New avenue for treating colon cancer

 by Biomechanism 

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An international research team led by cell biologists at the University of California, Riverside has uncovered a new insight into colon cancer, the third leading cause of cancer-related deaths in the United States. The research provides potential new avenues for diagnosing and treating the disease.

Led by Frances Sladek at UC Riverside and Graham Robertson at the University of Sydney, Australia, the team analyzed about 450 human colon cancer specimens and found that in nearly 80 percent of them the variants of a gene, HNF4A, are out of balance.

Human beings express several variants of the HNF4A gene, classified as P1 and P2 variants. Some tissues, like liver, have just one type of variant but the colon has both P1 and P2 variants. The P1 variant is found in the nuclei of cells in the normal colon but in the human colon cancer samples this variant is frequently either absent or located outside of the nucleus and, presumably, no longer functional.

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Using human colon cancer cell lines and in vitro assays, the researchers found that the imbalance observed in the human tumor tissues seemed to be the result of a complex, multi-step process by an enzyme, Src kinase. Src kinase has been known to be activated in colon cancer but, until now, it was not known to act on the HNF4a protein (HNF4A is the gene, a stretch of DNA; HNF4a is the protein encoded by HNF4A). The UCR group found that activated Src modifies the P1 but not the P2 variant. The net result is loss of the P1 variant in the nuclei of cells in the colon.

Study results appeared online last week in the Proceedings of the National Academy of Sciences.

“Loss of nuclear P1 HNF4a protein in the colon may be an early sign of colon cancer,” explained Sladek, a professor of cell biology and toxicologist. “A healthy colon has a good but delicate balance of the two HNF4a variants. If you could prevent the loss of the P1 variant via drugs, you might be able to maintain a normal colon and prevent colon cancer.”

The researchers found another factor that increases a person’s susceptibility to the disease: certain “single nucleotide polymorphisms” or SNPs located in the HNF4A gene. An SNP is a DNA sequence variation — a minor change in the genomic sequence that accounts for the variations we see between individuals. SNPs are the most common type of genetic variation among people.

Karthikeyani Chellappa (left) is a postdoctoral researcher in the lab of Frances Sladek, a professor of cell biology and toxicologist at UC Riverside. Photo credit: UCR Strategic Communications.

“Individuals with certain SNPs may be more susceptible to colon cancer,” said Karthikeyani Chellappa, a postdoctoral researcher in Sladek’s lab and the first author of the research paper. “That’s because these SNPs result in a greater amount of modification and a faster degradation of HNF4a by Src, at least in cell-based assays. It still needs to be investigated, though, whether individuals carrying these SNPs are indeed more susceptible to colon cancer.”

Sladek noted that drugs are already available for inhibiting the activity of Src kinase.

“Some of these drugs are in clinical trials for colon cancer,” she said. “It would be exciting to determine whether these drugs can maintain the P1 HNF4a protein levels, as well as inhibit the Src kinase activity.”

A multifactorial disease influenced by genetics and the environment, colon cancer starts as a small polyp in the large intestine (colon) or the rectum (end of the colon). While most of the polyps are benign, some do turn cancerous. With proper screening, the disease can be detected early, when it is most curable.

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The research was supported in part by a National Institutes of Health grant to Sladek.

Courtesy University of California, Riverside (http://www.ucr.edu) 

