report.