Researchers at the University of Nebraska Medical Center (UNMC) in Omaha have assisted in a significant discovery – the understanding of a common mechanism of cancer initiation – that could result in better cancer assessment, prevention and detection.

“We have a novel approach to cancer. We know the initiating step,” said Ercole Cavalieri, Ph.D., of the University of Nebraska Medical Center. “We think prevention of cancer can be solved by eliminating this initiating step.”

Eleanor Rogan, Ph.D., a UNMC research collaborator, continued: “We have found the first step that starts a cell down the road to becoming a cancer cell. By preventing this first step from happening, we think we can stop the development of breast or prostate cancer. The combination of an early detection test for cancer risk with administration of preventing agents should enable us to significantly reduce the number of women and men that develop breast or prostate cancer.”

The researchers have discovered that certain estrogen derivatives (metabolites) can react with deoxyribonucleic acid (DNA) to cause damage that may initiate a series of events leading to breast, prostate and other cancers. They found evidence in a simple urine test in humans. Estrogens can initiate cancer when natural mechanisms of protection do not work properly in the body, allowing estrogen metabolites to react with DNA.

“If these protections are insufficient, due to genetic, lifestyle or environmental influences, we think cancer can result,” Dr. Cavalieri said. “Now that we have the basic knowledge about this unifying mechanism of cancer initiation, we have a greater sense of urgency to assess people at risk and, at the same time, begin studies of prevention by using specific natural compounds.”

The findings are published in the December issue of the International Journal of Cancer. Findings were confirmed in a second, larger study and presented at a recent gathering of international scientists and physicians in San Antonio, Texas. The study involves researchers at the University of Nebraska Medical Center, Mayo Clinic and the Italian National Cancer Institute. A majority of the study was funded by the U.S. Army Breast Cancer Research Program Center of Excellence Award. Similar findings were reported and published about prostate cancer in the journal The Prostate in 2006.

The screening test developed by the researchers analyzes estrogen metabolite profiles in humans and can simultaneously associate the profile with risk of getting breast cancer. It involves testing a one-ounce sample of urine using a sophisticated method called tandem mass spectrometry, which analyzes about 40 estrogen-related compounds, including estrogen-DNA adducts formed by a chemical reaction of estrogen metabolites and DNA.

Researchers say the results are exciting because they show women at high risk of breast cancer can be identified by the level of adducts in a urine sample.

Researchers analyzed estrogen-DNA from 46 women with normal risk for breast cancer, 12 women at high risk of developing breast cancer, and 17 women diagnosed with breast cancer. They found women at high risk of breast cancer and the women with breast cancer had significantly higher levels of the estrogen-DNA adducts in their urine samples, while the women with normal risk for breast cancer had low levels.

“This is a very big step because we have a test in humans to determine the risk of getting breast or prostate cancer long before the tumor appears,” Dr. Cavalieri said. “We can use these estrogen-DNA adducts as a measure of cancer risk. In addition, we have begun to establish how effective natural compounds may be at preventing cancer by determining their ability to reduce the levels of these adducts in urine.”

He also said accumulating evidence suggests that specific metabolites of estrogens, if abundantly formed, can become cancer-initiating agents by reacting with DNA and generate mutations leading to cancer. DNA is composed of four bases, called adenine, guanine, cytosine and thymine, the alphabet of genetic information.

Estrogen metabolites react predominantly with the first two DNA bases, adenine and guanine, to form estrogen-DNA adducts, Cavalieri said. The resulting damage generated by the reaction can give rise to mutations that eventually initiate cancer. The important estrogen-DNA adducts spontaneously fall out of the DNA, leaving behind gaps that generate the cancer-initiating mutations.

The estrogen-DNA adducts eventually make their way out of cells and are excreted in urine.

“This finding identifies a new biomarker in the urine which appears to correlate with a women’s risk of developing breast cancer,” according to Kenneth Cowan, M.D., Ph.D., director of the UNMC Eppley Cancer Center. “While these studies need to be confirmed in a prospective study in a larger group of patients, this could become an important screening assay for women and could lead to new therapies to prevent breast cancer.”