Climate speeds up microbial change

THE UNIVERSITY OF WAIKATO

Climate change in Antarctica’s Dry Valleys may affect the area more rapidly than previously expected. Image: sandwich_girl, Flickr CC-licensed An international team of Antarctic researchers think climate change in Antarctica’s Dry Valleys may affect the area more rapidly than previously expected. The scientists, led by Professor Craig Cary at the University of Waikato, have been studying ecosystems in the region for many years and have found that microbial communities in the soil undergo rapid and lasting changes in response to contemporary environmental conditions. The results of their investigation have been published this week in Nature Communications, an international online science journal. Biological Changes “We used to think that changes in microbial change took place slowly over centuries,” says Professor Cary, “but the research we’ve been doing indicates that the bacteria living in the soil are inherently sensitive to climate variability - minor temperature variations could lead to cascading changes in hydrology and biogeochemical cycling and could dramatically affect ecosystem function.” Professor Cary says a recent climate change report for Antarctica predicts the continent may experience more changes as the ozone hole begins to close over the next 50 years. “It’s important we keep documenting the current biodiversity in Antarctica so we can better predict the effects of climate change.” The research was supported through grants from the New Zealand Foundation for Research Science and Technology, Antarctica New Zealand and the National Science Foundation. The scientists measured the rate at which observed biological changes occurred beneath a seal carcass and at a nearby control site. They found that under the carcass the soil environment changed by stabilising temperatures, elevating relative humidity and reducing ultraviolet exposure. They then had to find out how quickly these changes occurred. Using Seal Carcasses To do this they transferred a 250-year-old carcass to an untouched site and used community DNA fingerprinting and new sequencing techniques to track the changes in microbial composition and structure. It took only two years for major changes to occur during the five year study. Professor Cary says Polar systems are particularly susceptible to climate change and this study will provide a foundation for future observations on the fate of life in these extreme environments. Editor's Note: Original news release can be found here.

New power source found

RMIT UNIVERSITY

Researchers at the Massachusetts Institute of Technology (MIT) and RMIT University have made a breakthrough in energy storage and power generation. The power generated relative to the energy source size is three to four times greater than what is currently possible with the best lithium-ion batteries. While on sabbatical from RMIT in 2009 and 2010, Associate Professor Dr Kourosh Kalantar-zadeh, from the School of Electrical and Computer Engineering, joined MIT Associate Professor Michael Strano's nanotechnology research group. The team was working on measuring the acceleration of a chemical reaction along a nanotube when they discovered that the reaction generated power. Now the two researchers are using their combined expertise in chemistry and nanomaterials to explore this phenomenon. Their work titled Nanodynamite: Fuel-coated nanotubes could provide bursts of power to the smallest systems is in the December IEEE Spectrum Magazine, the publication of the IEEE, the world's largest professional technology association. Associate Professor Kalantar-zadeh said that his experimental system, based on one of the materials that have come from nanotechnology — carbon nanotubes — generates power, something researchers had not seen before. “By coating a nanotube in nitrocellulose fuel and igniting one end, we set off a combustion wave along it and learned that a nanotube is an excellent conductor of heat from burning fuel. Even better, the combustion wave creates a strong electric current,” he said. “Our discovery that a thermopower wave works best across these tubes because of their dual conductivity turns conventional thermoelectricity on its head. “It's the first viable nanoscale approach to power generation that exploits the thermoelectric effect by overcoming the feasibility issues associated with minimising dimensions. “But there are multiple angles to explore when it comes to taming these exotic waves and, ultimately, finding out if they're the wave of the future.” Editor's Note: Original news release can be found here.

Right time for 'end-of-life' talk

The vast majority of patients with incurable lung or colorectal cancer talk with a physician about their options for care at the end of life, but often not until late in the course of their illness, according to a new study by Harvard-affiliated Dana-Farber Cancer Institute investigators published in the Feb. 7 issue of the Annals of Internal Medicine.

The researchers found that such belated conversations tend to occur under particularly stressful conditions — when patients have been admitted to a hospital for acute care. And the doctor who shares in the end-of-life care talk is often a hospital physician rather than an oncologist who has treated the patient for much of his or her illness.

Together, these circumstances may deprive patients of the opportunity for extended reflection and deliberation that would have been possible months earlier, when the conversation also could have occurred under less trying and hectic conditions, the authors suggest.

“Previous studies have shown that patients who discuss their end-of-life care preferences with a physician are more likely to choose palliative, comfort-focused care over aggressive measures, and [to] receive hospice or other care consistent with their wishes. But studies haven’t looked at the timing of these discussions, or where and with whom they occur,” says the study’s lead author, Jennifer Mack of Dana-Farber/Children’s Hospital Cancer Center. Mack is also an assistant professor of pediatrics at Harvard Medical School (HMS).

