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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One man’s junk may be a genomic treasure

Scientists have only recently begun to speculate that what’s referred to as “junk” DNA – the 96 percent of the human genome that doesn’t encode for proteins and previously seemed to have no useful purpose – is present in the genome for an important reason. But it wasn’t clear what the reason was. Now, researchers at the University of California, San Diego (UCSD) School of Medicine have discovered one important function of so-called junk DNA.

Genes, which make up about four percent of the genome, encode for proteins, “the building blocks of life.” An international collaboration of scientists led by Michael G. Rosenfeld, M.D., Howard Hughes Medical Investigator and UCSD professor of medicine, found that some of the remaining 96 percent of genomic material might be important in the formation of boundaries that help properly organize these building blocks. Their work will be published in the July 13 issue of the journal Science.

“Some of the ‘junk’ DNA might be considered ‘punctuation marks’ – commas and periods that help make sense of the coding portion of the genome,” said first author Victoria Lunyak, Ph.D., assistant research scientist at UCSD.

In mice, as in humans, only about 4 percent of the genome encodes for protein function; the remainder, or “junk” DNA, represents repetitive and non-coding sequences. The research team studied a repeated genomic sequence called SINE B2, which is located on the growth hormone gene locus, the gene related to the aging process and longevity. The scientists were surprised to find that SINE B2 sequence is critical to formation of the functional domain boundaries for this locus.

Functional domains are stretches of DNA within the genome that contain all the regulatory signals and other information necessary to activate or repress a particular gene. Each domain is an entity unto itself that is defined, or bracketed, by a boundary, much as words in a sentence are bracketed by punctuation marks. The researchers’ data suggest that repeated genomic sequences might be a widely used strategy used in mammals to organize functional domains.

“Without boundary elements, the coding portion of the genome is like a long, run-on sequence of words without punctuation,” said Rosenfeld.

Decoding the information written in “junk” DNA could open new areas of medical research, particularly in the area of gene therapy. Scientists may find that transferring encoding genes into a patient, without also transferring the surrounding genomic sequences which give structure or meaning to these genes, would render gene therapy ineffective.

Contributors to the paper include Lluis Montoliu, Rosa Roy and Angel Garcia-Díaz of the Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología in Madrid, Spain; Christopher K. Glass, M.D., Ph.D., UCSD Department of Cellular and Molecular Medicine; Esperanza Núñez, Gratien G. Prefontaine, Bong-Gun Ju, Kenneth A. Ohgi, Kasey Hutt, Xiaoyan Zhu and Yun Yung, Howard Hughes Medical Institute, Department of Molecular Medicine, UCSD School of Medicine; and Thorsten Cramer, Division of Endocrinology, UCSD Department of Medicine.

The research was funded in part by the Howard Hughes Medical Institute and the National Institutes of Health.

Contact: Debra Kain
ddkain@ucsd.edu
619-543-6163
University of California – San Diego

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Low vitamin D levels may be common in otherwise healthy children

Many otherwise healthy children and adolescents have low vitamin D levels, which may put them at risk for bone diseases such as rickets. African American children, children above age nine and with low dietary vitamin D intake were the most likely to have low levels of vitamin D in their blood, according to researchers from The Children’s Hospital of Philadelphia.

A study in the current issue of the American Journal of Clinical Nutrition measured blood levels of vitamin D in 382 healthy children between six years and 21 years of age living in the northeastern U.S. Researchers assessed dietary and supplemental vitamin D intake, as well as body mass, and found that more than half of the children had low blood levels of vitamin D. Of the subjects, 55 percent of the children had inadequate vitamin D blood levels and 68 percent overall had low blood levels of the vitamin in the wintertime.

“The best indicator of a person’s vitamin D status is the blood level of a vitamin D compound called 25-hydroxyvitamin D,” said Babette Zemel, Ph.D., a nutritional anthropologist at Children’s Hospital and primary investigator of this study. “Vitamin D deficiency remains an under-recognized problem overall, and is not well studied in children.”

Vitamin D is crucial for musculoskeletal health. The primary dietary source of the vitamin is fortified milk, but the best way to increase vitamin D levels is from exposure to sunshine. Severe deficits in vitamin D may lead to muscle weakness, defective bone mineralization and rickets. In addition to musculoskeletal effects, vitamin D is important for immune function, and low blood levels of the vitamin may contribute to diseases such as hypertension, cancer, multiple sclerosis and type 1 diabetes. Decreased blood levels of vitamin D have also been linked to obesity.

Further study is needed to determine the appropriate blood levels of vitamin D in children, said Dr. Zemel, who added that a review of the current recommendations for vitamin D intake is needed.

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Grants from the National Institutes of Health and several private sources supported this study.

Dr. Zemel’s co-authors were Mary B. Leonard, M.D. and Virginia A. Stallings, M.D., of The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, as well as Francis L. Weng and Justine Shults, also of the University of Pennsylvania School of Medicine.

About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

Contact: Joey Marie McCool
McCool@email.chop.edu
267-426-6070
Children’s Hospital of Philadelphia

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