Dr. Cavalieri said one of the major obstacles in cancer research is related to the concept that cancer is a problem of 200 diseases, a viewpoint that has impeded researchers from looking at the origin of cancers because the search would be prohibitively complex. And for this reason, he said, the origin of breast, prostate and other human cancers has been virtually unknown.

While the expression of various cancers coincides with the concept of 200 diseases, some scientists believe a common origin is a factor for many prevalent types of cancer. There is widespread agreement in the scientific community that cancer is triggered by genetic mutations in critical genes, he said.

Jose Russo, M.D., senior member from the Fox Chase Cancer Center in Philadelphia, said: “The article is the best example of translational research. They have generated a unified concept of carcinogenesis and obtained a practical marker detectable in the urine of breast cancer patients. This article provides the adequate setting to explore this concept further by laying the basis to prepare a set of prospective clinical trials testing the preventive effects of the agents or mixtures of agents that can intercept the initiation event in breast or other cancers.”

David G. Longfellow, Ph.D., president and chief executive officer of the Toxicology Forum, an international, nonprofit organization devoted to conducting open dialogues among various segments of society concerned with problems in toxicology, said the work represents a paradigm shift in detection of cancer risk in humans and provides the earliest possible rational marker for prevention strategies and regimens.

“This work conveys a very exciting message that breast and prostate cancer risk can be identified years before the development of a tumor and suggests that natural preventive agents may be effectively used to prevent the initiation step in cancer,” Dr. Longfellow said. “Although this is a single manuscript, it is based on an extensive body of work in animal models and humans which consistently supports these findings and is complemented by collaboration with many international cancer scientists.”

Journal article abstract: http://www3.interscience.wiley.com/cgi-bin/abstract/117869053/ABSTRACT.

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Every cell contains a tiny clock called a telomere, which shortens each time the cell divides. Short telomeres are linked to a range of human diseases, including HIV, osteoporosis, heart disease and aging. Previous studies show that an enzyme within the cell, called telomerase, keeps immune cells young by preserving their telomere length and ability to continue dividing.

UCLA scientists found that the stress hormone cortisol suppresses immune cells’ ability to activate their telomerase. This may explain why the cells of persons under chronic stress have shorter telomeres.

The study reveals how stress makes people more susceptible to illness. The findings also suggest a potential drug target for preventing damage to the immune systems of persons who are under long-term stress, such as caregivers to chronically ill family members, as well as astronauts, soldiers, air traffic controllers and people who drive long daily commutes.

Rita Effros, professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA, and a member of the Jonsson Cancer Center, Molecular Biology Institute and UCLA AIDS Institute, is available for interviews.

“When the body is under stress, it boosts production of cortisol to support a “fight or flight” response,” explains Effros. “If the hormone remains elevated in the bloodstream for long periods of time, though, it wears down the immune system. We are testing therapeutic ways of enhancing telomerase levels to help the immune system ward off cortisol’s effect. If we’re successful, one day a pill may exist to strengthen the immune system’s ability to weather chronic emotional stress.”

The research was published in the May issue of the peer-reviewed journal Brain, Behavior and Immunity.

The study was supported by the National Institute of Aging, National Institute of Allergy and Infectious Disease, the Geron Corp. and TA Therapeutics, Ltd.

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Brain cells known as neurons process information by joining into complex networks, transmitting signals to each other across junctions called synapses. But “neurons don’t just connect to other neurons,” emphasizes Z. Josh Huang, Ph.D., “in a lot of cases, they connect to very specific partners, at particular spots.”

Dr. Huang, a professor at Cold Spring Harbor Laboratory (CSHL), leads a team that has identified molecules guiding this highly specific neuronal targeting in the developing brains of mice. The researchers report in PLoS Biology that in some cases, these molecular guides — non-signaling brain cells known as glia — form a kind of scaffold.  This scaffold, in turn, directs the growth of nerve fibers and their connections between specific types of neurons.

