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Agent orange chemical, dioxin, attacks the mitochondria to cause cancer, says Penn research team

Contact: Jordan Reese
jreese@upenn.edu
215-573-6604
University of Pennsylvania

PHILADELPHIA— Researchers with the University of Pennsylvania School of Veterinary Medicine have demonstrated the process by which the cancer-causing chemical dioxin attacks the cellular machinery, disrupts normal cellular function and ultimately promotes tumor progression.

The team identified for the first time that mitochondria, the cellular sub-units that convert oxygen and nutrients into cellular fuel, are the target of tetrachlorodibenzodioxin, or TCDD. The study showed that TCDD induces mitochondria-to-nucleus stress signaling, which in turn induces the expression of cell nucleus genes associated with tumor promotion and metastasis.

The mechanism the research team has described is directly relevant to understanding incidences of breast and other cancers in human populations exposed to these chemicals. With a better understanding of this underlying cellular mechanism, researchers hope to improve their understanding of tumor growth and promotion.

“Now that we have identified this signaling mechanism we can look at ways to disrupt this complex chain of events,” said Narayah Avadhani, chair of the Department of Animal Biology at Penn’s School of Veterinary Medicine and the study’s lead investigator. “Our ultimate goal is to block the propagation of this mitochondrial stress signaling and inhibit the expression of the proteins that combine to assist cancer growth.”

A well-characterized mechanism of TCDD action occurs through activation of arylhydrocarbon receptors, AhR, by directly binding to the protein subunits. Activated AhR mediates the transcriptional activation of many genes including those involved in fatty acid metabolism, cell cycle regulation and immune response. The present study, however, shows that TCDD starts the chain of events that promote tumor progression in vivo by directly targeting mitochondrial transcription and induction of mitochondrial stress signaling. A unique feature of this TCDD-induced signaling is that it does not involve the action of AhR but occurs through increased calcium levels in cells and activation of calcium responsive factors. A net result of signaling cascade is slowing down of cellular apoptosis, increased cell proliferation and tumor cell metastasis. Taken together, this study describes a novel mechanism of TCDD-induced tumor progression and emergence of metastatic cancer cells.

TCDD is the most toxic compound in the dioxin family. Formed as a by-product during waste incineration, paper, chemical and pesticide manufacturing, it was the toxic ingredient in Agent Orange and closed the Love Canal in Niagara Falls. The public health impact of dioxin, according to the Environmental Protection Agency, compares to that of the pesticide DDT.

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The study appears online and in the Dec. 17 issue of the Proceedings of the National Academy of Sciences and was performed by Avadhani, Gopa Biswas, Satish Srinivasan and Hindupur Anandatheerthavarada of the Penn School of Veterinary Medicine.

The research was supported by a grant from the National Cancer Institute and the National Institutes of Health.

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December 18, 2007 Posted by | Global, Global News, Cancer, PTSD, Washington DC, National Cancer Institute, World News, NIH, Cancer Biology, Washington DC City Feed, RSS Feed, Ottawa, Toronto, FMS Global News, London UK Feed, Ottawa City Feed, Toronto City Feed, London | , , , , | Leave a comment

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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July 31, 2007 Posted by | acute lymphoblastic leukemia, Alberta, Baltimore, Barcelona, Bethesda, Biological Sciences, Calgary, Canada, Cancer, Cancer Biology, Cancer Biology and Therapy, Childhood Lukemia, France, Genes, Genetic, Genetic Link, Genetics, Genome, Genomic, Germany, Global, Global Health Vision, Global News, Health Canada, Howard Hughes Medical Institute, Human Genome, Italy, Japan, Leukemia, Medical Journals, Molecular Biology, National Cancer Institute, National Institutes of Health, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, non-Hodgkin's lymphoma, Nova Scotia, Nunavut, Osaka, Ottawa, Prince Edward Island, Public Health, Quebec, Research, RSS, RSS Feed, Toronto, UK, US, Virginia, Washington DC, Washington DC City Feed, Wellcome Trust, World News | Leave a comment

Tobacco industry efforts to derail effective anti-smoking campaigns

Anti-smoking ads that reveal the tobacco industry’s deceptive practices have been aggressively quashed through various methods found Temple University Assistant Professor Jennifer K. Ibrahim, co-author of an analysis in the August issue of the American Journal of Public Health.

In the article, Ibrahim tracks the rise and fall of state and national efforts to curb smoking for the past 40 years. She chronicles industry strategies to prevent a campaign’s creation, steer messages to smaller audiences, limit the content of the message, limit or eliminate the campaign’s funding, and pursue litigation against the campaign. Ibrahim looks at campaigns in Minnesota, California, Arizona, Oregon, Florida, and a national campaign from the American Legacy Foundation.


