Scientists Probe Limits Of 'Cancer Stem-cell Model'

One of the most promising new ideas about the causes of cancer, known as the cancer stem-cell model, must be reassessed because it is based largely on evidence from a laboratory test that is surprisingly flawed when applied to some cancers, University of Michigan researchers have concluded.

By upgrading the lab test, the U-M scientists showed that melanoma---the deadliest form of skin cancer---does not follow the conventional cancer stem-cell model, as prior reports had suggested.

The findings, to be published as the cover article in the Dec. 4 edition of Nature, also raise questions about the model's application to other cancers, said Sean Morrison, director of the Center for Stem Cell Biology at the U-M Life Sciences Institute.

"I think the cancer stem-cell model will, in the end, hold up for some cancers," Morrison said. "But other cancers, like melanoma, probably won't follow a cancer stem-cell model at all. The field will have to be reassessed after more time is spent to optimize the methods used to detect cancer stem cells."

The cancer stem-cell model has steadily gained supporters over the last decade. It states that a handful of rogue stem cells drive the formation and growth of malignant tumors in many cancers. Proponents of the controversial idea have been pursuing new treatments that target these rare stem cells, instead of trying to kill every cancer cell in a patient's body.

But in a series of experiments involving human melanoma cells transplanted into mice, Morrison's team found that the tumor-forming cells aren't rare at all. They're quite common, in fact, but standard laboratory tests failed to detect most of them.

Scientists previously estimated that only one in 1 million melanoma cells has the ability to run wild, exhibiting the kind of unchecked proliferation that leads to new tumors. These aggressive interlopers are the cancer stem cells, according to backers of the model.

But after updating and improving the laboratory tests used to detect these aberrant cells, Morrison's team determined that at least one-quarter of melanoma cells are "tumorigenic," meaning they have the ability to form new tumors. The laboratory tests are known as assays.

"The assay on which the field is based misses most of the cancer cells that can proliferate to form tumors," Morrison said. "Our data suggest that it's not going to be possible to cure melanoma by targeting a small sub-population of cells."

Melanoma kills more than 8,000 Americans each year. The human melanoma cells used in the mouse experiments were provided---with the patients' consent---by a team from the U-M's Multidisciplinary Melanoma Program, one of the country's largest melanoma programs and part of the U-M Comprehensive Cancer Center.

"People were looking to the cancer stem-cell model as an exciting new source for the development of life-saving cures for advanced melanoma," said Dr. Timothy Johnson, director of the U-M melanoma program and a co-author of the Nature paper. "Unfortunately, our results show that melanoma does not strictly follow this model.

"So we'll need to redirect our scientific efforts and remain focused on the fundamental biological processes underlying the growth of melanomas in humans," said Johnson, a cutaneous oncologist. "And as we pursue new treatments for advanced melanoma, we'll have to consider that a high proportion of cancer cells may need to be killed."

Morrison and Johnson stressed that the team's findings do not broadly invalidate the cancer stem-cell model. Cancer stem cells likely do exist in some forms of cancer but are "probably much more common than people have been estimating," Morrison said.

The standard technique used to detect tumor-causing cancer cells in mouse transplants is called the NOD/SCID assay. NOD/SCID mice have defective immune systems. Scientists use the severely immunocompromised mice because the rodents don't reject transplanted human cancer cells the way normal mice would.

However, while the immune system in NOD/SCID mice is impaired, it's not completely inoperative. The mice lack T and B immune cells but still possess natural killer cells, which attack and destroy many of the transplanted human cancer cells.

Morrison's team replaced NOD/SCID mice with mice that lacked T cells, B cells and natural killer cells---and made a few other improvements to the assay. Using the modified assay, they found that about one in four transplanted melanoma cells formed tumors in the mice.

They concluded that previous studies using NOD/SCID mice vastly underestimated the number of tumor-causing melanoma cells, partly because natural killer cells wiped out many of the cancer cells. But once the natural killer cells were eliminated, the "more permissive conditions" allowed many of the transplanted melanoma cells to survive and thrive, the authors wrote.

Co-lead authors of the Nature paper are Life Sciences Institute research fellows Elsa Quintana and Mark Shackleton. In addition to Morrison and Johnson, other co-authors are U-M surgical oncologist Dr. Michael Sabel and U-M dermatopathologist Dr. Douglas Fullen.

The work was supported by the Howard Hughes Medical Institute, the Allen H. Blondy Research Fellowship and the Lewis and Lillian Becker gift.