As they learn through research like this how the brain develops its complex wiring, the scientists hope they can clarify what goes wrong in disorders like autism.

The Cerebellum’s ‘Organized Architecture’

Distinctive wiring patterns are unmistakable in the cerebellum, a brain region best known for controlling movement, in both mice and people. Compared to regions involved in more sophisticated functions like vision and thought, “the cerebellum is an easier place to start, because of its very organized architecture,” Dr. Huang says, although he notes that other parts of the brain have their own specific wiring patterns.

Central to the wiring architecture of the cerebellum are so-called Purkinje cells, a type of neuron that deploys a bushy array of fibers called dendrites that extend through layers of cerebellar territory. The dendrites gather signals from many other neurons in the cerebellum and send signals to other parts of the body.

The complex wiring pattern emerges during the early growth of the brain, when individual neurons migrate from their places of origin in other brain regions and emit filaments called axons that connect to particular parts of other neurons, such as the dendrites. Dr. Huang likens this process to the address on a letter that brings it from another country directly to your door by specifying the country, state, city, street, and house number. He and other brain researchers have learned much about the higher levels of this addressing scheme, identifying, for instance, chemical signals that guide axons to the right section of the brain, and different signals that lead them to the appropriate layer within that section.

How Neurons Form Synapses

Only recently, however, have Dr. Huang and his colleagues traced the chemical signals leading neurons to form synapses with specific parts of other neurons. Such sub-cellular specificity is critical to ensure the precision and reliability of communication among neurons. Synapses are the tiny gaps across which nerve cells exchange signals, conveyed by chemicals called neurotransmitters.

A few years ago, Dr. Huang’s team established that a protein from the immunoglobulin family directs one group of cerebellar neurons to connect with a specific part of Purkinje cells. Immunoglobulin proteins are best known for acting as antibodies in the immune system, where they take on myriad forms to attack new invaders. Here, however, they are observed to be involved in the wiring of the brain.

“The striking feature is that there is a lot of capacity for variety” in immunoglobulin molecules, Dr. Huang explains. In the nervous system, their versatility may help them guide cells to form synapses with specific partners. Intriguingly, Dr. Huang adds, immunoglobulins have been implicated in neural developmental disorders, such as autism. “There is good evidence that these disorders involve miswiring of the nervous system,” Dr. Huang says, which may reflect a problem with immunoglobulin-guided synapse formation.

A Guiding Scaffold Made of Glial Cells

In the work reported in their newly published paper, Dr. Huang’s team traced the sub-cellular targeting of a different set of cerebellar neurons called stellate cells, which make numerous connections to the dendritic “bush” emanating from clumps of Purkinje cells. Unlike the cells they had studied previously, however, these neurons need help to form synapses. The researchers developed sophisticated techniques to label different cell types with chemical markers, and found that non-signaling cells called glia act as a scaffold, guiding the growing axons of the stellate cells and determining where they form synapses to the Purkinje cells.

In this role, the glia act something like “matchmakers” to bring the stellate and Purkinje cells together. But Dr. Huang notes that the scaffold of glia interspersed among the neurons allows each stellate cell to make contact to many different Purkinje cells. A direct attraction between stellate and Purkinje cells, he suggests, might lead two cells two pair up exclusively.

“Bergmann Glia and the Recognition Molecule CHL1 Organize GABAergic Axons and Direct Innervation of Purkinje Cell Dendrites” appears in the April, 2008 edition of the journal PLoS Biology. The complete citation is: Fabrice Ango, Caizhi Wu, Johannes J. Van der Want, Priscilla Wu, Melitta Schachner, Z. Josh Huang
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pbio.0060103#aff1.

The paper is available online at http://dx.doi.org/10.1371/journal.pbio.0060103.

Cold Spring Harbor Laboratory is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.

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