Specific Lung Cancer Susceptibility Gene Identified

University of Cincinnati (UC) cancer cell biologists have identified a distinct gene linked to increased lung cancer susceptibility and development. They say this gene—known as RGS17—could result in a genetic predisposition to develop lung cancer for people with a strong family history of the disease.With further investigation, they believe the gene could be used to identify high-risk patients who may benefit from earlier, more aggressive lung cancer screening.

Marshall Anderson, PhD, and his colleagues report their findings in the April 15, 2009, issue of the journal Clinical Cancer Research.

“Understanding how the RGS17 gene impacts cancer development could change clinical diagnosis and treatment as radically as discovery of the breast cancer genes (BRCA1 and BRCA2) did,” explains Anderson, who has led the multi-institutional Genetic Epidemiology of Lung Cancer Consortium (GELCC) studying the genetic basis of lung cancer since 1997. “A proven genetic test could help us identify people at risk before the disease progresses.”

According to the American Cancer Society, lung cancer is the leading cause of cancer related disease and death. Although tobacco smoke is the primary environmental cause of the disease, science has shown there is also a strong genetic component to the disease.

“This study represents a significant contribution to our understanding of lung cancer susceptibility and is another step toward to the goal of preventive medicine,” says David Christiani, MD, MPH, a professor of occupational medicine and environmental health at the Harvard School of Public Health, whose two-page commentary on the study is published in conjunction with the GELCC team’s scientific findings. “The authors undertook a daunting challenge of performing a family-based study of lung cancer in an effort to identify specific causal genes.”

Genes, which are located in fixed positions on the cell's chromosomes, carry the DNA code that determines inherited characteristics, including a risk of certain diseases.

For this study, Anderson and his multi-institutional team collected biological samples from numerous multigenerational families with five or more members who were affected by lung cancer. Through a combination of what is known as “fine mapping”—where genetic information is dissected and analyzed—and genetic association studies, researchers identified RGS17 as a major candidate susceptibility gene for familial lung cancers.

Research has shown that lung cancer can occur sporadically—where people have no known risk factors or family history—or hereditarily, occurring in multiple members of the same family. In 2004, Anderson’s team reported the first genetic evidence of a major lung cancer “susceptibility locus” on chromosome 6, and evidence of a susceptibility region on three other chromosomes.

The region of the original chromosome where the lung cancer markers were found contained about 100 genes, including several genes suspected to be involved in tumor suppression and cell growth.

Using a genetically altered mouse model, researchers determined that when RGS17 was suppressed, lung tumors shrank, proving the gene was involved in cancer development and must be present for cancer growth.

“What was most interesting is that this same gene was over-expressed in 60 percent of the samples from non-hereditary lung tumors,” explains Anderson. “This suggests that perhaps epigenetic factors may be contributing to abnormal genetic development.”

The UC-led team will conduct additional research to investigate how environmental factors may influence familial cancer development.

Funding for this research comes from the National Institutes of Health through the Genetic Epidemiology of Lung Cancer Consortium, a collaborative research effort established in 1997 to research the genetic origins of familial lung cancers. Anderson serves as principal investigator. Collaborating institutions include Washington University-St. Louis, Mayo Clinic-Rochester, University of Colorado, University of Texas Southwestern Medical Center, Louisiana State University, Saccomanno Research Institute, National Cancer Institute, National Human Genome Research Institute, Karmanos Cancer Institute, University of Toledo and M.D. Anderson Cancer Center-Houston.

Mass Spec Technique Analyzes Defensive Chemicals On Seaweed Surfaces For Potential Drugs

A new analytical technique is helping scientists learn how organisms as simple as seaweed can mount complex chemical defenses to protect themselves from microbial threats such as fungus. Known as desorption electrospray ionization mass spectrometry (DESI-MS), the technique for the first time allows researchers to study unique chemical activity taking place on the surfaces of these organisms.Understanding this surface chemistry could one day allow scientists to borrow and adapt some of those defensive chemical compounds for use against cancer, HIV, malaria, drug-resistant bacteria and other diseases of humans. In a paper scheduled to be published online in the journal Proceedings of the National Academy of Sciences, researchers from the Georgia Institute of Technology describe a sophisticated chemical defense system that uses 28 different compounds to protect a species of seaweed against a single fungus.

"Plants and animals in the wild use chemistry as way to fight with one another," said Julia Kubanek, a professor in Georgia Tech's School of Biology. "Using this new technology, scientists can listen in on this fight to perhaps learn from what's going on and steal some of the strategies for human biomedical applications."

As part of a long-term project sponsored by the Natural Institutes of Health, Georgia Tech scientists have been cataloging and analyzing natural compounds from more than 800 species found in the waters surrounding the Fiji Islands. They have been particularly interested in Callophycus serratus, an abundant species of red seaweed that seems particularly successful – and adept at fighting off microbial infections.

Using the DESI-MS technique, the researchers analyzed recently-collected samples of the seaweed and found groups of potent anti-fungal compounds in light-colored microscopic surface patches covering what may be wounds on the surface of the seaweed. In laboratory testing, these bromophycolide compounds and callophycoic acids effectively inhibited the growth of Lindra thalassiae, a common marine fungus.

"It is possible that the alga is marshalling its defenses and displaying them in a way that blocks the entry points for microbes that might invade and cause disease," Kubanek said. "Seaweeds don't have B cells, T cells and immune responses like humans do. But instead they have some chemical compounds in their tissues to protect them."

