News from the Harvard Medical School research community.
Another way to grow blood vessels: Scientists find alternate pathway to angiogenesis
Researchers at Dana-Farber Cancer Institute have found a previously unknown molecular pathway in mice that spurs the growth of new blood vessels when body parts are jeopardized by poor circulation.
At present, their observation adds to the understanding of blood vessel formation.
In the future, though, the researchers suggest it is possible that the pathway could be manipulated as a means of treating heart and blood vessel diseases and cancer. The paper appeared in the Feb. 21 issue of the journal Nature.
Bruce Spiegelman, PhD, and his colleagues at Dana-Farber discovered that PGC-1alpha - a key metabolic regulatory molecule - senses a dangerously low level of oxygen and nutrients when circulation is cut off and then triggers the formation of new blood vessels to re-supply the oxygen-starved area - a process known as angiogenesis.
A similar response to hypoxia, or oxygen deprivation, has been observed before. The response is regulated by a group of proteins known as Hypoxia Inducible Factors (HIF) that detect hypoxia and activate the production of VEGF (vascular endothelial growth factor). VEGF, in turn, stimulates angiogenesis.
The newly discovered pathway provides "an independent way of getting there," says Spiegelman, who is also a professor of cell biology at Harvard Medical School. Along with lead author Zoltan Arany, MD, PhD, and colleagues, Spiegelman found that HIF was completely left out of the loop when PGC-1alpha accomplished the same feat in single cells and in live mice using a different regulator, known as ERR-alpha (estrogen-related receptor-alpha).
When the scientists knocked out the activity of PGC-1 alpha (which was first identified in the Spiegelman lab) in cells and live mice, the hypoxia-induced response and angiogenesis were sharply decreased. "We were surprised to find this novel mechanism," comments Spiegelman.
"It was apparently there all along," adds Arany. "That means there is now a second pathway that you need to know about if you are trying to activate or inhibit angiogenesis."
Angiogenesis occurs in the normal development of the body, but it's also an on-call service when an injury or an artery blockage - the cause of heart attacks and strokes leaves normal tissues starved for blood.
Generating a new network of small vessels to nourish the area can protect against further injury. Muscle-building exercise also triggers angiogenesis to provide circulation for the enlarging muscle tissue.
On the downside, cancer has evolved the ability to commandeer VEGF and other angiogenic factors to encourage blood vessel growth around tumors that have outgrown their oxygen supplies.
In recent years, companies have developed a number of drugs that manipulate the angiogenic pathway - in both directions. Among them are anti-angiogenic cancer drugs, including thalidomide and Avastin, which are designed to starve tumors by blocking the formation of blood vessels.
Avastin is also used to dampen the abnormal growth of small vessels in the retina that causes macular degeneration in the eye.
Conversely, researchers have tried using VEGF and other compounds to improve the circulation in the legs and feet - and even heart muscle - of patients with poor blood supply.
"We're still far from having good drugs to modulate angiogenesis through the HIF pathway," commented Arany. The discovery of a second, alternate pathway, involving PGC-1 alpha and ERR-alpha, leading to angiogenesis may offer new opportunities for therapy "in any situation where angiogenesis is a factor," he said.
PathologyStudy analyzes best approach for treating abdominal aortic aneurysms in the elderly
Abdominal aortic aneurysm (AAA)-a condition in which the large vessel that supplies blood to your abdomen, legs, and pelvis swells to over 50 percent its normal size-occurs in approximately 4 out of 100 adults. The risk increases with age, peaking after age 70.
AAA is more common in men than women, and more common in smokers or former smokers than those who never smoked. If the aneurysm ruptures, most patients die before they even get to the hospital.
Since the 1950s, open surgery, in which the damaged portion of the aorta is replaced with a synthetic graft through a large surgical incision, has been the mainstay of AAA repair. Open surgery entails a substantial risk of death and complications, as well as a prolonged recovery period lasting months.
Over the past decade, a newer procedure, called endovascular aneurysm repair (EVAR) has become increasingly popular.
