Cancer research: fruit flies take it down a notch

You wouldn’t think that those pesky flies hovering around your fruit bowl could help scientists understand cancer. Flies don’t have cancer, and a fly is, well, just a fly. However, the fruit fly Drosophila melanogaster has been one of scientists' favourite animal models for over a century, and is nowadays used to study many human diseases. New research using fruit flies has now uncovered molecular details in tissue overgrowth that explain some long-standing questions in cancer research.

Why Drosophila? When compared to other lab animals like mice, for instance, flies have many advantages. They are tiny and hence you can grow them anywhere, they are cheap to maintain (in the old days they were fed with rotten bananas) and they breed in just 12 days while mice take 12 weeks. But the most important fact is that, even though flies and humans look very different, most of their genes are the same, or very similar. So while manipulating fly genes in the lab is quite easy, when scientists understand how a gene works in the fly, these discoveries can have significant implications for human medicine.

Fruit fly Drosophila melanogaster (Credit: therealbeast/everystockphoto)

To study a human disease in flies scientists begin by making them sick. They mutate, or disrupt, the same gene that is known (or suspected) to cause the human disease, and then they try to figure out why meddling with this particular gene causes the disease symptoms, which in flies are called phenotypes. And this is exactly what Sarah Bray’s team at the University of Cambridge did to understand the molecular details of tissue overgrowth that may lead to cancer.

In a study published in the January issue of EMBO Journal, the Cambridge scientists introduced in flies a modified version of the Notch gene that makes it overactive, or in other words, the gene is always turned on, and this set off massive tissue overgrowth in the larvae, mimicking what happens in cancer. Notch is a gene that is overactive in many cancers such as breast, lung and cervical cancers, but how Notch activation triggers cancer is not understood.

The Notch gene encodes for a protein involved in cell communication. When Notch receives a signal from a neighbouring cell, it becomes activated and instructs specific genes to switch on. Each of these genes does a different job in the cell, such as telling the cell to multiply. The problem is that, with the same signal, Notch can activate many genes, and it is difficult for scientists to predict what the combined effect of turning on all these genes will be for a cell or a tissue. To make matters worse, Notch activation can have opposite cellular outcomes. For instance, in some cases Notch causes tissue overgrowth and cancer, while in others Notch stops tissue growth. This paradox has been puzzling scientists for over a decade, and is a major factor hindering progress in Notch cancer research.

Magnified Drosophila larval tissue with fluorescent marker. Left: normal tissue, right: tissue with overactive Notch. (Credit: Bray lab, University of Cambridge)

To try and solve this problem, Bray's team used genomic approaches to search for genes activated by Notch in the overgrown tumour-like larval tissues. The researchers figured that knowing which genes are abnormally activated by Notch in their simplified ‘cancer’ fly model might explain the different cellular responses to Notch. And this is exactly what they found. “We found that in a same tissue, Notch activates genes that seem antagonistic” says Alexandre Djiane, leading author in the study. But when they had a closer look the team found that these opposing genes “are actually activated in different subsets of the tissue.” Notch activation produced a central region in the tissue where cells divided slowly, surrounded by cells that multiplied very quickly. How does Notch induce these different cellular responses? Djiane explains “this regionalisation of the response is at least in part a consequence of cross-regulation between the different Notch targets themselves”. Notch can not only activate different genes in the same tissue, but some genes can also interfere with one another, in a sort of battle between genes where the winner gets to tell the cell what to do.

But are these newly found genes involved in cancer? By comparing their results with cancer patients’ databases, the authors found that several of the genes abnormally activated by Notch in the fly overgrown tissue were overactive in human cancers. This is a good indication that the genes identified in the fly may be potential candidate cancer-promoting genes in humans. But the researchers went even further. They used genetic tricks that turned these genes up or down to test what they actually do in living flies, and found that about two thirds “play a role in tissue growth and mediate the effect of Notch,” says Djiane.

“The advantage of the fruit fly is, as demonstrated in this work, that several of these candidates can be rigorously tested via fast and efficient genetic testing to confirm the functional importance of each target gene” says Marcos Vidal, a cancer biologist at the Beatson Institute for Cancer Research in Glasgow who was not involved in this study. “This kind of research complements the one performed directly from clinical samples and cell lines.”

Current cancer drugs targeting Notch have side effects because Notch is critical for many biological processes. Vidal says “[…] direct inhibition of Notch appears to have undesired side effects and therefore may not be an ideal therapeutic target itself. On the other hand, the gene targets specifically regulated by Notch in tumorous growth identified in this study, could potentially be better therapeutic targets in Notch-driven cancers.”