Though all the seaweed they studied was from a single species, the researchers were surprised to find two distinct groups of anti-fungal chemicals. From one seaweed subpopulation, dubbed the "bushy" type for its appearance, 18 different anti-fungal compounds were identified. In a second group of seaweed, the researchers found 10 different anti-fungal compounds – all different from the ones seen in the first group.

"This species is producing some unique chemical compounds that other seaweeds don't produce, and it is producing a large number of compounds, each of which has a role to play in the overall defense against the fungus," Kubanek noted. "We think the compounds work together in an additive way."

Though chemically different, the compounds are structurally related and seem to arise from a similar metabolic pathway in the seaweed. Why one species of simple organism would produce 28 different anti-fungal compounds remains a mystery, though Kubanek believes the chemicals may also have other uses that are not yet understood.

The compounds have been tested for potential activity against drug-resistant bacteria, cancer, HIV, malaria and other human health threats. So far, preliminary testing suggests they have anti-malarial effects.

The DESI-MS technique allowed the researchers for the first time to analyze chemical activity occurring on the surface of the seaweed. Earlier techniques allowed identification of chemicals in the organism's tissue, but being able to confirm their location on the surface – the first line of defense against infection – confirms the role they play as defensive chemicals.

In DESI-MS, a charged stream of polar solvent is directed at the surface of a sample under study at ambient pressure and temperature. The spray desorbs molecules, which are then ionized and delivered to the mass spectrometer for analysis.

"This technique allows us to examine intact organisms and see how the chemical compounds are distributed," Kubanek explained. "For our research with seaweed, this is important because we'd like to understand how an organism distributes these compounds to protect itself from enemies."

In addition to Kubanek, others researchers contributing to the study included Leonard Nyadong, Asiri Galhena, Tonya Shearer, E. Paige Stout, R. Mitchell Parry, Mark Kwasnik, May Wang, Mark Hay, and Facundo Fernandez – all from Georgia Tech – and Amy Lane, now at Scripps Institution of Oceanography. Beyond the National Institutes of Health support, the research has also been sponsored by the National Science Foundation.

For the future, Kubanek and a graduate student are working to modify the most promising of the anti-malarial compounds, replacing some oxygen atoms for nitrogen atoms and bromine for chlorine and fluorine. The hope is to create a compound more potent against the malaria organism with less toxicity for humans.

"We are doing reaction chemistry using these 28 compounds as a starting point," she explained. "Learning about how other species avoid diseases may give us something we can use to avoid or treat our own diseases."

Molecule Prompts Damaged Heart Cells To Repair Themselves After A Heart Attack

A protein that the heart produces during its early development reactivates the embryonic coronary developmental program and initiates migration of heart cells and blood vessel growth after a heart attack, researchers at UT Southwestern Medical Center have found.The molecule, Thymosin beta-4 (TB4), is expressed by embryos during the heart's development and encourages migration of heart cells. The new findings in mice suggest that introducing TB4 systemically after a heart attack encourages new growth and repair of heart cells. The research findings indicate that the molecule affects developmental gene expression as early as 24 hours after systemic injection. The UT Southwestern study is online and will appear in an upcoming issue of the Journal of Molecular and Cellular Cardiology.

"This molecule has the potential to reprogram cells in the body to get them to do what you want them to do," said Dr. J. Michael DiMaio, associate professor of cardiothoracic surgery at UT Southwestern and senior author of the study. Obviously, the clinical implications of this are enormous because of the potential to reverse damage inflicted on heart cells after a heart attack."

Tremendous medical progress has been made to counter the damaging effects of heart attacks, but ordinarily, mammalian hearts are incapable of repairing themselves following damage. They are also limited in their ability to form new blood vessels. Earlier studies demonstrated that TB4 is expressed in the embryonic heart and stimulates cardiac vessels to form. It was therefore thought that introduction of TB4 might activate new vessel growth in the adult heart.

In this mouse study researchers found that TB4 initiates capillary tube formation of adult coronary endothelial cells in tissue culture. The molecule also encourages cardiac regeneration by inhibiting death in heart cells after an injury such as a heart attack and by stimulating new vessel growth.

"We observed that by injecting this protein systemically, there was increased cardiac function after a heart attack," said Dr. Ildiko Bock-Marquette, assistant professor of cardiothoracic surgery at UT Southwestern and the study's lead author. "We hope this protein can inhibit cell death that occurs during a heart attack in the short term, and that it may initiate new growth of coronary vessels by activating progenitor cells in the long term."

Researchers assessed the effect of TB4 on new vessel growth in adult mice after inducing heart attacks and then following up by introducing TB4 into the animals. An examination of the capillary smooth muscle cells following treatment with TB4 showed a significant increase in capillary density in the heart three days afterward near the site of the heart attack, the scientists reported.

Further studies will examine whether the same events occur in larger mammals and which receptors are responsible for the action of this molecule.

Other UT Southwestern researchers involved in the study were Santwana Shrivastava, research assistant; and John Shelton, senior research scientist. Study authors also included Dr. Teg Pipes, former postdoctoral fellow; Jeffrey Thatcher, a doctoral candidate in biomedical engineering; Dr. Cristi Galindo, postdoctoral research fellow; and co-senior author, Dr. Eric Olson, chairman of molecular biology.

The work was supported by the Ted Nash Long Life Foundation, the American Heart Association, and the National Institutes of Health.