New technique identifies first events in tumor development

Friday 11 October 2013

Islamabad, Oct 12 (Newswire): A novel technique that enables scientists to measure and document tumor-inducing changes in DNA is providing new insight into the earliest events involved in the formation of leukemias, lymphomas and sarcomas, and could potentially lead to the discovery of ways to stop those events.

Developed by a team of researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the National Cancer Institute (NCI), both parts of the National Institutes of Health, and The Rockefeller University, the technology focuses on chromosomal rearrangements known as translocations.

Translocations occur when a broken strand of DNA from one chromosome is erroneously joined with that of another chromosome. Sometimes these irregularities can be beneficial in that they enable the immune system to respond to a vast number of microorganisms and viruses. However, translocations can also result in tumors.

Translocations can take place during the course of normal cell division, when each chromosome -- a single strand of DNA containing many genes -- is copied verbatim to provide genetic information for the daughter cells. Sometimes, during this process, byproducts of normal metabolism or other factors can cause breaks in the DNA.

"The cell expresses specific enzymes whose primary purpose is to repair such lesions effectively, but when the enzymes mistakenly join pieces of two different chromosomes, the cell's genetic information is changed," said Rafael C. Casellas, Ph.D., senior investigator in the Genomics and Immunity Section at the NIAMS, who led the research team along with Michel C. Nussenzweig, M.D., Ph.D., from Rockefeller.

Casellas likens the phenomenon to breaking two sentences and then rejoining them incorrectly. For example, "The boy completed his homework." and "The dog went to the vet." might become "The dog completed his homework." or "The boy went to the vet." When a cell gets nonsensical information such as this, it can become deregulated and even malignant.

Scientists have known since the 1960s that recurrent translocations play a critical role in cancer. What was unclear was how these genetic abnormalities are created, since very few of them were studied, and only within the context of tumors, said Casellas. To better understand the nature of these tumor-inducing rearrangements, the authors had to create a system to visualize their appearance in normal, non-transformed cells.

The system the teams created involved introducing enzymes that recognize and cause damage at a particular sequence in the DNA into cells from mice, thereby constructing a genome where a unique site is broken continuously. The group then used a technique called polymerase chain reaction -- which allows scientists to quickly amplify short sequences of DNA -- to check all the sites in the genome that would get translocated to this particular break. Using this technique, they were able to examine more than 180,000 chromosomal rearrangements from 400 million white blood cells, called B cells.

Based on this large data set, the scientists were able to make several important observations about the translocation process. They learned that most of the translocations involve gene domains, rather than the space on the DNA between the genes. They also found that most translocations target active genes, with a clear bias for the beginning of the gene, as opposed to its middle or end. The team also showed that a particular enzyme that normally creates DNA breaks in B cells dramatically increases the incidence of translocations during the immune response. This feature explains the long-standing observation that more than 95 percent of human lymphomas and leukemias are of B cell origin.

"This knowledge is allowing us to understand how tumors are initiated," said Casellas. "It is the kind of information that in the near future, might help us prevent the development of cancer."

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Big tobacco knew radioactive particles in cigarettes posed cancer risk but kept quiet

Islamabad, Oct 12 (Newswire): Tobacco companies knew that cigarette smoke contained radioactive alpha particles for more than four decades and developed "deep and intimate" knowledge of these particles' cancer-causing potential, but they deliberately kept their findings from the public, according to a new study by UCLA researchers.

The analysis of dozens of previously unexamined internal tobacco industry documents, made available in 1998 as the result of a legal settlement, reveals that the industry was aware of cigarette radioactivity some five years earlier than previously thought and that tobacco companies, concerned about the potential lung cancer risk, began in-depth investigations into the possible effects of radioactivity on smokers as early as the 1960s.
"The documents show that the industry was well aware of the presence of a radioactive substance in tobacco as early as 1959," the authors write. "Furthermore, the industry was not only cognizant of the potential 'cancerous growth' in the lungs of regular smokers, but also did quantitative radiobiological calculations to estimate the long-term lung radiation absorption dose of ionizing alpha particles emitted from cigarette smoke." The study, published in Nicotine & Tobacco Research, the peer-reviewed journal of the Society for Research on Nicotine and Tobacco, adds to a growing body of research detailing the industry's knowledge of cigarette smoke radioactivity and its efforts to suppress that information.

