Embryonic stem cells used to grow cartilage

Rice method is first to yield cartilage-like cells, engineer human cartilage

HOUSTON, Sept. 6, 2007 – Rice University biomedical engineers have developed a new technique for growing cartilage from human embryonic stem cells, a method that could be used to grow replacement cartilage for the surgical repair of knee, jaw, hip, and other joints.

“Because native cartilage is unable to heal itself, researchers have long looked for ways to grow replacement cartilage in the lab that could be used to surgically repair injuries,” said lead researcher Kyriacos A. Athanasiou, the Karl F. Hasselmann Professor of Bioengineering. “This research offers a novel approach for producing cartilage-like cells from embryonic stem cells, and it also presents the first method to use such cells to engineer cartilage tissue with significant functional properties.”

The results are available online and slated to appear in the September issue of the journal Stem Cells. The study involved cells from an NIH-sanctioned stem cell line.

Using a series of stimuli, the researchers developed a method of converting the stem cells into cartilage cells. Building upon this work, the researchers then developed a process for using the cartilage cells to make cartilage tissue. The results show that cartilages can be generated that mimic the different types of cartilage found in the human body, such as hyaline articular cartilage — the type of cartilage found in all joints — and fibrocartilage — a type found in the knee meniscus and the jaw joint. Athanasiou said the results are exciting, as they suggest that similar methods may be used to convert the stem cell-derived cartilage cells into robust cartilage sections that can be of clinical usefulness.

Tissue engineers, like those in Athanasiou’s research group, are attempting to unlock the secrets of the human body’s regenerative system to find new ways of growing replacement tissues like muscle, skin, bone and cartilage. Athanasiou’s Musculoskeletal Bioengineering Laboratory at Rice University specializes in growing cartilage tissues.

The idea behind using stem cells for tissue engineering is that these primordial cells have the ability to become more than one type of cell. In all people, there are many types of “adult” stem cells at work. Adult stem cells can replace the blood, bone, skin and other tissues in the body. Stem cells become specific cells based upon a complex series of chemical and biomechanical cues, signals that scientists are just now starting to understand.

Unlike adult stem cells, which can become only a limited number of cell types, embryonic stem cells can theoretically become any type of cell in the human body.

Athanasiou’s group has been one of the most successful in the world at studying cartilage cells and, especially, engineering cartilage tissues. He said that for his research the primary advantage that embryonic stem cells have over adult stem cells is their ability to remain malleable.

“Identifying a readily available cell source has been a major obstacle in cartilage engineering,” Athanasiou said. “We know how to convert adult stem cells into cartilage-like cells. The more problematic issue comes in trying to maintain a ready stock of adult stem cells to work with. These cells have a strong tendency to convert from stem cells into a more specific type of cell, so the clock is always ticking when we work with them.”

By contrast, Athanasiou said his research group has found it easier to grow and maintain a stock of embryonic stem cells. Nonetheless, he is quick to point out that there is no clear choice about which type of stem cell works best for cartilage engineering.

“We don’t know the answer to that,” Athanasiou said. “It’s extremely important that we study all potential cell candidates, and then compare and contrast those studies to find out which works best and under what conditions. Keep in mind that these processes are very complicated, so it may well be that different types of cells work best in different situations.”

Athanasiou began studying embryonic stem cells in 2005. Since funding for the program was limited, he asked two new graduate students in his group if they were interested in pursuing the work as a secondary project to their primary research. Those students, Eugene Koay and Gwen Hoben, are co-authors of the newly published study. Both are enrolled in the Baylor College of Medicine Medical Scientist Training Program, a joint program that allows students to concurrently earn their medical degree from Baylor while undertaking Ph.D. studies at Rice.

“Eugene and Gwen are both outstanding students,” Athanasiou said. “Each earned their undergraduate degree from Rice and each worked in my laboratory as undergraduate students. They have chosen to do this research because they think this may represent the future of regenerative medicine.”

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The research was funded by Rice University.

Contact: Jade Boyd
jadeboyd@rice.edu
713-348-6778
Rice University

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Nicotine in breast milk disrupts infants’ sleep patterns

Smoking shortens nap time of breastfed babies
PHILADELPHIA (September 4, 2007) – – A study from the Monell Chemical Senses Center reports that nicotine in the breast milk of lactating mothers who smoke cigarettes disrupts their infants’ sleep patterns.

