The tiny translucent egg nestled in the special laboratory gel was a mere 30 days old, but its four-week birthday caused researchers to quietly celebrate. This was the first time anyone had successfully grown a woman’s immature egg cells, contained in a tiny sac called a follicle, to a healthy and nearly mature egg in the laboratory. When an egg is fully mature, it is ready to be fertilized.

The researchers from Northwestern University Feinberg School of Medicine have completed the first critical step in the development of a new technique, which, if successful in the next steps, may eventually provide a new fertility option for women whose cancer treatments destroy their ability to reproduce.

The nearly mature follicles grown for 30 days in the laboratory had been plucked from ovarian tissue of cancer patients before they began chemotherapy and radiation treatments that would destroy their fertility. The cancer patients, from Northwestern Memorial Hospital, had agreed to participate in the experimental fertility study, which was funded by the National Institutes of Health.

“By being able to take an immature ovarian follicle and grow it to produce a good quality egg, we’re closer to that holy grail, which is to get an egg directly from ovarian tissue that can be fertilized for a cancer patient,” said Teresa Woodruff, chief of fertility preservation at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

“This represents the basic science breakthrough necessary to better accomplish our goals of fertility preservation in cancer patients in the future,” added Woodruff, who developed the new technique with colleagues.

Woodruff is the senior author of a paper on the findings in the July 14 issue of the journal Human Reproduction.

The next step will be for Northwestern researchers to try to induce the egg’s final division, called meiosis, so it sheds half of its DNA in order to be fertilized. The ultimate goal is for scientists to be able to freeze the immature follicles, then thaw and mature them in a culture to the point where they are ready to be fertilized.

“This is a very significant achievement because the early stage of the human ovarian follicle is really hard to grow in vitro. They’re very fragile and delicate,” said Min Xu, a paper coauthor and research assistant professor at the Feinberg School.

As the immature egg grew inside the follicle, it produced hormones just as it would inside a woman’s body.

“That’s a good sign that these follicles are healthy. The actual egg also is growing to the same size that we would see in an egg that a woman’s body has ovulated,” said Susan Barrett, a coauthor and post-doctoral fellow at the Feinberg School.

Women currently have few good options to save their ability to reproduce after cancer treatment. Men are able to freeze their sperm for later use before they begin fertility-destroying cancer therapies. The best option to preserve the fertility of a female cancer patient is to collect her eggs, fertilize them with sperm and freeze the resulting embryos. However, this option is often not a practical choice because it can delay cancer treatment, can’t be performed on those who have not reached puberty, and requires fertilization — a problem for those who do not have a male partner or do not wish to use donor sperm.

Other researchers have experimented with freezing entire ovaries or strips of ovarian tissue and implanting them in a woman’s body once she is ready to have children. But for cancer patients, it is possible that cancer cells may be present in the ovarian tissue and result in a new cancer after the tissue is implanted. However, if follicles could be removed from the tissue and grown in the laboratory successfully, as this study suggests, then a new fertility preservation technique might become available for women who could not safely have an ovarian transplant.

The new Northwestern findings build on earlier research by the scientists, who grew mouse follicles in a culture, induced the eggs they contained to mature, fertilized them with mouse sperm and implanted them into female mice to establish pregnancy. The technique produced healthy, fertile generations of mice.

Woodruff, working with Lonnie Shea, professor of chemical and biological engineering at McCormick School of Engineering and Applied Science, achieved the new advance by suspending the human ovarian follicle in two different kinds of three-dimensional gels. Previous attempts to grow ovarian follicles had been on a flat surface, which the researchers now believe does not replicate conditions inside the body. These earlier attempts failed to develop good quality eggs that were healthy enough for fertilization.

Woodruff said the research also is significant because it is the first time scientists have been able to isolate and study a functioning individual human ovarian follicle.

“Because you don’t take an ovary out of young women, we’ve never before been able to look inside the follicle of the human and ask how does it work, how do hormones change, how does the estrogen change in the follicle?” explained Woodruff, who also is the Thomas J. Watkins Professor of Obstetrics and Gynecology. “We never knew how an individual follicle regulated these hormones. This paper for the first time shows these individual hormones being regulated by one growing follicle.”

The discovery, Woodruff said, will enable researchers to understand how nurse cells (granulosa cells), the cells that support and surround the maturing egg, communicate with the egg. “They provide a lot of information that the egg needs to grow and develop properly,” Woodruff said. “It’s a big priority for us to understand how the nurse cells talk to the egg.” The information, she said, will help scientists understand how eggs grow and develop properly.

Source:
Marla Paul

Northwestern University

A study based on computer modeling of radiation risk suggests that widespread screening for the buildup of calcium in the arteries using computed tomography scans would lead to an estimated 42 additional radiation-induced cancer cases per 100,000 men and 62 cases per 100,000 women, according to a report in the July 13 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Coronary artery calcification is associated with coronary artery disease. “Computed tomography (CT) has been proposed as a tool for routine screening for coronary artery calcification in asymptomatic individuals as part of a comprehensive risk assessment,” the authors write as background information in the article. Evidence suggests that this type of screening may detect the presence of calcium in the arteries of individuals who would be at low risk when assessed by traditional risk factors. “However, the potential risks of screening, including the risk of radiation-induced cancer, have to be considered along with the potential benefits.”