"They knew that the cigarette smoke was radioactive way back then and that it could potentially result in cancer, and they deliberately kept that information under wraps," said the study's first author, Hrayr S. Karagueuzian, a professor of cardiology who conducts research at UCLA's Cardiovascular Research Laboratory, part of the David Geffen School of Medicine at UCLA. "Specifically, we show here that the industry used misleading statements to obfuscate the hazard of ionizing alpha particles to the lungs of smokers and, more importantly, banned any and all publication on tobacco smoke radioactivity."

The radioactive substance -- which the UCLA study shows was first brought to the attention of the tobacco industry in 1959 -- was identified in 1964 as the isotope polonium-210, which emits carcinogenic alpha radiation. Polonium-210 can be found in all commercially available domestic and foreign cigarette brands, Karagueuzian said, and is absorbed by tobacco leaves through naturally occurring radon gas in the atmosphere and through high-phosphate chemical fertilizers used by tobacco growers. The substance is eventually inhaled by smokers into the lungs.

The study outlines the industry's growing concerns about the cancer risk posed by polonium-210 inhalation and the research that industry scientists conducted over the decades to assess the radioactive isotope's potential effect on smokers -- including one study that quantitatively measured the potential lung burden from radiation exposure in a two-pack-a-day smoker over a two-decade period.

Karagueuzian and his colleagues made independent calculations using industry and academic data and arrived at results that very closely mirrored those of that industry study, which was conducted nearly a quarter-century ago. They then compared those results to rates used by the Environmental Protection Agency to estimate lung cancer risk among individuals exposed to similar amounts of alpha particle-emitting radon gas in their homes.

"The gathered data from the documents on the relevant radiobiological parameters of the alpha particles -- such as dose, distribution and retention time -- permitted us to duplicate the industry's secretly estimated radiation absorbed dose by regular smokers over a 20- or 25-year period, which equaled 40 to 50 rads," he said. "These levels of rads, according to the EPA's estimate of lung cancer risk in residents exposed to radon gas, equal 120 to 138 deaths per 1,000 regular smokers over a 25-year period."
Despite the potential risk of lung cancer, tobacco companies declined to adopt a technique discovered in 1959 and then another developed in 1980 that could have helped eliminate polonium-210 from tobacco, the researchers said. The 1980 technique, known as an acid-wash, was found to be highly effective in removing the radioisotope from tobacco plants, where it forms a water-insoluble complex with the sticky, hair-like structures called trichomes that cover the leaves.

And while the industry frequently cited concerns over the cost and the possible environmental impact as rationales for not using the acid wash, UCLA researchers uncovered documents that they say indicate the real reason may have been far different.

"The industry was concerned that the acid media would ionize the nicotine, making it more difficult to be absorbed into the brains of smokers and depriving them of that instant nicotine rush that fuels their addiction," Karagueuzian said. "The industry also were well aware that the curing of the tobacco leaves for more than a one-year period also would not eliminate the polonium-210, which has a half-life of 135 days, from the tobacco leaves because it was derived from its parent, lead-210, which has a half-life of 22 years."

Karagueuzian said the insoluble alpha particles bind with resins in the cigarette smoke and get stuck and accumulate at the bronchial bifurcations of the lungs, forming "hot spots," instead of dispersing throughout the lungs. In fact, previous research on lung autopsies in smokers who died of lung cancer showed that malignant growths were primarily located at the same bronchial bifurcations where these hot spots reside.

"We used to think that only the chemicals in the cigarettes were causing lung cancer," Karagueuzian said. "But the case of the these hot spots, acknowledged by the industry and academia alike, makes a strong case for an increased probability of long-term development of malignancies caused by the alpha particles. If we're lucky, the alpha particle-irradiated cell dies. If it doesn't, it could mutate and become cancerous."

Karagueuzian said the findings are very timely in light of the June 2009 passage of the Family Smoking Prevention and Tobacco Control Act, which grants the U.S. Food and Drug Administration broad authority to regulate and remove harmful substances -- with the exception of nicotine -- from tobacco products. The UCLA research, he said, makes a strong case that the FDA ought to consider making the removal of alpha particles from tobacco products a top priority.

"Such a move could have a considerable public health impact, due to the public's graphic perception of radiation hazards," he said.