“Infants spent less time sleeping overall and woke up from naps sooner when their mothers smoked prior to breastfeeding,” says lead author Julie A. Mennella, PhD, a psychobiologist at Monell.

The findings, published in the journal Pediatrics, raise new questions regarding whether nicotine exposure through breast milk affects infant development.

While many women quit or cut down on smoking while pregnant, they often relapse following the birth of the baby. Mennella comments, “Because nicotine is not contraindicated during lactation, mothers may believe that smoking while breastfeeding will not harm their child as long as the child is not exposed to passive smoke. However, there has been very little research on either short- or long-term effects of nicotine delivered through breast milk.”

Nicotine is a pharmacological stimulant that affects the developing brain and has been shown to cause long-term behavioral and learning deficits.

In the Monell study, researchers measured the feeding behavior and sleep patterns of 15 breastfed infants over a 3-1/2 hour observation period on two separate days. The infants were between two and seven months of age. All mothers were current smokers who abstained from smoking for at least 12 hours before each observation period.

Each mother smoked one to three cigarettes immediately prior to the observation period on one day and refrained from smoking on the other. On both occasions, mothers breastfed their infants on demand over the ensuing 3-1/2 hours. Following each feed, mothers laid infants down on their backs in a crib or on the floor.

An actigraph strapped to the infant’s ankle enabled researchers to measure activity and sleep time. Levels of nicotine and cotinine, a major metabolite of nicotine, were measured in breast milk samples provided by the mothers before each feed, allowing researchers to determine the dose of nicotine passed to each infant.

Total sleep time over the 3-1/2 hours declined from an average of 84 minutes when mothers refrained from smoking to 53 minutes on the day they did smoke, a 37% reduction in infant sleep time. This was due to a shortening of the longest sleep bout, or nap, and to reductions in the amount of time spent in both active and quiet sleep.

The level of sleep disruption was directly related to the dose of nicotine infants received from their mothers’ milk, consistent with a role for nicotine in causing the sleep disruptions.

Infants consumed the same amount of breast milk on both days, suggesting that they were accepting of tobacco flavor in breast milk. Previous research from Mennella’s laboratory has shown that infants demonstrate increased enjoyment of flavors experienced through transmission in breast milk.

Noting that children whose mothers smoke are more likely to smoke as teenagers, Mennella speculates that early experiences with tobacco flavor during breastfeeding may increase its appeal later in life.

She comments that additional studies are needed to examine the long-term developmental effects of nicotine delivered through breast milk.

An earlier study from Mennella’s lab demonstrated that breast milk nicotine levels peak 30 – 60 minutes after smoking one or two cigarettes and clear by three hours after the smoking episode. Emphasizing the many benefits of breastfeeding on infant health and development, Mennella notes that lactating mothers who smoke occasionally can time their smoking episodes to minimize nicotine exposure to their child.

The present findings highlight the need for targeted smoking cessation programs that address issues relevant to lactating women. Mennella suggests that concerns about tobacco flavor in their milk and disruptions of their infants’ sleep may help motivate breastfeeding mothers to abstain from smoking.

Lauren M. Yourshaw and Lindsay K. Morgan also contributed to the study.

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The Monell Chemical Senses Center is a nonprofit basic research institute based in Philadelphia, Pennsylvania. For 39 years, Monell has been the nation’s leading research center focused on understanding the senses of smell, taste and chemical irritation: how they function and affect lives from before birth through old age. Using a multidisciplinary approach, scientists collaborate in the areas of: sensation and perception, neuroscience and molecular biology, environmental and occupational health, nutrition and appetite, health and well being, and chemical ecology and communication. For more information about Monell, visit http://www.monell.org.

FUNDING: National Institute on Alcohol Abuse and Alcoholism (NIH) and the Pennsylvania Department of Health. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.