The new study, which involved 2,155 patients with stage IV (highly advanced) lung or colorectal cancer, found that 73 percent of the patients had a conversation about end-of-life care with a physician, according to medical records or an interview with the patient or a companion. Among the nearly 1,000 patients who passed away and whose records document an end-of-life care discussion with a physician, the median time of those discussions was 33 days before death.

Other findings pertain to the location of those discussions and the type of physician involved. Of the more than 1,000 end-of-life care discussions in medical records, 55 percent occurred in the hospital. Oncologists documented end-of-life care talks with only 27 percent of their terminally ill patients in the study.

Data for the study was provided by the Cancer Outcomes Research and Surveillance Consortium (CanCORS), a multi-region, population- and health system-based study of more than 10,000 patients with lung or colorectal cancer. Researchers interviewed patients at two time points and analyzed their medical records 15 months after diagnosis.

“It’s encouraging to see such a high percentage of patients had end-of-life care conversations with a physician,” Mack says. “There’s a concern, though, that so many of these talks are taking place late in the trajectory of the disease.”

Previous studies had estimated that fewer than 40 percent of patients with advanced cancer had end-of-life care discussions. Mack theorizes that this lower figure may reflect that earlier studies didn’t record end-of-life talks that took place shortly before patients’ death.

Other research has suggested that physicians may delay end-of-life care discussions because of a natural reluctance to broach the subject, or because it conflicts with physicians’ problem-solving, hope-giving image. While such motivations are understandable, Mack says, they may work to patients’ detriment if they postpone the conversations too long.

Mack and her colleagues are planning future studies to examine the quality and content of end-of-life care conversations, and then explore whether having such talks earlier in the course of illness can benefit patients.

The study’s senior author is HMS Professor of Medicine Jane Weeks of Dana-Farber. Co-authors include Angel Cronin and Nathan Taback of Dana-Farber; Haiden Huskamp and Nancy Keating of Harvard Medical School; Jennifer Malin of the University of California, Los Angeles; and Craig Earle of the Ontario Institute for Cancer Research.

The study was funded by grants from the National Cancer Institute, the U.S. Department of Veterans Affairs, the American Cancer Society, and the National Palliative Care Research Center.

More information: http://www.annals.org/

 

Provided by Harvard University

This story is published courtesy of the Harvard Gazette

 

, Harvard University's official newspaper. For additional university news, visitHarvard.edu

 

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Robert Karl Stonjek

Anyone can learn to be more inventive, cognitive researcher says

 

There will always be a wild and unpredictable quality to creativity and invention, says Anthony McCaffrey, a cognitive psychology researcher at the University of Massachusetts Amherst, because an "Aha moment" is rare and reaching it means overcoming formidable mental obstacles. But after studying common roadblocks to problem-solving, he has developed a toolkit for enhancing anyone's skills.

McCaffrey believes his Obscure Features Hypothesis (OFH) has led to the first systematic, step-by-step approach to devising innovation-enhancing techniques to overcome a wide range of cognitive obstacles to invention. His findings appear now in an early online issue of Psychological Science. McCaffrey, a post doctoral research fellow at the Center for e-Design at UMass Amherst and Virginia Tech, recently won a two-year, $170,000 grant from the National Science Foundation to turn his technique into software with a user-friendly graphical interface. Initial users will likely be engineers.

Looking at more than 100 significant modern and 1,000 historical inventions, McCaffrey analyzed how successful inventors overcame various cognitive obstacles to uncover the key obscure information needed to solve problems. He found that almost all innovative solutions follow two steps, as articulated by the OFH: Noticing an infrequently-seen, obscure feature and second, building a solution based on that feature.

"I detected a pattern suggesting that something everyone else had overlooked often became the basis of an inventive solution," he says. So the cognitive psychologist with degrees in computer science and philosophy, who says all three disciplines "have come in very handy to approach this from different angles," set out to study aspects of human perception and cognition that inhibit our noticing obscure features.