With this newer procedure, a fabric covered stent is delivered to the damaged site through the blood vessels via a catheter, thereby rerouting blood through the stent and away from the weakened wall of the aneurysm.Currently, about half of AAA repairs done in Medicare patients are performed using EVAR.
While EVAR is typically a less onerous procedure on the patient compared to open repair, there is concern that the repair might not be as durable, with a small ongoing risk of rupture requiring reinterventions, potentially leading to higher future mortality.
So then, which intervention are doctors and patients to choose?
In a large cohort study of over 45,000 Medicare beneficiaries treated for AAA, researchers at Harvard Medical School and Beth Israel Deaconess Medical Center have found that reinterventions of EVAR are balanced by late complications of open repair.
When all these risks are factored together, the increased mortality of open repair makes EVAR the preferable option. Results were published in the January 31 edition of the New England Journal of Medicine.
The research team, led by Marc Schermerhorn of the department of surgery at Beth Israel Deaconess Medical Center, and Bruce Landon, associate professor of health care policy at Harvard Medical School, looked at data from 45,660 closely matched patients from the Medicare program who underwent one procedure or the other.
All patients were treated for AAA, half with open repair, and half with EVAR.
The researchers found that during the perioperative period-the recovery period immediately following surgery-mortality was substantially higher for open repair patients than for EVAR patients, 4.8 percent vs. 1.2 percent.
The mortality benefit of EVAR increased with age, with a mortality difference of over 8 percent for those over age 85. This mortality advantage persisted for at least three years.
Reinterventions for the aneurysm were considerably higher for the EVAR group (although these were mostly minor) than for the open repair group, 9.0 percent vs. 1.7 percent.
However, because open repair involves an invasive procedure called laparotomy, where the surgeon needs to enter the patient through the abdomen, complications such as hernia and bowel obstruction requiring surgery were more than twice as high four years after the procedure for open repair patients compared with EVAR patients.
"This last observation is particularly relevant because until now, no one has looked at this," says Schermerhorn.
The researchers reason that when laparotomy complications are compared with EVAR reinterventions, both procedures carry roughly equivalent risks during the four year period following surgery.
When the perioperative mortality of open repair is taken into account, EVAR is clearly the more logical choice, particularly for the elderly and frail.
Gene variants may increase risk of anxiety disorder
Massachusetts General Hospital (MGH) researchers - in collaboration with scientists at the University of California at San Diego and Yale University - have discovered perhaps the strongest evidence yet linking variation in a particular gene with anxiety-related traits.
In the March issue of Archives of General Psychiatry, the team described finding that particular versions of a gene that affects the activity of important neurotransmitter receptors were more common in both children and adults assessed as being inhibited or introverted and also were associated with increased activity of brain regions involved in emotional processing.
"We found that variations in this gene were associated with shy, inhibited behavior in children, introverted personality in adults and the reactivity of brain regions involved in processing fear and anxiety," says Jordan Smoller, MD, ScD, of the MGH Department of Psychiatry, the report's lead author.
"Each of these traits appears to be a risk factor for social anxiety disorder, the most common type of anxiety disorder in the U.S."
It has long been recognized that the tendency to anxiety disorders can run in families and is believed to be influenced by the interaction of several genes. Because of the different forms of these disorders and their complex patterns of inheritance, identifying specific susceptibility genes has been difficult.
Studies in mice have associated an area of chromosome 1 with anxious temperament, particularly the gene that codes for a protein called RGS2, which mediates the activity of neurotransmitter receptors that are also the targets of many antidepressant and antipsychotic drugs. Mice in whom RGS2 is knocked out exhibit increased fearful behavior.
To more comprehensively investigate the role of RGS2 in humans, the researchers conducted several experiments. They analyzed blood samples from children from 119 families who had participated in an earlier study assessing their reactions to unfamiliar situations at the ages of 21 months, 4 and 6 years.The participants had been evaluated on their levels of behavioral inhibition, a form of temperament linked to increased risk of anxiety disorders.
Testing several sites in the RGS2 gene identified nine variations that appeared to be associated with inhibition.
The second experiment involved more than 700 college students who had completed questionnaires designed to measure several personality traits. Analyzing blood samples from this group, the research team genotyped the four gene markers that had demonstrated the strongest effects in the first group.