Contact: Leslie Stein
stein@monell.org
267-519-4707
Monell Chemical Senses Center

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New study highlights link between unemployment and hospital trauma admissions

Press Releases

Heidelberg, 8 August 2007

Unemployment cuts

Socioeconomic status, and unemployment rates in particular, predict both the type of trauma seen in emergency rooms and the population groups more likely to be victims of trauma, according to Atul Madan (1) from the University of Tennessee Health Science Center and his team. Their findings have just been published online in Springer’s World Journal of Surgery.

The researchers looked at the link between unemployment rates and the types of trauma admissions in New Orleans over six years. Unemployment rates were obtained from the Bureau of Labor Statistics. The trauma registry of the Medical Center of Louisiana at New Orleans (Charity Hospital) provided data on the trauma emergency room admissions, including patient demographics.

Between January 1994 and November 1999, there were over 24,000 trauma admissions. During that period, the higher the unemployment rate, the higher the number of admissions for penetrating trauma – injuries that occur primarily by an object piercing the skin or entering a tissue of the body, such as bullets and knives.

The lower the unemployment rates, the higher the number of admissions for blunt trauma – physical trauma caused to a body part, either by impact, injury of physical attack which can result in contusions, abrasions, lacerations and bone fractures. In this instance, the majority of blunt trauma was the result of motor vehicle collisions. The authors suggest that a possible explanation for this surprising finding could be the fact that with higher incomes, more travel is likely, which in turn increases the likelihood of motor vehicle collisions. Alternatively, more tourism to the area may have reduced unemployment but caused more road accidents.

The study also shows that as the socioeconomic status, measured here by unemployment rates, of the community changes, so do the demographics and mortality rates of the trauma population. There were more male patients, African American patients and deaths at times of high unemployment. These results suggest that during times of economic hardship, certain population groups are at higher risk of life-threatening injuries.

The authors recommend that “injury prevention efforts targeted at economically disadvantaged populations and high-risk groups should be stressed when designing community trauma outreach programs, especially during times of economic hardships.”

Reference
(1) Madan A et al (2007). Unemployment rates and trauma admissions. World Journal of Surgery (DOI 10.1007/s00268-007-9190-4)

Contact:
Renate Bayaz
tel +49-6221-487-8531

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A pioneering study opens roads for tailor-made antidepressants

In spite that the causes of depression have not still been fully identified, scientists acknowledge that genetic and environmental factors play a common role in the onset of this disorder. One of the environmental risk factors more often related to depression is exposure to threatening life events. On the other side, from a genetic point of view, the serotonin transporter gene, with a crucial role in communication between neurons, could predispose to depression.

An international group of scientists, headed by professors Jorge Cervilla Ballesteros and Blanca Gutiérrez Martínez, from the department of Legal Medicine, Toxicology and Psychiatry of the University of Granada, has recently published in the prestigious journal Molecular Psychiatry the pioneering study PREDICT-gene, confirming the relation between allele s in the serotonin transporter gene and exposure to threatening life events in the onset of depression. The study proves, for a population sample accounting for gender, age and family history of psychiatric disorders, that 24% of the Spanish population, comprising people with the s/s genotype, need minimal exposure to threatening life events, unlike individuals with s/l or l/l genotypes, thus confirming the relation between genetic and environmental factors in this mental disorder.

Tailor-made antidepressants

The most important consequence of research on interaction between genetic and environmental factors is that, in a foreseeable future, scientists will be able to produce measures to predict response to antidepressants taking into account each individual’s genotype, i. e. they will be able to design tailor-made drugs according to each person’s genetic configuration and their exposure to environmental factors.

The research group headed by professor Cervilla Ballesteros and Gutiérrez Martínez is currently working at the University of Granada to open roads for psycho-pharmaco-genetics, a field that will allow for individual treatments, tailor-made drugs, for each patient with depression, a disorder affecting one in every five Spaniards visiting the doctor’s.

This study is framed in the international project PREDICT and is funded by the European Union and the Spanish Ministry of Education and Science. One of its most important novelties is that it has been carried out through a very representative sample: a total of 737 people agreed to participate in the genetic tests, with ages ranging from 18 to 75, patients of nine primary care centres in the South of Spain. That is why this is the first representative population-based replication of earlier research, as until now research had been done into restricted population samples, comprising only women, adolescents, twins or people with affective disorders.

