Green tea boosts production of detox enzymes, rendering cancerous chemicals harmless

PHILADELPHIA − Concentrated chemicals derived from green tea dramatically boosted production of a group of key detoxification enzymes in people with low levels of these beneficial proteins, according to researchers at Arizona Cancer Center.

These findings, published in the August issue of Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research, suggest that a green tea concentrate might help some people strengthen their metabolic defense against toxins capable of causing cancer.

In a study of 42 people, the concentrate − composed of chemicals known as green tea catechins in amounts equal to that found in 8-16 cups of green tea − boosted production of the enzymes, which belong to the glutathione S-transferase (GST) family, by as much as 80 percent in some participants.

GST enzymes are believed to be crucial to the body’s defense against cancer-causing chemicals and other toxins, according to the study’s lead investigator, H.-H. Sherry Chow, Ph.D., a research associate professor at the University of Arizona. They modify the cancer-causing molecules that would otherwise damage cellular DNA, thus rendering them inert.

“They actually convert known carcinogens to non-toxic chemicals, and studies have shown a correlation between deficient expression of these enzymes and increased risk of developing some cancers,” Chow said.

“Expression of this enzyme varies dramatically in people due to genetic variation and environmental factors,” Chow added. “Green tea catechins somehow increase gene expression of these enzymes, which can be an advantage to people with low levels to start with.”

Green tea has long been of interest to researchers given studies that have shown populations in which it is often consumed, such as the Chinese and Japanese, generally have lower rates of cancer. To find out if green tea can protect against cancer, the NCI has sponsored a number of rigorous scientific studies testing capsules of the extract, Polyphenon E, that have been prepared in Japan to meet exact specifications. These pills contain epigallocatechin gallate (EGCG), a catechin known for its potent antioxidant activity, and are currently being tested against a variety of cancers in clinical trials.

This study was designed to see if green tea catechin concentrate had any effect on the levels of GST enzymes in healthy individuals − research that could explain the tea’s anti-cancer properties. Healthy volunteers were asked to abstain from consuming any tea or tea-related products for four weeks. At the end of this “washout period,” blood was drawn and baseline GST enzyme levels were determined for each participant. Then, the volunteers were asked to take four Polyphenon E capsules, for a total of 800 milligrams of EGCG, each morning on an empty stomach for four weeks and to abstain from drinking tea or eating many cruciferous vegetables, which contain other beneficial chemicals. Another blood sample was taken after four weeks, and GST activity was determined.

Researchers found that use of Polyphenon E enhanced GST activity when data from all participants were included for analysis. But it had its most significant effect in volunteers whose baseline blood measurements showed low GST activity − an 80 percent increase compared to baseline GST activity. Activity did not change in volunteers with medium GST expression, or in those with the highest levels, GST seemed to decrease slightly although researchers believe that decline was due to random variation.

“This is the first clinical study to show proof that chemicals in green tea can increase detoxification enzymes in humans,” Chow said. “There may be other mechanism in play by which green tea may protect against cancer development, but this is a good place to start.”

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The NCI supported the study and researchers from NCI also participated in conducting the study.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 26,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.

Contact: Greg Lester
lester@aacr.org
267-646-0554
American Association for Cancer Research

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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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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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New research provides hope for childhood cancer sufferers

Dr Richard Lock, Head of the Leukaemia Biology Program at the Children’s Cancer Institute Australia for Medical Research, Sydney, along with collaborators from the Childrens Hospital Los Angeles and University of Southern California, USA, recently published their findings in the prestigious scientific journal Blood.

ALL is the most common form of childhood cancer. Over the years, improvements in primary therapy have increased the cure rate to approximately 80 percent. However, for the 20 percent of patients who relapse, the majority will die.

“When used in combination with common drugs administered in ALL therapy, ABT-737 has the ability to enhance the combined toxicity of these drugs against the leukaemia cells with minimal effects on the normal cells of the body,” said Dr Lock.

Resistance to common therapeutic drugs is associated with poor long-term outcomes in leukaemia patients. In the study, the effects of ABT-737 in combination with three common chemotherapeutic agents: L-Asparaginase, vincristine and dexamethasone, were tested on a number of ALL cell lines under conditions which were considered clinically relevant for the disease.

ABT-737, developed by Abbott Laboratories, acts by inhibiting the Bcl-2 family of proteins. These proteins are expressed in ALL and inhibit the mechanisms responsible for destroying leukaemia cells. High levels of expression of Bcl-2 is linked with chemoresistance in a variety of cancers.

“There is a critical need for new drugs with novel mechanisms of action that might improve the outcome for relapsed ALL patients,” said Dr Lock.

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The manuscript is available online at http://bloodjournal.hematologylibrary.org/papbyrecent.dtl Children’s Cancer Institute Australia for Medical Research is associated with the University of NSW and Sydney Children’s Hospital.

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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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