Stress-related Disorders Affect Brain’s Processing Of Memory

Researchers using functional MRI (fMRI) have determined that the circuitry in the area of the brain responsible for suppressing memory is dysfunctional in patients suffering from stress-related psychiatric disorders. Results of the study will be presented December 3 at the annual meeting of the Radiological Society of North America (RSNA).

"For patients with major depression and other stress-related disorders, traumatic memories are a source of anxiety," said Nivedita Agarwal, M.D., radiology resident at the University of Udine in Italy, where the study is being conducted, and research fellow at the Brain Imaging Center of McLean Hospital, Department of Psychiatry at Harvard Medical School in Boston. "Because traumatic memories are not adequately suppressed by the brain, they continue to interfere with the patient's life."

Dr. Agarwal and colleagues used brain fMRI to explore alterations in the neural circuitry that links the prefrontal cortex to the hippocampus, while study participants performed a memory task. Participants included 11 patients with major depression, 13 with generalized anxiety disorder, nine with panic attack disorders, five with borderline personality disorder and 21 healthy individuals. All patients reported suffering varying degrees of stressful traumatic events, such as sexual or physical abuse, difficult relationships or "mobbing" – a type of bullying or harassment – at some point in their lives.

After reviewing a list of neutral word pairs, each participant underwent fMRI. During imaging, they were presented with one of the words and asked to either recall or to suppress the memory of its associated word.

The fMRI images revealed that the prefrontal cortex, which controls the suppression and retrieval of memories processed by the hippocampus, showed abnormal activation in the patients with stress-related disorders compared to the healthy controls. During the memory suppression phase of the test, patients with stress-related disorders showed greater activation in the hippocampus, suggesting that insufficient activation of the prefrontal cortex could be the basis for inadequate suppression of unwanted traumatic memories stored in the hippocampus.

"These data suggest that the mechanism for memory suppression is dysfunctional in patients with stress-related disorders primarily because of an alteration of the prefrontal cortex," Dr. Agarwal said. "These patients often complain of poor memory, which might in part be attributed to this altered circuitry," she added.

According to Dr. Agarwal, fMRI is an important tool in understanding the neurobiological basis of psychiatric disorders and in identifying imaging markers to psychiatric disease, helping clinicians target specific parts of the brain for treatment.

People With Peanut Allergy Can React To Lupin

Lupin is a legume belonging to the same plant family as the peanut. Lupin seeds are used for flour production and in various types of commercial foods. People afflicted with peanut allergy may also react to lupin, and the EU has recently introduced compulsory labelling of all products containing lupin.

During her doctoral work, Lise Holden developed a method of identifying lupin protein in food products. She also investigated the incidence of lupin allergy among children with food allergy and studied the proteins in lupin responsible for allergy production.

Several hundred species of lupin exist. Lupin seed, rich in protein and fibre, has formed part of the diet of some southern European and south American countries for centuries. Many are cultivated as house plants, but these are inedible. Selective breeding has given us the sweet lupin, which tastes good and has a lower content of alkaloids than previous variants.

During recent years, the use of sweet lupin has become more widespread throughout Europe. Lupin-based ingredients improve both the nutritional value and baking qualities of food, and they are commonly added to wheaten flour. Another use is as a replacement for soya, since many consumers associate soya with gene manipulation. In addition, lupin seed is gluten-free and can therefore be safely eaten by people afflicted with coeliac disease. New studies indicate that lupin protein can have cholesterol-reducing properties.

The increased use of lupin in food has led to several reported cases of allergic reactions against lupin, including in Norway. Lupin may produce allergy either by primary sensitisation or through cross-reaction with other legumes, especially peanut. People with peanut allergy should therefore be aware that they can react to food labelled as containing lupin.

Authorities, producers and sufferers all need a reliable way of identifying even small amounts of allergens in food. For her doctorate, Lise Holden developed a quantitative and sensitive immunological method for demonstrating lupin protein. The method, the first of its kind, now forms the basis of a commercial kit developed in co-operation with an English firm, HAVen. This method was utilised in a comprehensive investigation of lupin in food for the Norwegian market in 2006 - 2007, which showed that lupin is used in many different types of food such as bread, biscuits, cakes, pasta and chocolate spreads. Even though consumers are exposed to lupin in their food, lupin allergy remains a relatively rare form of allergy in Norway today.