Contact: Professor Jorge Cervilla Ballesteros
jacb@ugr.es
34-663-075-835
Universidad de Granada

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Multicenter study nets new lung tumor-suppressor gene

BOSTON–Collaborating scientists in Boston and North Carolina have found that a particular gene can block key steps of the lung cancer process in mice. The researchers report in the journal Nature that LKB1 is not only a “tumor-suppressor” gene for non-small cell lung cancer in mice, it also may be more powerful than other, better-known suppressors. The study will be published on the journal’s Web site on Aug. 5 and later in a print version.

If further research shows LKB1 has a similar effect in human lung cells, it could influence the way non-small cell lung cancer is diagnosed and treated, says the study’s senior author, Kwok-Kin Wong, MD, PhD, of Dana-Farber, one of three institutions, along with Massachusetts General Hospital and the University of North Carolina School of Medicine, leading the work. If tumors with LKB1 mutations are found to be especially fast-growing, for example, patients with such tumors might be candidates for more aggressive therapy.

People born with defective versions of LKB1 often develop Peutz-Jeghers syndrome, which is marked by intestinal growths and an increased risk for certain cancers. Non-inherited mutations of the gene have been found in some lung cancers. This suggested that LKB1 normally thwarts tumors from forming. Mutated versions may be unable to act as a brake on cancer.

To find out, the investigators ran a series of experiments in mice with a defective form of a gene called Kras, which drives the formation and growth of lung cancer. They tracked the development of lung cancer in animals with mutated LKB1 and compared it to the experience of animals with abnormalities in either of two well-known tumor-suppressor genes.

They found that while Kras “cooperated” with the mutated tumor-suppressor genes to produce lung cancer, it cooperated even more strongly with mutated LKB1. “The LKB1-deficient tumors grew more rapidly and spread more frequently than the others, and comprised all three types of non-small cell lung cancer — squamous cell carcinoma, large-cell carcinoma, and adenocarcinoma — rather than just one or two,” Wong says. “This suggests that LKB1 plays a role at major stages of the tumors’ development: initiation, differentiation of normal lung cells into cancer cells, and metastasis.”

An examination of human non-small-cell lung tissue suggests LKB1 mutations play a role there as well. Of 144 samples analyzed, 34 percent of the lung adenocarcinomas and 19 percent of the squamous cell carcinomas contained abnormal versions of the gene, researchers report.

“We were surprised at how significant a role LKB1 mutations play in non-small cell lung cancer development in mice,” say Wong, who is also an assistant professor of medicine at Harvard Medical School. “This suggests there may be additional lung tumor-suppressor genes yet to be discovered. We’re currently examining whether these results apply to human lung cancers as well and, if so, how such information can improve treatment.”

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The lead author of the study was Hongbin Ji, PhD, of Dana-Farber. Other Dana-Farber co-authors include Dongpo Cai, PhD, Liang Chen, PhD, Pasi Janne, MD, PhD, Bruce Johnson, MD, Jussi Koivunen, MD, PhD, Danan Li, Mei-Chih Liang, PhD, Kate McNamara, Matthew Meyerson, MD, PhD, Samanthi Perera, PhD, Geoffrey Shapiro, MD, PhD, and Takeshi Shimamura, PhD. Other authors were based at Children’s Hospital Boston, Brigham and Women’s Hospital, Broad Institute of Harvard University and Massachusetts Institute of Technology, University of Tennessee Health Science Center, and the University of Texas Southwestern Medical Center.

The research was supported by the National Institutes of Health, the Sidney Kimmel Foundation for Cancer Research, the American Federation of Aging, the Joan Scarangello Foundation to Conquer Lung Cancer, the Flight Attendant Medical Research Institute, the Waxman Foundation, the Harvard Stem Cell Institute, and the Linda Verville Foundation.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute

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European heat waves double in length since 1880

The most accurate measures of European daily temperatures ever indicate that the length of heat waves on the continent has doubled and the frequency of extremely hot days has nearly tripled in the past century. The new data shows that many previous assessments of daily summer temperature change underestimated heat wave events in western Europe by approximately 30 percent.