They found that the versions associated with inhibited behavior in the children were also more common in the college students who scored high on measures of introversion, a personality trait that also involves social inhibition.
Another group of 55 college students had functional MRI brain imaging done after they had completed a standard interview screening for anxiety and mood disorders.
While in the MR scanner, the participants viewed a series of faces expressing various emotions, a test that previously was shown to influence activity in the amygdala, a brain structure involved in emotion processing.
Participants with the inhibition/introversion-associated alleles also had increased activity of the amygdala and the insula, another anxiety-related brain region.
"Now we need to investigate whether these RGS2 variants actually are associated with particular disorders and how they act on a cellular level," says Smoller, an associate professor of Psychiatry at Harvard Medical School.
"We hope that ultimately this work will lead to new drug targets and treatment options for anxiety disorders."
Data shows a declining incidence of cystic fibrosis since introduction of prenatal carrier screening
A study led by researchers at the New England Newborn Screening Program (NENSP) of the University of Massachusetts Medical School, and at Children's Hospital Boston, provides what may be the first population-based demonstration in the U.S. of a decline in the number of babies born with a genetic disease after the introduction of prenatal carrier screening.
Their brief report, which links data from two independent population-based screening programs, appears in the February 28, 2008, New England Journal of Medicine.
The state of Massachusetts has offered universal newborn screening to detect cystic fibrosis (CF) since 1999. Newborn screening for cystic fibrosis (much like newborn screening for other conditions) is a public health service geared toward early diagnosis and referral of infants for diagnostic evaluation and care, as well as tracking the numbers of infants who are diagnosed with the disease.
Independently, recommendations for nationwide (adult) prenatal carrier screening for CF were introduced in the U.S. around 2002, coming from the National Institutes of Health, the American College of Obstetrics and Gynecology and the American College of Medical Genetics.
Using the Massachusetts newborn screening data, the researchers compared two four-year periods: 1999 to 2002, just before prenatal CF carrier screening came into wide practice, and 2003-2006.
The number of live-born infants with cystic fibrosis dropped by about 50 percent from one four-year period to the next. Moreover, among the babies who were born, markedly fewer had two copies of the delta F508 gene mutation, associated with a severe form of CF.
The authors hypothesize that the gradual implementation of recommendations to offer pre-conception and prenatal screening to identify carriers of CF might have led to a decrease in the number of infants born with CF, particularly the type that causes the most severe disease.
"Our data cannot distinguish the reason for the reported decrease," notes Richard Parad, MD, MPH, a newborn medicine specialist at Children's Hospital Boston and Brigham and Women's Hospital, who co-authored the study with NENSP director Anne Comeau, PhD, and Jamie Hale of NENSP.
"Carrier couples may have chosen not to conceive, or they may have resorted to donor egg or sperm or to pre-implantation genetic diagnosis, or they may have decided to terminate affected pregnancies."
The authors, who work closely with the clinician directors of the five Massachusetts CF Centers - at Children's Hospital Boston, Baystate Medical Center in Springfield, Massachusetts General Hospital, New England Medical Center and the University of Massachusetts Medical School - are confident that the decrease is real, not an aberration of the screening program and not a normal fluctuation.
Clinical researchers have understood that a major challenge of CF newborn screening is developing treatments to maintain the health of relatively asymptomatic newborns.
"Our observations that fewer infants are being born with CF recently - particularly fewer infants with a severe genotype - provides an additional challenge to researchers developing new treatments or using population data for trend analyses," says Comeau, also an associate professor of pediatrics at the University of Massachusetts Medical School.
"We should not fool ourselves into thinking that our treatments are working better than they are if the treatment may be tested on a population that was already bound to be more healthy."CF affects all races, and is the most common autosomal recessively inherited disorder in Caucasians (about 1/3000 births).
Fifty years ago, most children with CF died before they reached school age, but today, with early diagnosis and improved treatment, the median survival is 36 years.
OncologyStudy helps explain fundamental process of tumor growth
Nearly 80 years ago, scientist Otto Warburg observed that cancer cells perform energy metabolism in a way that is different from normal adult cells. Many decades later, this observation was exploited by clinicians to better visualize tumors using PET (positron emission technology) imaging.