To uncover the information, Karagueuzian and his team combed through the internal tobacco industry documents made available online as part of the landmark 1998 Tobacco Master Settlement Agreement. Documents from Philip Morris, R.J. Reynolds, Lorillard, Brown I Williamson, the American Tobacco Company, the Tobacco Institutes and the Council for Tobacco Research, as well as the Bliley documents, were examined, Karagueuzian said.

The team searched for key terms such as "polonium-210," "atmospheric fallout," "bronchial epithelium," "hot particle" and "lung cancer," among others.

Karagueuzian said the earliest causal link between alpha particles and cancer was made in around 1920, when alpha particle-emitting radium paint was used to paint luminescent numbers on watch dials. The painting was done by hand, and the workers commonly used their lips to produce a point on the tip of the paint brush. Many workers accumulated significant burdens of alpha particles through ingestion and absorption of radium-226 into the bones and subsequently developed jaw and mouth cancers. The practice was eventually discontinued.

Another example involves liver cancer in patients exposed to chronic low-dose internal alpha particles emitted from the poorly soluble deposits of thorium dioxide after receiving the contrast agent Thorotrast. It has been suggested that the liver cancers resulted from point mutations of the tumor suppressor gene p53 by the accumulated alpha particles present in the contrast media. The use of Thorotrast as contrast agent was stopped in the 1950s.

In addition to Karagueuzian, authors of the study include the late Amos Norman, professor emeritus in the departments of radiation oncology and radiological sciences at UCLA; James Sayre, of the departments of biostatistics and radiological sciences at UCLA; and Celia White, who served from 1999 to 2002 as director of content and services at the Legacy Tobacco Documents Library, which contains more than 13 million documents created by major tobacco companies related to their advertising, manufacturing, marketing, sales and scientific research activities.

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Researchers explain hormonal role in glucose and fat metabolism

Islamabad, Oct 12 (Newswire): Hormone researchers at the University of Houston (UH) have their sights set on providing long-term treatment options for diabetes, obesity and cardiovascular diseases by better understanding estradiol, the most potent naturally occurring estrogen.

They now believe that this estrogen hormone is a prominent regulator of several body functions in both females and males. While estradiol is more commonly associated with processes and diseases specific to women, the team determined that the hormone actually functions as a unisex hormone with multiple actions. Research has indicated that when there is an excessive or insufficient amount of estradiol present, the metabolic network becomes imbalanced, which can result in metabolic diseases.

"Female hormones have always been associated with the menstrual cycle, pregnancy, breast-feeding and some diseases, such as osteoporosis and breast cancer, typically associated with women," said Dr. Rodrigo Barros, a research assistant professor with the UH Center for Nuclear Receptors and Cell Signaling (CNRCS). "Our group, however, has discovered that one of these hormones, estradiol, has much wider actions than previously thought. It is no longer considered exclusively a 'female sex hormone,' but a 'unisex hormone' with multiple actions across several organ systems."

Working with CNRCS director and professor Dr. Jan-Åke Gustafsson, Barros says that part of their research is dedicated to understanding how estradiol regulates feeding and food metabolism, explaining that this hormone is involved with several metabolic diseases, including eating disorders, obesity and diabetes.

"We believe that all the systems in the body involved with food consumption and metabolism, which include the brain, liver, pancreas, heart, muscles and fat, are connected by estradiol, resulting in a 'metabolic network' regulated by the hormone," Barros said. "Our evidence shows that when too much or too little estradiol is available, this delicate network loses its balance and metabolic diseases set in."

This research has important implications for the average consumer, as well as for physicians. While hormones like estradiol are important for the adequate maintenance of body functioning, they may pose serious risks to a person's health if misused as supplements. This comes into play when people use alternative forms of hormones, such as natural plant derivatives, that may be harmful if used inappropriately.
For specialists dealing with hormonal treatments, this research underscores that they should be aware that several organs and body functions are affected when estradiol is prescribed and may cause or worsen metabolic diseases. Due to the number of organs and functions affected by fluctuating levels of estradiol, its use as a hormonal treatment for patients with delayed puberty, menopausal symptoms, osteoporosis and prostate cancer is a source of debate within the medical and research communities. Exploring the impact of such treatments as reported by Barr

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