Paul Della-Marta and a team of researchers at the University of Bern in Switzerland compiled evidence from 54 high-quality recording locations from Sweden to Croatia and report that heat waves last an average of 3 days now—with some lasting up to 4.5 days—compared to an average of around 1.5 days in 1880. The results are published 3 August in the Journal of Geophysical Research-Atmospheres, a publication of the American Geophysical Union. The researchers suggest that their conclusions contribute to growing evidence that western Europe’s climate has become more extreme and confirm a previously hypothesized increase in the variance of daily summer temperatures since the 19th century.

The study adds evidence that heat waves, such as the devastating 2003 event in western Europe, are a likely sign of global warming; one that perhaps began as early as the 1950s, when their study showed some of the highest trends in summer mean temperature and summer temperature variance.

“These results add more evidence to the belief among climate scientists that western Europe will experience some of the highest environmental and social impacts of climate change and continue to experience devastating hot summers like the summer of 2003 more frequently in the future,” Della-Marta said.

The authors note that temperature records were likely overestimated in the past, when thermometers were not kept in modern Stevenson screens, which are instrument shelters used to protect temperature sensors from outside influences that could alter its readings. The researchers corrected for this warm bias and other biases in the variability of daily summer temperatures and show that nearly 40 percent of the changes in the frequency of hot days are likely to be caused by increases in summer temperatures’ variability. This finding demonstrates that even a small change in the variance of daily summer temperatures can radically enhance the number of extremely hot days.

“These findings provide observational support to climate modeling studies showing that European summer temperatures are particularly sensitive to global warming,” Della-Marta said. “Due to complex reactions between the summer atmosphere and the land, the variability of summer temperatures is expected to [continue to] increase substantially by 2100.”

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The research was supported by the European Environment and Sustainable Development Program, the Swiss National Science Foundation and the National Center for Excellence in Climate Research (NCCR Climate).

Contact: Jonathan Lifland
jlifland@agu.org
202-777-7535
American Geophysical Union

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Identifying the mechanism behind a genetic susceptibility to type 2 diabetes

Type 2 diabetes is reaching epidemic proportions in the developed world. Determining if and how certain genes predispose individuals to type 2 diabetes is likely to lead to the development of new treatment strategies for individuals with the disease.

In a study appearing in the August issue of the Journal of Clinical Investigation Valeriya Lyssenko and colleagues from Lund University in Sweden show that certain variants of the gene TCF7L2 make individuals more susceptible to type 2 diabetes. The susceptibility variants were associated with increased expression of TCF7L2 in pancreatic islet cells and decreased islet cell secretion of insulin. Consistent with this, ectopic overexpression of TCF7L2 in human islet cells decreased insulin secretion in response to exposure to glucose. This study identifies TCF7L2 type 2 diabetes susceptibility variants and provides a mechanism by which these genetic variants might cause susceptibility to the disease. As discussed by the authors and in the accompanying commentary by Andrew Hattersley from Peninsula Medical School in the United Kingdom, future studies are likely to investigate the potential for manipulating the signaling pathways controlled by TCF7L2 for the development of new therapeutics for type 2 diabetes.

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TITLE: Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes

AUTHOR CONTACT:
Valeriya Lyssenko
Lund University, University Hospital Malma, Malma, Sweden.
Phone: 46-40-391214; Fax: 46-40-391222; E-mail: Valeri.Lyssenko@med.lu.se.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30706

ACCOMPANYING COMMENTARY
TITLE: Prime suspect: the TCF7L2 gene and type 2 diabetes risk

AUTHOR CONTACT:
Andrew T. Hattersley
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom.
Phone: 44-1392-406806; Fax: 44-1392-406767; E-mail: Andrew.Hattersley@pms.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33077

Contact: Karen Honey
press_releases@the-jci.org
215-573-1850
Journal of Clinical Investigation

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U-M researchers find family of ‘on switches’ that cause prostate cancer

Gene fusions trigger cancer growth, could impact treatment choices

ANN ARBOR, Mich. — Researchers at the University of Michigan Comprehensive Cancer Center have discovered how genes turn on the switch that leads to prostate cancer.

The team discovered that pieces of two chromosomes can trade places with each other and cause two genes to fuse together. The fused genes then override the “off” switch that keeps cells from growing uncontrollably, causing prostate cancer to develop.

