Genetic Link Between Misery and Death Discovered; Novel Strategy Probes 'Genetic Haystack'

Interaction between nerves (red) and tumor cells (blue) in an ovary provides one way by which stress biochemistry signals can be distributed to sites of disease in the body

In ongoing work to identify how genes interact with social environments to impact human health, UCLA researchers have discovered what they describe as a biochemical link between misery and death. In addition, they found a specific genetic variation in some individuals that seems to disconnect that link, rendering them more biologically resilient in the face of adversity.
Perhaps most important to science in the long term, Steven Cole, a member of the UCLA Cousins Center for Psychoneuroimmunology and an associate professor of medicine in the division of hematology-oncology, and his colleagues have developed a unique strategy for finding and confirming gene-environment interactions to more efficiently probe what he calls the "genetic haystack."
The research appears in the current online edition of Proceedings of the National Academy of Sciences.
Using an approach that blends computational, in vivo and epidemiological studies to focus their genetic search, Cole and his colleagues looked at specific groups of proteins known as transcription factors, which regulate gene activity and mediate environmental influences on gene expression by binding to specific DNA sequences. These sequences differ within the population and may affect a gene's sensitivity to environmental activation.
Specifically, Cole analyzed transcription factor binding sequences in a gene called IL6, a molecule that is known to cause inflammation in the body and that contributes to cardiovascular disease, neurodegeneration and some types of cancer.
"The IL6 gene controls immune responses but can also serve as 'fertilizer' for cardiovascular disease and certain kinds of cancer," said Cole, who is also a member of UCLA's Jonsson Comprehensive Cancer Center and UCLA's Molecular Biology Institute. "Our studies were able to trace a biochemical pathway through which adverse life circumstances -- fight-or-flight stress responses -- can activate the IL6 gene.
"We also identified the specific genetic sequence in this gene that serves as a target of that signaling pathway, and we discovered that a well-known variation in that sequence can block that path and disconnect IL6 responses from the effects of stress."
To confirm the biochemical link between misery and death, and the genetic variation that breaks it, the researchers turned to epidemiological studies to prove that carriers of that specific genetic variation were less susceptible to death due to inflammation-related mortality causes under adverse social-environmental conditions.
They found that people with the most common type of the IL6 gene showed an increased risk of death for approximately 11 years after they had been exposed to adverse life events that were strong enough to trigger depression. However, people with the rarer variant of the IL6 gene appeared to be immune to those effects and showed no increase in mortality risk in the aftermath of significant life adversity.
This novel method of discovery -- using computer modeling and then confirming genetic relationships using test-tube biochemistry, experimental stress studies and human genetic epidemiology -- could speed the discovery of such gene and environmental relationships, the researchers say.
"Right now, we have to hunt down genetic influences on health through blind searches of huge databases, and the results from that approach have not yielded as much as expected," Cole said. "This study suggests that we can use computer modeling to discover gene-environment interactions, then confirm them, in order to focus our search more efficiently and hopefully speed the discovery process.
"This opens a new era in which we can begin to understand the influence of adversity on physical health by modeling the basic biology that allows the world outside us to influence the molecular processes going on inside our cells."
Other authors on the study were Jesusa M. G. Arevalo, Rie Takahashi, Erica K. Sloan and Teresa E. Seeman, of UCLA; Susan K. Lutgendorf, of the University of Iowa; Anil K. Sood, of the University of Texas; and John F. Sheridan, of Ohio State University. Funding was provided by the National Institutes of Health, the UCLA Norman Cousins Center and the James L. Pendleton Charitable Trust. The authors report no conflict of interest.