This billboard was part of a weak media campaign in Michigan after Gov. John Engler’s political staff took control of the campaign, excluding the state health department’s staff from any…

“It tells the story behind the smoke. People often judge these ads and now you know what the tobacco industry was doing trying to undermine them,” Ibrahim said.

Research has found ads that reveal the deceptive practices of the tobacco industry are the most effective media campaigns that reduce smoking rates, she said.


This billboard ad from California in 2001 is considered a more effective message to reduce smoking rates.

For example, one billboard in California read “Tobacco is legal, profitable, and kills people” featuring an alligator labeled big tobacco with a smirk saying “Two out of three’s not bad.”

However, these messages aren’t always getting out there because of the money spent by the tobacco industry to eliminate them, said Ibrahim, an assistant professor of public health.

State health departments face an uphill battle when dealing with the political clout of the industry with its lobbying, campaign contributions and specials events, Ibrahim said.

One tactic also involves the industry producing its own ineffective campaigns in order to portray state programs as duplicative and a waste of public dollars. Campaigns designed by the tobacco companies patronize youth in their early teen years, with messages like “Think, Don’t smoke”, Ibrahim said.

In contrast, Florida’s “truth” anti-smoking campaign empowered them by giving them information about how the tobacco industry tried to manipulate by marketing.

The tobacco industry has spent more money in advertising in light of successful media campaigns that target large audiences.

From 1975 to 2003, tobacco industry expenditures in advertising and promotion grew from $491 million to $15.5 billion. During this period, the percentage of smokers in the United States fell from about 37 percent to 22 percent, according to the Behavioral Risk Factor Surveillance System.

Attitudes are changing as the public is becoming more aware about the dangers of smoking, secondhand smoke, and the deceptive practices of the industry, Ibrahim said.

While the numbers offer some promise, more initiatives are needed to keep anti-smoking efforts alive.

“It’s naïve to think the industry is still not following these practices and preparing tactics to respond,” Ibrahim said.

The Master Settlement Agreement in 1998 marked an important step when seven tobacco companies agreed to change the way tobacco products are marketed, release previously secret industry documents, dispand trade groups, and pay the states an estimated $206 billion. The tobacco companies also agreed to finance a $1.5 billion public anti-smoking campaign.

States’ attorney generals continue to enforce the provisions of the agreement, Ibrahim said.

A recent product that has created uproar is Camel’s No. 9s pink cigarettes that public health advocates say target teenage girls not women. In June, congress sent a letter to the editors of 11 major magazines, from Glamour to Cosmopolitan, requesting them to stop running the ads for the cigarettes.

Aggressive efforts to battle current marketing efforts and litigation from the tobacco industry are vital to keep the best media campaigns from disappearing, Ibrahim said.

“The efforts put forth by California and the American Legacy Foundation as they pursued legal battles with tobacco companies provide a good example of the tenacity needed to successfully defend and promote tobacco control campaigns,” said Ibrahim. “Persistence can pay off. We need to go with campaigns that work,”

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The research was funded by the National Cancer Institute. For the article, Ibrahim collected the data, conducted the analysis, and drafted the article. Co-author Stanton A. Glantz from the Center for Tobacco Control Research and Education at the University of California, San Francisco, supervised the data collection, edited and revised the article.

Contact: Anna Nguyen
anna.nguyen@temple.edu
215-707-1731
Temple University

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July 11, 2007 Posted by | Alberta, American Journal of Public Health, American Legacy Foundation, Baltimore, Barcelona, Bethesda, Calgary, Cancer, COPD, Global, Global Health Vision, Global News, Italy, Japan, Lung Cancer, Medical Journals, National Cancer Institute, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, Osaka, Ottawa, Pennsylvania, RSS, RSS Feed, Slovakia, Spain, Temple University, Toronto, Uncategorized, Virginia, WASHINGTON, Washington DC, Washington DC City Feed, World News | Leave a comment

U-M, Israeli scientists report major advance in search for genes associated with colon cancer

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

Single variation on chromosome 8 may account for sizable percentage of cases
ANN ARBOR, Mich. – A 10-year study involving thousands of Israeli Jews and Arabs, led by researchers from American and Israeli institutions, has yielded important new information in the search for the genes that make a person more likely to develop colon cancer.

In a paper to be published in the July issue of Cancer Biology and Therapy, the international research team reports finding a significant link between genetic variation in a single region of human chromosome 8 and the risk of colorectal cancer.

The link was found by detailed comparisons of genetic material from thousands of colon cancer patients and non-patients, and by evaluating the incidence of colon cancer among the immediate family members of colon cancer patients.