By testing these gene fusions in mice and in cell cultures, the researchers showed that the fusions are what cause prostate cancer to develop. But it’s not just one set of genes that fuse. The researchers found that any one of several in a family of genes can become scrambled and fuse. Results of the study appear in the Aug. 2 issue of Nature.

“Each of these switches, or gene fusions, represent different molecular subtypes. This tells us there’s not just one type of prostate cancer. It’s a more complex disease and potentially needs to be treated differently in each patient,” says lead study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology, a new U-M center whose goal is to translate research into real world practice.

The gene fusion research is the centerpiece project of the new center. In the current study, researchers found one of several abnormal gene fusions in the prostate cancer tissue samples they tested. In 2005, the researchers identified a prostate-specific gene called TMPRSS2, which fuses with either ERG or ETV1, two genes known to be involved in several types of cancer.

The Nature paper reports on five additional genes that fuse with ERG or ETV1 to cause prostate cancer. Gene fusions were involved in 60 percent to 70 percent of the prostate cancer cell lines the researchers looked at. The genes involved are all controlled by a different mechanism. For example, four of the genes are regulated by androgen, a male sex hormone known to fuel prostate cancer. Androgen deprivation is a common therapy for prostate cancer.

Knowing which gene fusion is involved in an individual patient’s tumor could impact treatment options. If an androgen-regulated gene is involved, androgen therapy would be appropriate. But if the gene fusion involves a gene that represses androgen, the anti-androgen therapy could encourage the cancer’s growth. This may also explain why androgen treatment is not effective for some prostate cancers.

“Typing someone’s prostate cancer by gene fusion can affect the treatment given. We would not want to give androgen to someone whose prostate cancer gene fusion is not regulated by androgen,” says Chinnaiyan, who is the S.P. Hicks Collegiate Professor of Pathology at the U-M Medical School.

Rearrangements in chromosomes and fused genes are known to play a role in blood cell cancers like leukemia and lymphoma, and in Ewing’s sarcoma. A fused gene combination that plays a role in chronic myelogenous leukemia led researchers to develop the drug Gleevec, which has dramatically improved survival rates for that disease.

Chinnaiyan believes the prostate gene fusions will eventually lead to similar treatments for prostate cancer.

“More immediately, we hope to develop tests for diagnosis or prognosis. But long-term, we hope this will lead to better therapies to treat prostate cancer. The key challenge is to find a drug that would go after this gene fusion,” Chinnaiyan says.

The gene fusion technology has been licensed to San Diego-based Gen-Probe Inc., which is working on a screening tool to detect gene fusions in urine. The tool could one day supplement or replace the prostate specific antigen, or PSA, test currently used to screen for prostate cancer.

The idea of translating laboratory research findings into a test or treatment that will impact patients is central to the new Michigan Center for Translational Pathology. The center brings together experts in genomics, proteomics and bioinformatics to look at common patterns and potential targets in cancer and other diseases. This is the first center of its kind in the nation in that it is associated with one of 39 National Cancer Institute-designated “comprehensive” cancer centers, a premier medical school and a large health system with both clinicians and patients.

The center’s goal is to study the genes, proteins and other markers on cells to develop new diagnostic tests or screening tools as well as targeted treatments for cancer and other diseases, with the key being to translate these laboratory discoveries into clinical applications.

Chinnaiyan and his team have received numerous awards and honors, including the American Association for Cancer Research Team Science Award for their previously published work on gene fusions, and the Specialized Program of Research Excellence Outstanding Investigator award. The new Center for Translational Pathology supported in part by the Prostate Cancer Foundation, which has offered to match up to $1 million dollars in donations to support work related to developing therapies against prostate cancer gene fusions at the university.

“Mapping of the human genome was only the beginning. Equipped with the comprehensive analysis of the human genome, we can now systematically examine the blueprint of disease at the molecular level. This essential knowledge may lead to better diagnostic tests and promising new treatments for cancer, cardiovascular disease, diabetes and other illnesses,” Chinnaiyan says.

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For information about the Michigan Center for Translational Pathology, go to http://www.med.umich.edu/mctp.