"I felt that if I could understand why people overlook certain things, then develop techniques for them to notice much more readily what they were overlooking, I might have a chance to improve creativity."

Psychologists use the term "functional fixedness" to describe the first mental obstacle McCaffrey investigated. It explains, for example, how one person finding burrs stuck to his sweater will typically say, "Ugh, a burr," while another might say, "Hmmm, two things lightly fastened together. I think I'll invent Velcro!" The first view is clouded by focusing on an object's typical function.

To overcome functional fixedness, McCaffrey sought a way to teach people to reinterpret known information about common objects. For each part of an object, the "generic parts technique" (GPT) asks users to list function-free descriptions, including its material, shape and size. Using this, the prongs of an electrical plug can be described in a function-free way to reveal that they might be used as a screwdriver, for example.

"The trick is how to unconceal the features relevant to your purposes," McCaffrey points out. The result of creating the function-free parts list is a tree diagram in which the description of each part does not imply a use, helping subjects see beyond common functions of any object and its parts.

Using "insight problems" involving common objects because they require no special engineering knowledge, McCaffrey designed an experiment to test whether GPT improved problem solving in a group of 14 undergraduates trained in GPT compared to a control group of 14 who were not. Both groups were given insight problems commonly used in psychological testing, plus new ones designed by McCaffrey's colleagues.

Overall, the GPT group solved 67.4 percent more problems than the control group, a dramatic and statistically significant improvement in performance. In a follow-up study asking subjects to list features for the same objects (independent of a problem), GPT-trained subjects listed the key obscure feature required for the solution 75 percent of the time compared to 27 percent for controls. This suggests it is not mere exposure to problems but rather the GPT that leads to uncovering the key obscure feature more often.

Two ideas from his philosophy background helped him think about such problems in a broad way, McCaffrey says. In Nietzsche, McCaffrey found his broad definition of "feature" that doesn't limit a theory of creativity. From Heidegger, he borrowed the notion of "unconcealment," the idea that any object can have an unlimited number of features that are gradually unconcealed within an endless array of contexts.

"I was an elementary school teacher for several years," McCaffrey adds. "With these ideas bubbling around in my brain, I gave my students a steady stream of puzzles and observed carefully when they were getting stuck." Eventually, he decided it was time for him to formally and scientifically study how people overcome these mental obstacles.

"I want to help people to notice things consciously that they might not otherwise see, and remain open to the possibilities. Noticing is one thing, and building on it or connecting it to other things is the next step. Some of this can be learned and we now have a discipline for it." He is already looking at other obstacles and plans to publish a series of innovation-enhancing techniques to address as many as two dozen distinct creativity blocks caused by the normal function of our perceptual and cognitive systems.

Provided by University of Massachusetts at Amherst

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Obesity is associated with altered brain function

 

Glucose metabolism of the caudate nucleus in the midbrain (A) was significantly higher in obese versus lean individuals (B).

In most western countries the annual increase in the prevalence and the severity of obesity is currently substantial. Although obesity typically results simply from excessive energy intake, it is currently unclear why some people are prone to overeating and gaining weight.

Because the central nervous system is intimately involved in processing of hunger signals and controlling food intake, it is possible that the cause of weight gain and obesity might be in the brain.

Researchers at the University of Turku and Aalto University have now found new evidence for the role of the brain in obesity. The researchers measured the functioning brain circuits involved in with multiple brain imaging methods.

The results revealed that in obese versus lean individuals, brain glucose metabolism was significantly higher in the brain's striatal regions, which are involved in processing of rewards. Moreover, obese individual's reward system responded more vigorously to food pictures, whereas responses in the frontal cortical regions involved in cognitive control were dampened.

"The results suggest that obese individuals' brains might constantly generate signals that promote eating even when the body would not require additional energy uptake," says Adjunct Professor Lauri Nummenmaa from the University of Turku.