Blocking Inflammation Receptor Kills Breast Cancer Stem Cells, Study Finds

Scientists at the University of Michigan Comprehensive Cancer Center have uncovered an important link between inflammation and breast cancer stem cells that suggests a new way to target cells that are resistant to current treatments.
The researchers identified a receptor, CXCR1, on the cancer stem cells which triggers growth of stem cells in response to inflammation and tissue damage. A drug originally developed to prevent organ transplant rejection blocks this receptor, killing breast cancer stem cells and preventing their metastasis in mice, according to the study.
Cancer stem cells, the small number of cells that fuel a tumor's growth, are believed to be resistant to current chemotherapies and radiation treatment, which researchers say may be the reason cancer so often returns after treatment.
"Developing treatments to effectively target the cancer stem cell population is essential for improving outcomes. This work suggests a new strategy to target cancer stem cells that can be readily translated into the clinic," says senior study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center. Wicha was part of the team that first identified stem cells in breast cancer.
Results of the current study appear online Jan. 4 in the Journal of Clinical Investigation and will appear in the journal's February print issue.
CXCR1 is a receptor for Interleukin-8, or IL-8, a protein produced during chronic inflammation and tissue injury. When tumors are exposed to chemotherapy, the dying cells produce IL-8, which stimulates cancer stem cells to replicate. Addition of the drug repertaxin to chemotherapy specifically targets and kills breast cancer stem cells by blocking CXCR1.
Mice treated with repertaxin or the combination of repertaxin and chemotherapy had dramatically fewer cancer stem cells than those treated with chemotherapy alone. In addition, repertaxin-treated mice developed significantly fewer metastases than mice treated with chemotherapy alone.
"These studies suggest that important links between inflammation, tissue damage and breast cancer may be mediated by cancer stem cells. Furthermore, anti-inflammatory drugs such as repertaxin may provide a means of blocking these interactions, thereby targeting breast cancer stem cells," Wicha says.
Repertaxin has been tested in early phase clinical trials to prevent rejection after organ transplantation. In these studies, side effects seem to be minimal. There are no reports of using repertaxin to treat cancer.
Note to patients: This work was done in cell cultures and mice. Repertaxin is not available to patients at this time and no clinical trials are yet planned.
Breast cancer statisitics: 194,280 Americans will be diagnosed with breast cancer this year and 40,610 will die from the disease, according to the American Cancer Society.
Additional authors: Christophe Ginestier, Suling Liu, Mark Diebel, Hasan Korkaya, Ming Luo, Marty Brown, Jun-Lin Guan, Gabriela Dontu, all from U-M; and Julien Wicinski, Olivier Cabaud, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, all from Universite de la Mediterranee, Marseille, France
Funding: National Institutes of Health, Breast Cancer Foundation, Taubman Institute, Department of Defense, Inserm, Institut Paoli-Calmettes, Institut National du Cancer, Ligue Nationale Contre le Cancer
Disclosure: The University of Michigan has filed for patent protection on this technology, and is currently looking for a commercialization partner to help bring the technology to market.

Natural Compounds in Pomegranates May Prevent Growth of Hormone-Dependent Breast Cancer

Eating fruit, such as pomegranates, that contain anti-aromatase phytochemicals reduces the incidence of hormone-dependent breast cancer, according to results of a study published in the January issue of Cancer Prevention Research, a journal of the American Association for Cancer Research.

Pomegranate is enriched in a series of compounds known as ellagitannins that, as shown in this study, appear to be responsible for the anti-proliferative effect of the pomegranate.
"Phytochemicals suppress estrogen production that prevents the proliferation of breast cancer cells and the growth of estrogen-responsive tumors," said principal investigator Shiuan Chen, Ph.D., director of the Division of Tumor Cell Biology and co-leader of the Breast Cancer Research Program at City of Hope in Duarte, Calif.
Previous research has shown that pomegranate juice -- punica granatum L -- is high in antioxidant activity, which is generally attributed to the fruit's high polyphenol content. Ellagic acid found in pomegranates inhibits aromatase, an enzyme that converts androgen to estrogen. Aromatase plays a key role in breast carcinogenesis; therefore, the growth of breast cancer is inhibited.
Chen, along with Lynn Adams, Ph.D., a research fellow at Beckman Research Institute of City of Hope, and colleagues, evaluated whether phytochemicals in pomegranates can suppress aromatase and ultimately inhibit cancer growth.
After screening and examining a panel of 10 ellagitannin-derived compounds in pomegranates, the investigators found that those compounds have the potential to prevent estrogen-responsive breast cancers. Urolithin B, which is a metabolite produced from ellagic acid and related compounds, significantly inhibited cell growth.
"We were surprised by our findings," said Chen. "We previously found other fruits, such as grapes, to be capable of the inhibition of aromatase. But, phytochemicals in pomegranates and in grapes are different."
According to Gary Stoner, Ph.D., professor in the Department of Internal Medicine at Ohio State University, additional studies will be needed to confirm the chemopreventive action of Urolithin B against hormone-dependent breast cancer.
"This is an in vitro study in which relatively high levels of ellagitannin compounds were required to demonstrate an anti-proliferative effect on cultured breast cancer cells," said Stoner, who is not associated with this study. "It's not clear that these levels could be achieved in animals or in humans because the ellagitannins are not well absorbed into blood when provided in the diet."
Stoner believes these results are promising enough to suggest that more experiments with pomegranate in animals and humans are warranted.
Powel Brown, M.D., Ph.D., medical oncologist and chairman of the Clinical Cancer Prevention Department at the University of Texas M. D. Anderson Cancer Center, agreed with Stoner's sentiments and said these results are intriguing. He recommended that future studies focus on testing pomegranate juice for its effect on estrogen levels, menopausal symptoms, breast density or even as a cancer preventive agent.
"More research on the individual components and the combination of chemicals is needed to understand the potential risks and benefits of using pomegranate juice or isolated compounds for a health benefit or for cancer prevention," Brown said. "This study does suggest that studies of the ellagitannins from pomegranates should be continued."
Until then, Stoner said people "might consider consuming more pomegranates to protect against cancer development in the breast and perhaps in other tissues and organs."