Holden and her colleagues have in clinical studies of children conducted provocation testing with lupin. Many of the children had lupin-specific antibody in their blood without showing clinical allergy, demonstrating just how important provocation testing is for accurate diagnosis of lupin allergy.

In addition, Lise Holden worked with the identification of specific proteins in lupin that may produce allergy. Mapping such proteins may lead to a better understanding of allergy in its entirety.

Cand. scient. Lise Holden defended her thesis for Ph. D. degree, entitled "Lupin - a new food allergen: studies on the detection, antigenicity and allergenicity of lupin proteins", on October 17, 2008.

Mineral points to Martian water suitable for life

Mineral evidence for a water environment capable of supporting life has been discovered on Mars, scientists said Thursday.

An artist's conception shows what NASA's Mars Reconnaissance Orbiter has revealed, vast Martian glaciers of water ice under protective blankets of rocky debris at much lower latitudes than any ice previously identified on the Red Planet. REUTERS/NASA/Handout

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Deposits of carbonate, formed in neutral or alkaline water, were spotted by NASA's Mars Reconnaissance Orbiter, the scientists told a meeting of the American Geophysical Union in San Francisco.

"Obviously this is very exciting," said John Mustard of Brown University in Rhode Island. "It's white -- it's a bulbous, crusty material."

Carbonate is formed when water and carbon dioxide mix with calcium, iron or magnesium. It dissolves quickly in acid, so its discovery counters the theory that all water on Mars was at one time acidic.

"It would have been a pretty clement, benign environment for early Martian life," said Bethany Ehlmann, a graduate student at Brown University who led the study published in the journal Science.

"It preserves a record of a particular type of habitat, a neutral to alkaline water environment."

Carbonates on Earth like chalk or limestone sometimes preserve organic material, but scientists have found no such evidence on Mars.

The 3.6 billion-year-old carbonate was discovered in bedrock at the edge of a 930-mile-wide (1,490-km-wide) crater.

Carbonate previously had been found in minuscule amounts in soil samples provided by the Phoenix Mars Lander, Martian dust and Martian meteorites on Earth. But this is the first time scientists have found a site where carbonate formed.

The deposits are about the size of football fields and are visible in images taken by the Mars Reconnaissance Orbiter.

The deposits appear to be limited, but the neutral or alkaline water environment may once have been more widespread, said Scott Murchie, a scientist at Johns Hopkins University in Baltimore.

Phyllosilicates, which form under similar conditions to carbonate but do not dissolve in acidic environments, are abundant on Mars.

"There were these different water environments in early Mars history, (which) increases the possibilities that life started," said Richard Zurek of NASA's Jet Propulsion Laboratory in California.

New Anti-cancer Components Of Extra-virgin Olive Oil Revealed

Good quality extra-virgin olive oil contains health-relevant chemicals, ‘phytochemicals’, that can trigger cancer cell death. New research sheds more light on the suspected association between olive oil-rich Mediterranean diets and reductions in breast cancer risk.
Javier Menendez from the Catalan Institute of Oncology and Antonio Segura-Carretero from the University of Granada in Spain led a team of researchers who set out to investigate which parts of olive oil were most active against cancer. Menendez said, “Our findings reveal for the first time that all the major complex phenols present in extra-virgin olive oil drastically suppress overexpression of the cancer gene HER2 in human breast cancer cells”.
Extra-virgin olive oil is the oil that results from pressing olives without the use of heat or chemical treatments. It contains phytochemicals that are otherwise lost in the refining process. Menendez and colleagues separated the oil into fractions and tested these against breast cancer cells in lab experiments. All the fractions containing the major extra-virgin phytochemical polyphenols (lignans and secoiridoids) were found to effectively inhibit HER2.
Although these findings provide new insights on the mechanisms by which good quality oil, i.e. polyphenol-rich extra-virgin olive oil, might contribute to a lowering of breast cancer risk in a HER2-dependent manner, extreme caution must be applied when applying the lab results to the human situation. As the authors point out, “The active phytochemicals (i.e. lignans and secoiridoids) exhibited tumoricidal effects against cultured breast cancer cells at concentrations that are unlikely to be achieved in real life by consuming olive oil”.
Nevertheless, and according to the authors, “These findings, together with the fact that that humans have safely been ingesting significant amounts of lignans and secoiridoids as long as they have been consuming olives and extra-virgin oil, strongly suggest that these polyphenols might provide an excellent and safe platform for the design of new anti breast-cancer drugs”.