In all, people who carry the specific genetic variation, called a marker, were found to be 23 percent more likely to have colon cancer than individuals without the marker. The researchers estimate that this single genetic variation might account for 14 percent of colorectal cancer cases in Israel, where colon cancer is the leading cause of cancer deaths. The specific marker is called the C allele of rs10505477.

Three other research teams are reporting similar findings today in the journal Nature Genetics, having simultaneously found their way to the same small area of chromosome 8, called 8q24, in the search for colon cancer genetic links. The fact that these studies were performed among other populations around the world suggests that this one genetic marker is highly influential across ethnic groups.

The new Cancer Biology and Therapy paper is by an international group of scientists from the University of Michigan Medical School and U-M School of Public Health, the Catalan Institute of Oncology in Spain, the CHS National Israeli Cancer Control Center and Technion – the Israel Institute of Technology.

It’s the product of an ongoing Michigan-Israel collaboration, the Molecular Epidemiology of Colorectal Cancer project, which for 10 years has searched for clues to colon cancer’s genetic roots using samples from large numbers of people in Israel with known ancestral heritage. The project is funded by the National Cancer Institute, with additional funding from the Irving Weinstein Foundation.

The researchers compared the genetic makeup and family history of more than 1,800 colorectal cancer patients with that of 1,900 healthy people with the same breakdown of age, gender and ethnicity – either Ashkenazi Jew, Sephardic Jew or Arab/non-Jew. Samples of tumor tissue from many cancer patients were also tested. The genetic link between the marker and colon cancer was especially strong among patients diagnosed with colon cancer at a young age, under 50 years.

Stephen Gruber, M.D., Ph.D., the co-leader of the Michigan-Israeli team and first author of the new paper, says that the new finding is particularly interesting when considered alongside recent discoveries in the genetics of prostate and breast cancer.

“The same genetic region that predisposes to colon cancer has also recently been shown to be an important region predisposing to breast cancer and prostate cancer,” he says. “The specific genetic cause for this joint susceptibility to three different cancers has not yet been discovered, but several groups are working to close in on the mechanism that might cause these cancers.”

Gruber is an associate professor of internal medicine and of human genetics in the U-M Medical School, and of epidemiology in the U-M School of Public Health. He directs the Cancer Genetics program in the U-M Comprehensive Cancer Center, which focuses on inherited cancer risks.

Genetic discovery in Israel through MECC has already proven highly informative. Senior author Gad Rennert M.D., Ph.D., of the Carmel Medical Center and the B. Rappaport Faculty of Medicine at Technion in Haifa, Israel, says “The study of populations in Israel has been shown to be exceptionally fruitful in contributing to knowledge about the genetics of leading cancers. This is due to the unique characteristics of the population and our ability to study it in a representative manner.”

Unraveling the mysteries of the susceptibility to disease is moving rapidly since the publication of the complete sequence of the human genome in 2003. Says Gruber, “The mystery of the relationship between our genetic code and disease is now starting to become clear, and many scientists are turning to the same chapter to find important clues to colorectal cancer.” He and his colleagues plan to continue their effort to zero in on the genetic variations involved in cancer.

While there is not yet a screening test for the genetic variation that was pinpointed in the study, Gruber and his co-authors emphasize that genetic testing is available for other known genetic variations linked to colorectal cancer. People with a strong family history of colon cancer, especially cases that began when relatives were younger than age 50, should get genetic counseling and have colonoscopies or other screening tests starting earlier in life than age 50.

“Colon cancer is one of the most common cancers in the United States, and the good news is that it’s largely preventable with early screening,” says Gruber. The American Cancer Society estimates that some 150,000 new cases of colon cancer will be diagnosed in 2007, and more than 50,000 deaths from colorectal cancer will occur.

Although most cancers are not “inherited,” some families are particularly susceptible to cancer and may benefit from early detection or other risk reduction strategies. People concerned about a family history of cancer, or those who have been diagnosed with colon cancer before age 50 or after having two or more relatives diagnosed with the disease, should talk to their doctor about the possible benefits of genetic counseling, Gruber says. Counseling can be done for both patients and family members.

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In addition to Gruber and Rennert, the new paper’s co-authors are Victor Moreno of U-M and the Catalan Institute of Oncology in Spain, Laura S. Rozek of U-M Hematology/Oncology, Hedy Rennert and Flavio Lejbkowicz of CHS National Cancer Control Center and Technion, Joseph D. Bonner, formerly of U-M and now at Michigan State University, and Joel K. Greenson, Thomas J. Giordano and Eric R. Fearon of the U-M Department of Pathology.