"The results highlight the role of the brain in obesity and weight gaining. The results have major implications on the current models of obesity, but also on development of pharmacological and psychological treatments of obesity," Nummenmaa says.

The participants were morbidly obese individuals and lean, healthy controls. Their brain glucose metabolism was measured with positron emission tomography during conditions in which the body was satiated in terms of insulin signalling. Brain responses to pictures of foods were measured with functional magnetic resonance imaging.

The research is funded by the Academy of Finland, Turku University Hospital, University of Turku, Åbo Akademi University and Aalto University.

The results were published on January 27th, 2012 in scientific journal PLoS ONE.

Provided by Academy of Finland

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Tell me how you are -- and I know how long you will live

The way people rate their health determines their probability of survival in the following decades. Researchers from the Institute of Social and Preventive Medicine at the University of Zurich demonstrate that for ratings ranging from "excellent," "good," "fair," and "poor" to "very poor," the risk of mortality increases steadily – independently of such known risk factors as smoking, low education levels or pre-existing diseases.

How would you rate your health? This is a question that often appears on questionnaires. The answer is linked to the respondent's probability of survival or death. Needless to say, a pessimistic assessment goes hand in hand with an increased risk of illness or death. It can be assumed that on average people who rate their health as poor have an unhealthier lifestyle, are often in a fragile state of health or are already sick. However, earlier studies that only monitored the participants for a few years after the survey reveal that the correlation persists even if these factors are taken into account.

Self-rating more permanent ...

Now, researchers from the Institute of Social and Preventive Medicine at the University of Zurich demonstrate that self-rated health is also linked to the probability of survival or death over a long period of more than thirty years. In the study, which was conducted in Switzerland, men who rated their health as "very poor" were 3.3 times more likely to die than men of the same age who rated their health as "excellent", and the risk of death was 1.9 times higher in women who rated their health as "very poor" than for those who rated it as "excellent". Here, the risk increased steadily from an optimistic to a pessimistic rating: people in "excellent" health had better chances of survival than those in "good" health, the latter better chances than those in a "fair" state of health, and so on. "The steady increase in risk and the long time of over thirty years between the self-rating and the end of the observation period render it practically impossible for medical history or a dark foreboding to be main causes of the correlation observed," explains head of the study Matthias Bopp.

... risk factors taken into consideration

Even taking education levels, marital status, tobacco-related strains, medical history, the use of medication, blood pressure and blood glucose into account, the correlation between self-rated health and mortality only weakened marginally. The difference in the risk of death between the best and the worst rating was still 1:2.9 in men and 1:1.5 in women. "Our results indicate that people who rate their state of health as excellent have attributes that improve and sustain their health," concludes specialist in preventive medicine David Fäh. "These might include a positive attitude, an optimistic outlook and a fundamental level of satisfaction with one's own life."

The results of the study support the broad concept of health advocated by the World Health Organization not as the absence of disease, but rather as complete physical, mental and social wellbeing. "Good doctors should therefore not just look for the presence of risk factors or diseases, but also check which health resources their patients have and boost and consolidate them if need be," says David Fäh.

More information: Bopp M, Braun J, Gutzwiller F, Faeh D. Health Risk or Resource? Gradual and Independent Association Between Self-rated Health and Mortality Persists Over 30 years. February 9, 2012. PLoS ONE 2012. doi:10.1371/journal.pone.0030795

 

Provided by University of Zurich

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Gap between Scottish and English suicide rates widens

A new study has revealed the widening gap in suicide rates between Scotland and England & Wales due to a large extent to the number of young Scottish men taking their lives.

The research, carried out by the Universities of Manchester and Edinburgh and the Medical Research Council Social and Public Health Sciences Unit in Glasgow, examined suicide rates north and south of the border between 1960 and 2008.

The team found that the suicide rate in both men and women was in fact lower in Scotland until around 1968 when it overtook the rate in England & Wales. Suicides among men continued to rise on both sides of the border until the early 1990s when rates in England & Wales began to fall and the gap between north and south widened markedly.