Kwang Pyo Kim, Ph.D., then of the National Cancer Institute, Bethesda, Md., and now of Kyung Hee University, Gyeonggi-do, Republic of Korea, and colleagues estimated the radiation doses delivered to adult patients undergoing CT screening for coronary artery calcification from a range of available protocols in the literature (there is not yet one agreed-upon standard). “Radiation risk models, derived using data from Japanese atomic bomb survivors and medically exposed cohorts, were used to estimate the excess lifetime risk of radiation-induced cancer,” the authors write.

Because of differences in scanner models and techniques, radiation dose from a single scan varied more than 10-fold, the authors note. Organs or tissues estimated to receive measurable radiation doses included the breast, lung, thyroid, esophagus, bone surface and adrenal glands. “The wide dose variation also resulted in wide variation in estimated radiation-induced cancer risk,” they continue. “Assuming screening every five years from the age of 45 to 75 years for men and 55 to 75 years for women, the estimated excess lifetime cancer risk using the median dose of 2.3 millisieverts was 42 cases per 100,000 men (range, 14 to 200 cases) and 62 cases per 100,000 women (range, 21 to 300 cases).”

There are currently no estimates of the benefits of CT screening for coronary artery calcification, but when they become available, they could be compared with these estimates of radiation-induced cancer risk to design appropriate detection and prevention strategies. “Many technical factors influence radiation dose from coronary artery calcification measurement with multidetector CT,” the authors write. “Careful optimization of these factors may reduce radiation exposure without detriment to the clinical purpose of the screening examination. Further efforts by professional societies are necessary to standardize protocols in order to decrease unnecessary radiation exposure and to minimize cancer risk.”

Arch Intern Med. 2009;169[13]:1188-1194. A

Source
Archives of Internal Medicine

When cells experiencing DNA damage fail to repair themselves, they send a signal to their neighbors letting them know they’re in trouble. The discovery, which shows that a process dubbed the DDR (DNA Damage Response) also controls communication from cell to cell, has implications for both cancer and aging. The findings appear in the July 13 online edition of the Nature Cell Biology.

When a cell experiences DNA damage, its first response is to try to repair the damage. If that doesn’t work the cell, hopefully, either commits suicide or stops dividing, two intrinsic mechanisms for preventing cancer according to Judith Campisi, PhD, lead author of the study and a faculty member at the Buck Institute for Age Research. The discovery of the extracellular signaling mechanism, which sets off an inflammatory response, explains how unsuccessful DNA repair at the cellular level impacts tissues, which are the vital units of function in complex organisms like humans, she said.

“With regard to cancer, we found that if there is a mutant and potentially cancerous cell in the vicinity of the damaged cell, the signals from the damaged cell can encourage that mutant cell to behave more aggressively cancerous,” said Campisi. “With regard to aging, we think the inflammatory signals from damaged cells propagate an aging ‘field’ whereby damage builds up over time, impacting not only the individual damaged cells, but the function of the tissue itself.” When Buck scientists disabled particular proteins involved in the DDR, the cell-to-cell communication was cut off.

Buck Institute scientist Francis Rodier, PhD, led the team that did the research in the Campisi lab. He was surprised to find that even though the DDR signaling process was activated inside the cultured human cells within minutes of the DNA damage, it took 24 to 48 hours for the damaged cells to start secreting the inflammatory signals.

“We think the cell is giving itself time to repair its DNA before alerting the immune system that there’s a problem,” said Rodier. He added that scientists were also surprised to discover that the damage-induced communication signaling pathway bypasses a powerful tumor suppressor gene known as p53. That finding gives scientists a target to shut down the inflammatory process without hampering the activity of p53, which is essential to prevent cancer. It also explains why cancerous tumors are still able to secrete inflammatory signals when p53 has mutated and lost its tumor suppressing capabilities.

“Inflammation is a hallmark symptom of cancer,” said Rodier. “Inflammation also promotes cancer, so this helps us begin to understand what’s involved in that process.”

The findings also help explain the aging process Campisi said. The immune system, which destroys damaged cells (such as skin cells whose DNA has been exposed to UV radiation), is not perfect, she said. “Damaged cells that survive the activity of the immune system are sending out continuous danger signals to surrounding cells. That constant alarm drives inflammation, which helps drive aging.” Campisi added, “Now we have a target to focus on that could stop those damaged cells from sending out the inflammatory signals.”

Other researchers involved in the study include Jean-Philippe Coppe, Christopher K. Patil, Adam Freund, Denise P. Muñoz and Albert R. Davalos, also of the Buck Institute, along with Eric Campeau, Wieteke A. M. Hoeijmakers, and Saba R. Raza of the Lawrence Berkeley National Laboratory, Berkeley, CA. The work was supported by grants from the National Institutes of Health, a grant from the California Breast Cancer Research Program, a Larry L. Hillblom Foundation fellowship, the Netherlands Organization for International Cooperation in Higher Education, the Dutch Cancer Society, and the Department of Energy under contract to the University of California.

Source:
Kris Rebillot

Buck Institute for Age Research