For more information, contact:

Nicole Fawcett
nfawcett@umich.edu

Kara Gavin
kegavin@umich.edu
734-764-2220

For more information on colon cancer, genetic counseling for cancer and colonoscopy, call the U-M Cancer AnswerLine toll-free at 800-865-1125 or visit http://www.mcancer.org.

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July 8, 2007 Posted by | Ancestral Heritage, B. Rappaport Faculty of Medicine at Technion in Haifa, Bethesda, Calgary, Cancer, Cancer Biology and Therapy, Catalan Institute of Oncology in Spain, Chromosome 8, CHS National Cancer Control Center and Technion, CHS National Israeli Cancer Control Center, Genetic Marker C allele of rs10505477, Irving Weinstein Foundation, journal Nature Genetics, Molecular Epidemiology, National Cancer Institute, the Israel Institute of Technology | 2 Comments

Inherited genes linked to toxicity of leukemia therapy

Contact: Summer Freeman
summer.freeman@stjude.org
901-495-3061
St. Jude Children’s Research Hospital

St. Jude researchers discover that variations in genes that affect the behavior of leukemia chemotherapy drugs in the body are linked to drug toxicity, a finding that will likely help clinicians predict how patients will respond to specific agents
Investigators at St. Jude Children’s Research Hospital have discovered inherited variations in certain genes that make children with acute lymphoblastic leukemia (ALL) susceptible to the toxic side effects caused by chemotherapy medications. The researchers showed that these variations, called polymorphisms, occur in specific genes known to influence pharmacodynamics (how drugs work in the body and how much drug is needed to have its intended effect).

The findings, made during a study of 240 children, are important because these side effects in ALL can be life-threatening and interrupt delivery of treatment, increasing the risk of relapse. The new insights gained in this study could help individualize ALL chemotherapy according to a patient’s inherited tendencies to develop toxic reactions to specific drugs.

“Such individualized therapy would eliminate the time-consuming trial-and-error approach to finding the right dose for a patient,” said Mary Relling, Pharm.D., chair of the Pharmaceutical Sciences department at St. Jude. “When the results of our findings are translated into routine clinical care, we should see less toxicity among children being treated for ALL.” Relling is senior author of a report of this work that appears in the May 15 issue of “Blood.”

The St. Jude team extracted DNA from healthy white blood cells of patients and looked for 16 polymorphisms previously known to be present in genes linked to drug pharmacodynamics. Using a variety of statistical analyses, the investigators identified links between specific polymorphisms and gastrointestinal, infectious, hepatic (liver), and neurologic toxicities during each phase of treatment. The three treatment phases were induction, the initial phase designed to cause remission of the cancer; consolidation, the follow-up after induction; and consolidation, the final phase to ensure comprehensive elimination of cancer cells.

The study showed that some of the 16 genetic polymorphisms are linked to toxic side effects during more than one treatment phase; and some caused more than one type of toxicity. Certain polymorphisms were linked to the pharmacokinetics of specific drugs— how drugs are absorbed by the body, distributed, chemically modified or broken down and eliminated. Variations in pharmacokinetics can alter the levels of drugs in the body, leading to ineffective or toxic levels in individual patients.

For example, during the induction phase, when a variety of different types of chemotherapy drugs are used, polymorphisms in the two genes that were part of a biochemical pathway that breaks down chemotherapy drugs were linked to gastrointestinal toxicity and infection, respectively. In the consolidation phase, when drugs called antifolates were the main treatment, a folate was linked to gastrointestinal toxicity, as it was during the continuation phase. And in all three phases, one polymorphism was linked to hyperbilirubinemia, or jaundice, partly caused by the drug methotrexate.

“Scientists at St. Jude and elsewhere have dramatically improved survival rates from childhood leukemia, but it’s still challenging to find the right dose for each patient,” said Rochelle Long, Ph.D., director of the National Institutes of Health Pharmacogenetics Research Network. “By finding specific genetic variations linked to how individual patients respond to therapy, this work will make medicines safer and more effective for everyone.”

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Other authors of this work include Shinji Kishi, Cheng Cheng, Deborah French, Deqing Pei, Nobuko Hijiya, Ching-Hon Pui and William Evans (St. Jude); Soma Das and Edwin Cook (University of Chicago); Carmelo Rizzari (University of Milan, Italy), Gary Rosner (M.D. Anderson Cancer Center, Houston) and Tony Frudakis (DNAPrint Genomics, Sarasota, Fla.).

This work was supported in part by the National Cancer Institute; the National Institutes of Health/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database; a Center of Excellence grant from the State of Tennessee and ALSAC.

St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org.

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May 11, 2007 Posted by | acute lymphoblastic leukemia, Chemotherapy, Genes, Leukemia, National Cancer Institute, St. Jude Children's Research Hospital | Leave a comment