"Our research reveals that the suicide rate in Scotland compared to that in England & Wales has three distinct phases," said joint lead researcher Dr Roger Webb, from The University of Manchester's Centre for Suicide Prevention.

"Up until the late 1960s, the suicide rate in England was always higher than that in Scotland, but around 1968 the rates 'crossed over' with Scotland having the higher rate in both genders. In phase two, between 1969 and 1991, the rates remained steadily higher in Scotland than in England, but from 1992 onwards we see a third phase where the suicide mortality gap between the two countries widened markedly."

The study, published online by The British Journal of Psychiatry today (Thursday), looked at suicide trends by gender and by age group (15-44, 45-64 and 65-plus years), as well as method of suicide.

Dr Webb said: "The research clearly indicates that much of the divergence in the national suicide rates has been driven by a marked increase in risk among Scottish young adults, especially males, and deaths by hanging in this group in particular. Our analyses also suggest that the difference in risk over time between countries is unlikely to be explained by cause of death classification differences.

"However, one of the key changes in methods used during the study period was the marked increase in suicide by hanging, particularly among young men in Scotland. This is of particular concern as hanging has high case fatality and is difficult to prevent, except within institutional settings. It has been proposed that a public information campaign about hanging would be the most useful way to tackle the increase of suicide deaths by this method."

Joint lead researcher Professor Stephen Platt, from the University of Edinburgh's Centre for Population Health Sciences, added: "This study adds to our understanding about patterns of suicide in Great Britain by producing sound evidence on divergences in long-term trends in Scotland compared to England & Wales. In a future companion paper we will suggest explanations for the persisting higher rate of suicide in Scotland."

More information: 'Trends in national suicide rates for Scotland and for England & Wales, 1960-2008,' British Journal of Psychiatry.

Provided by University of Manchester

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Tackling financial exploitation of elderly people

Professionals who are in close contact with elderly people could soon be in a better position to spot if they are being financially exploited, for example through a lottery scam or by a deceitful relative draining the bank account, thanks to a pioneering new study funded by the UK Research Councils' New Dynamics of Ageing programme (NDA).

Researchers have started to untangle the complex decision-making process that professionals go through when confronted with an elderly person whose financial situation raises suspicions that exploitation may be taking place. The research was led by psychologist Professor Mary Gilhooly of Brunel University, who worked with colleagues from Brunel and the universities of Hertfordshire, Plymouth, Northumbria and East Anglia.

"The number of frail and mentally impaired older people in society is increasing, and there are growing challenges with money handling," said Professor Gilhooly. "There are many stories of elderly people being financially exploited through scams or relatives - although there has not been enough academic research on the issue. "

The researchers wanted to find out how professionals who deal with the elderly make decisions relating to potential financial exploitation – what information they use, how they weigh it up, and whether they decide to act or not.

"It is a complex process," said Professor Gilhooly. "First you have to notice that something is wrong, then you have to decide whether it is abuse and this is clearly not straightforward. You need to make the decision whether to do something or not, and if you do decide to intervene you need the appropriate skills. Things could go wrong at any one of these points."

The researchers focused on three groups of professionals: healthcare workers, social care workers and bankers. The professionals were presented with a range of scenarios based on real-life cases of financial abuse and questioned on how they would respond and what 'cues' would raise their suspicions of something being amiss.

"We found that while there may be multiple cues that could be taken into account when considering the likelihood that financial exploitation is taking place, only two or three are really important," said Professor Gilhooly.

Amongst social care and health professionals only two factors had a significant influence on the certainty of abuse: 

• The older person's mental capacity. 
  In cases where the older person was more confused and forgetful, this increased suspicion that financial abuse was taking place.
• The nature of the financial problem. 
  Financial problems where building work had been paid for but had not been carried out were seen as the strongest indicator of abuse. Cases where there was very little money for day-to-day necessities were given the lowest certainty of abuse.