About 218,890 men will be diagnosed with prostate cancer this year, and 27,050 will die from the disease, according to the American Cancer Society. The gene fusion work is not currently available for treatment or diagnosis, and no clinical trials are currently recruiting. For information about prostate cancer and currently available treatments, go to http://www.mcancer.org or call the U-M Cancer AnswerLine at 800-865-1125.

In addition to Chinnaiyan, U-M study authors were Scott Tomlins; Saravana Dhanasekaran, Ph.D.; Bharathi Laxman; Qi Cao; Beth Helgeson; Xuhong Cao; David Morris, M.D.; Anjana Menon; Xiaojun Jing; Bo Han; James Montie, M.D.; Kenneth Pienta, M.D.; Diane Roulston; Rajal Shah, M.D.; Sooryanarayana Varambally, Ph.D.; and Rohit Mehra, M.D. Mark Rubin, M.D., from Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School is also a study author.

Funding for the study came from the U.S. Department of Defense, the National Institutes of Health, the Early Detection Research Network, the Prostate Cancer Foundation and Gen-Probe Inc.

The University of Michigan has filed for a patent on the detection of gene fusions in prostate cancer, on which Tomlins, Mehra, Rubin and Chinnaiyan are co-inventors. The diagnostic field of use has been licensed to Gen-Probe Inc. Chinnaiyan also has a sponsored research agreement with Gen-Probe; however, GenProbe has had no role in the design or experimentation of this study, nor has it participated in the writing of the manuscript.

Reference: Nature, Vol. 448, No. 7153, Aug. 2, 2007

Contact: Nicole Fawcett
nfawcett@umich.edu
734-764-2220
University of Michigan Health System

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Huntington’s disease study shows animal models on target

This release is available in French.

An international team of researchers has published a benchmark study showing that gene expression in several animal models of Huntington’s Disease (HD) closely resembles that of human HD patients.

The results, published August 1, 2007, in the , validate the applicability of using animal models to study human disease and will have important consequences for the pertinence of these models in preclinical drug testing.

Huntington’s disease is an incurable and fatal hereditary neurodegenerative disorder caused by a mutation in the gene that encodes the huntingtin protein. Neurons in certain regions of the brain succumb to the effects of the altered protein, leading to severe motor, psychiatric, and cognitive decline. Several recent studies have shown that the mutant huntingtin protein modifies the transcriptional activity of genes in affected neurons. This disease mechanism is a promising new avenue for research into the causes of neuronal death and a novel potential approach for treatment.

Led by EPFL professor Ruth Luthi-Carter, and involving collaborators from six countries, the current study found a marked resemblance between the molecular etiology of neurons in animal models and neurons in patients with HD. This implies that animal models are relevant for studying human HD and testing potential treatments.

To come to this conclusion, the scientists measured the gene expression profile of seven different transgenic mouse models of HD, representing different conditions and disease stages. These profiles clarified the role of different forms and dosages of the protein hungtintin in the transcriptional activity of neurons. They then designed and implemented novel computational methods for quantifying similarities between RNA profiles that would allow for comparisons between the gene expression in mice and in human patients. “Interestingly, results of different testing strategies converged to show that several available models accurately recapitulate the molecular changes observed in human HD,” explains Luthi-Carter. “It underlines the suitability of these animal models for preclinical testing of drugs that affect gene transcription in Huntington’s Disease.”

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More Information:

EPFL Laboratory of functional neurogenomics, http://lngf.epfl.ch/

Alexandre Kuhn ; +41 21 693 1731
alexandre.kuhn@epfl.ch

Professor Ruth Luthi-Carter; +41 21 693 9533
ruth.luthi-carter@epfl.ch

Contact: Alexandre Kuhn
alexandre.kuhn@epfl.ch
41-216-931-731
Ecole Polytechnique Fédérale de Lausanne

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Flip of genetic switch causes cancers in mice to self-destruct, Stanford researchers find

STANFORD, Calif. – Killing cancerous tumors isn’t easy, as anyone who has suffered through chemotherapy can attest. But a new study in mice shows that switching off a single malfunctioning gene can halt the limitless division of tumor cells and turn them back to the path of their own planned obsolescence.