But it has not been known exactly how tumor cells perform this alternate metabolic feat, nor was it known if this process was essential for tumor growth.
Two papers appeared in the March 13 issue of the journal Nature that help answer these questions. Led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, the papers find that the metabolic process that has come to be known as the Warburg effect is essential for tumors' rapid growth, and identifies the M2 form of pyruvate kinase (PKM2), an enzyme involved in sugar metabolism, as an important mechanism behind this process. This discovery could provide a target for the development of future cancer therapies.
"With this study we have answered a fundamental question regarding the ability of tumor cells to rapidly grow and proliferate," explains senior author Lewis Cantley, PhD, Director of the Cancer Center at BIDMC and Professor of Systems Biology at Harvard Medical School.
Metabolic regulation in rapidly growing tissues, such as fetal tissue or tumors, is different from that of normal adult tissue, Cantley explains. "Through aerobic glycolysis, or the Warburg effect, cancer cells produce energy by taking up glucose at much higher rates than other cells while, at the same time, using a smaller fraction of the glucose for energy production. This allows cancer cells to function more like fetal cells, promoting extremely rapid growth."
This unique metabolic property of cancer cells has led to the success of PET imaging as a means of cancer detection; because radioactive glucose injected into patients prior to the imaging exam is preferentially taken up by glucose-hungry tumor cells, the areas of high glucose uptake are displayed dramatically on the PET scan.
Using a novel proteomic screen to identify new phosphotyrosine binding proteins, Cantley and his colleagues first determined that PKM2 can bind to phosphotyrosine-containing peptides.
"We observed that in contrast to the forms of pyruvate kinase found in most normal adult tissues, only PKM2, which is found in fetal cells, interacted with phosphotyrosine," explains Cantley.
"This finding was particularly interesting because previous reports had shown that this M2 form was the pyruvate kinase form used by all cancer cells."
In order to understand the implications of this discovery, Cantley and his coauthors next embarked upon experiments to evaluate the importance of PKM2 to cancer cells.
Reasoning that tumor tissue switches pyruvate kinase expression from an adult M1 isoform to the embryonic M2 isoform, they performed immunoblotting and immunohistochemistry analysis of numerous cancer cell lines, breast cancer models and human colon cancer, confirming that PKM2 was the only form of pyruvate kinase found in cancerous tissue.
The authors then knocked down PKM2 expression in human cancer cell lines and expressed the adult M1 form instead. This switch from the fetal M2 form to the adult M1 isoform led to reduced lactate production and increased oxygen consumption - a reversal of the Warburg effect.
"We were able to show that only cells which express the M2 form of pyruvate kinase - and metabolize glucose in the way described by Otto Warburg 80 years ago - had the ability to form tumors in mice," notes Cantley.
In addition, the investigators demonstrated that it is the ability of PKM2 to interact with phosphotyrosine that enables this form of pyruvate kinase to promote the unique glucose metabolism seen in cancer cells, thereby allowing these cells to make tumors in vivo.
The findings are consistent with the idea that tumor cells preferentially use glucose for purposes other than making adenosine triphosphate (ATP), the energy currency used by normal cells.
"We suspect that this mechanism evolved to ensure that fetal tissues only use glucose for growth when they are activated by appropriate growth factor receptor protein-tyrosine kinases," adds Cantley.
"By re-expressing PKM2, cancer cells acquire the ability to use glucose for anabolic processes.
"Because PKM2 is found in all of the cancer cells that we have examined, because it is not found in most normal adult tissues, and because it is critical for tumor formation, this form of pyruvate kinase is a possible target for cancer therapy," he adds.
Research Matters brings together selected research being conducted at Harvard Medical School's 18 affiliated institutions. For more information, visit the Harvard Medical School website at www.hms.harvard.edu.This article is provided courtesy of Harvard Medical International.For all the latest health tips & news from the UAE and Gulf countries, follow us on Twitter and Linkedin, like us on Facebook and subscribe to our YouTube page, which is updated daily.
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