Amongst banking and finance professionals, three case features significantly influenced certainty of financial abuse: 

• The nature of the financial problem. 
  Certainty of abuse was highest when the financial problem involved a customer asking to transfer money overseas to claim a cash prize. Cases where the bank account was unexpectedly overdrawn were rated the lowest certainty of abuse.
• The older person's mental capacity. 
  In cases where the older person was more confused and forgetful, there was increased suspicion that financial abuse was taking place.
• Person in charge of the money. 
  Banking and financial professionals were less certain if financial abuse was occurring if the older person was in charge of his or her own finances.

"By systematically analysing how these decisions are arrived at, such as is exploitation taking place and should we act upon it, should allow a better understanding of the most important signs to look out for and then how best to tackle the issue," said Professor Gilhooly. "We think that the case studies we devised could be useful training tools." A follow-up study sponsored by the Economic and Social Research Council (ESRC) has recently been launched to investigate the potential of online training of professionals in understanding these various cues.

Provided by Economic & Social Research Council

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Cancer’s First Step

A single mutant cell breaks free of its neighbors in the early stages of cancer development.

By Megan Scudellari |

Normal, healthy tissues regularly suppress the growth of tumors, preventing cancerous cells from proliferating and metastasising. Yet how this process happens on a molecular level has largely remained a mystery. Now researchers have presented one model of how the local environment regulates and prevents the expansion of a single mutant cell into a tumour.

The finding, published this week in Nature, confirms past studies that show cancer is not simply a product of the buildup of DNA mutations in a cell, but rather is dependent on the architecture of a cell’s local environment.

“It’s definitely an interesting phenomenon,” says Douglas Brash

 

, who studies skin cancer at Yale University and was not involved in the research. “This paper affirms that cancer is not a cell autonomous process; that the neighborhood really matters.”

Past experiments demonstrated that embryos can suppress tumors. In one classic study

 

, for example, injection of a tumor-causing virus rapidly induced tumors in the wings of hatched chicks but not in 4-day-old chick embryos. But there have been few experiments examining the phenomenon on a molecular level in tissue culture.

Joan Brugge

 

 and Cheuk Leung at Harvard Medical School used a 3D cell culture of human mammary epithelial cells to examine what happens to a single oncogene-expressing cell in a tissue-like environment. The researchers used viral vectors to over-express oncogenes, which had been previously associated with epithelial cancer, one at a time in single cells in the 3D structure. Overexpression of Myc, a master transcription factor, or mutant activated AKT1, which perturbs cell checkpoints, did not result in the proliferation of the cell. “We found that majority of the oncogenes were unable to proliferate as single cells in the context of a normal, growth-arrested structure,” says Brugge.

But cells that overexpressed ERBB2—a cell receptor encoded by a gene that is amplified in 30 percent of breast tumors—moved into the center of the tissue culture, an open space called the lumen. There, freed from its normal neighbors, the single mutant cell began to proliferate.

Through additional experiments, the researchers found that ERBB2 expression affects extracellular matrix proteins, disrupting local cell-matrix attachments and allowing the cell to break free and move into the unrestricted space of the lumen. When the ERBB2 cell’s ability to move to the lumen was blocked, it remained next to neighboring cells and was no longer able to proliferate. They also found that simply by weakening cell-cell connections in the tissue, mutants expressing other oncogenes that were previously benign, including activated AKT1, were able to move into the lumen and proliferate. “The geography of a mutant cell’s neighbors is affecting whether the mutant cell moves to a different part of the tissue,” says Brash.

Next, Brugge plans to investigate how mature neighboring cells prevent single mutated cells from proliferating and if other factors in the environment, such as immune cells, influence the fate of the mutated cell. “We want to understand the nature of the suppressive effect of normal mature structures,” she says.

C. Leung et al., “Outgrowth of single oncogene-expressing cells from suppressive epithelial environments,” Nature

 

, doi:10.1038/nature10826, 2012.

Source: TheScientist
http://the-scientist.com/2012/02/08/cancers-first-step/

 

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