The surprising possibility that a cell’s own natural mechanism for ensuring its mortality could be used to vanquish tumors opens the door to a new approach to developing drugs to treat cancer patients, according to Dean Felsher, MD, PhD, associate professor of medicine (oncology) and of pathology at the Stanford University School of Medicine. Felsher is the senior author of the study to be published July 30 in the advance online version of the Proceedings of the National Academy of Sciences.

“Our research implies that by shutting off a critical cancer gene, tumor cells can realize that they are broken and restore this physiologic fail-safe program,” said Felsher.

Cancer can be notoriously resistant to medical treatment. Not only do cancer cells proliferate uncontrollably, they somehow circumvent the mechanism that causes normal cells to die when they get old or malfunction. That makes cancer cells effectively immortal unless doctors manage to squelch them.

The gene Felsher’s team studied produces a protein called Myc (pronounced “mick”), which promotes cell division. A mutation of the gene causes cells to overproduce the protein, prompting perpetual cell division and tumor growth. By turning off the mutated gene, the researchers found that not only did uncontrolled cell division cease, but the cells also reactivated a normal physiological mechanism, called senescence, which makes it possible for a cell to eventually die.

“What was unexpected was just the fact that cancer cells had retained the ability to undergo senescence at all,” said Felsher. Cancer researchers had long thought the senescence process had to be irreversibly disrupted for a tumor to develop.

The researchers worked with a series of mice engineered to have Myc-triggered cancers of either the liver, blood or bones, along with a specially constructed version of the Myc gene that they could switch off by feeding the mice antibiotics. When the mice dined on doses of the drugs, invariably, the tumors ceased growing and then diminished, with some disappearing over the course of just a few days.

Although Felsher’s lab had previously shown that mouse tumors diminished and disappeared when Myc was switched off, they hadn’t been sure how the process actually worked. Historically, most research involving genetic methods of battling cancer cells has focused on reactivating genes called tumor-suppressor genes, which are generally overcome by a proliferating cancer. No one had explored the idea that senescence might play a key role in diminishing tumors.

Felsher described senescence as acting like a fail-safe mechanism to stop cancer. When a cell detects a deleterious mutation, it launches the senescence process, resulting in the permanent loss of the cell’s ability to proliferate, thus halting any cancer.

“In order to become tumor cells, those cells have to overcome senescence,” said Chi-Hwa Wu, PhD, postdoctoral researcher in Felsher’s lab and first author of the study. Wu had the inspiration to explore whether the sudden diminishment they had observed in the tumors might be due to the reactivation of some latent remnant of the trigger for senescence.

Through a series of experiments looking at enzymes associated with the senescence process, as well as some molecular markers, Wu confirmed her suspicion. And not only was senescence occurring in cells that had been thought to be incapable of it, the process was reactivated in all the different tumors they studied.

Consider it a cell version of the Jekyll-and-Hyde transformation. “It’s sort of like Mr. Hyde realizing that there’s something wrong with him and then being able to put himself back into his normal state as Dr. Jekyll,” Felsher said.

In addition to the deepened understanding of how the process of senescence works, Felsher and Wu see a lot of potential for new approaches to treating cancer, beyond the traditional tactic of trying to kill cancer cells directly. “This work implies that maybe part of the strategy should involve figuring out how to get the cancer cells to just be allowed to do what they originally wanted to do anyway, which is to not be proliferating endlessly and growing uncontrolled,” said Felsher.

The next step for the team is to see how well the approach works in human cancer cells. “And we’re also trying to figure out what the mechanism is,” Felsher said. “What are the molecular mechanisms of this, so that we can figure out how to better treat cancer””

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Other authors on the research paper are Jan van Riggelen, PhD, postdoctoral researcher; Alper Yetil, graduate student in cancer biology; Alice Fan, MD, instructor in medicine (oncology), and medical student Pavan Bachireddy.

The study was funded by the National Cancer Institute, the National Institutes of Health, the Leukemia and Lymphoma Society, the Burroughs Wellcome Fund, the Damon Runyon Lilly Clinical Investigator Award, the Lymphoma Research Foundation and the Howard Hughes Medical Institute.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions – Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at http://mednews.stanford.edu.

Contact: Lou Bergeron
louisb3@stanford.edu
650-723-3900
Stanford University Medical Center

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