Reference:

Djiane, A., Krejci, A., Bernard, F., Fexova, S., Millen, K., & Bray, S. (2013). Dissecting the mechanisms of Notch induced hyperplasia The EMBO Journal, 32 (1), 60-71 DOI: 10.1038/emboj.2012.326

This article was published in The Munich Eye on the 21-01-13. You can read it here.

Smoking: the beginning of the end?

The first time on an airplane is one of those experiences that leave a stamp on your memory. My first plane trip was about 20 years ago, and I would have great recollections of that flight if not only for what happened after the 'no smoking' lights went out. Shortly after the 'ding', a cloud of cigarette smoke filled the air cabin. For hours on end, I was crammed with over hundred other people in a small, enclosed space breathing recycled smoke-infested air. Not a pleasant memory.

As appalling as this may seem today, smoking on airplanes was only banned by most airlines in the late 1990s. Since then, smoke-free laws have been gradually introduced by many countries in public transportation, hospitals and workplaces, and more recently, in indoor public spaces such as bars and restaurants.

Smoking kills up to half of its users. This is the grim reality that slaps you in the face when you read the tobacco fact sheet of the World Heath Organization (WHO). A staggering amount of scientific evidence accumulated over the past 50 years shows that smoking causes several types of cancer, cardio-vascular and respiratory diseases. Nevertheless, smoking kills over 5 million people every year and the death toll continues to rise, especially in low and middle-income countries. 

To tackle this global tobacco epidemic, the WHO established the Framework Convention on Tobacco Control in 2005. More than 170 countries have joined this treaty and agreed to put into practice a set of public health policies to protect people from second-hand smoking, to combat tobacco illegal trade and to encourage smokers to quit.

Do tobacco control policies work?

Brazil is one of the pioneer countries in implementing such policies for tobacco control. In 1990, Brazil introduced the first rises in cigarette taxes, which doubled cigarette prices in just ten years. This and other subsequent anti-smoking policies such as smoking bans on public spaces and tobacco marketing restrictions for instance, led to a remarkable drop in smoking rates from 35% in 1989 to nearly half in 2008. But it wasn't known which policies were responsible for this steep decline in the number of smokers.

In a new study published in PLoS Medicine, David Levy from Georgetown University used a computational model to answer this question. Levy found that as much as half of the reduction in smoking rates was due to cigarette price increases alone, while smoking bans and marketing controls each accounted for a 14% drop, and other policies contributed slightly less. The raw numbers are even more impressive: the model estimates that anti-smoking policies saved over 400 thousand lives over the past 20 years in Brazil, and the prediction is that by 2050 almost 7 million more lives will be saved. 

Brazil's success story tells us that anti-smoking measures can work even in low to middle-income countries, where smoking is more prevalent. However, Levy's model estimates that an additional 1.3 million deaths could be prevented by 2050 if stricter policies were introduced. So are tougher anti-smoking policies needed to eradicate smoking all together? The answer might be found on the other side of the globe.

A licence to smoke

Australia is a country strongly engaged in reducing smoking and protecting second-hand smokers. In the past 30 years since the first anti-smoking policies were implemented, the number of smokers in Australia has dropped from 34% of the population to 15% in 2010. Last week the Australian government introduced a complete ban on tobacco company logos and coloured cigarette packets, which now have a uniform greyish colour and display health warnings and gruesome images of people with smoking-related diseases (the company name is in small print at the bottom of the packet). Plain packaging might represent the beginning of the end of the smoking industry in Australia, but tobacco control activists think more can be done. 

"We are the first nation to introduce plain packaging, we have the largest per capita spend on hard-hitting campaigns, some of the most expensive cigarettes in the world, but still 14% of adults smoke and it continues to kill more people, by far, than any other cause of death" says Simon Chapman, an expert in Public Health and Tobacco Control at the University of Sydney "We don't give up at 14%".

Chapman recently proposed the controversial idea of a 'smoking licence' that would limit the access to tobacco products. He believes it is unacceptable that even though tobacco threatens both personal and public health, it can be sold anywhere and to anyone with hardly any controls. The smoker's licence would be accepted only in licensed retailers and have a set limit of cigarettes per day (the higher the limit, the more you pay). The idea is that because the access to tobacco products would be limited, young people would be put off from smoking and adult users would be encouraged to quit. 

Jeff Collin from the Global Public Health Unit at the University of Edinburgh is against the smoker's licence: 

"I think it's very unlikely that such a proposal would receive necessary levels of support for it to be politically feasible, and it could jeopardise wider support for other tobacco control measures, critically including the active support of many smokers" he says. 

Collins thinks the smoker's licence would stigmatize smokers and "shift attention away from the tobacco industry", which he believes is the driving source of the tobacco epidemic. He agrees that it is an "historical absurdity" that tobacco products are so easily accessible and not subjected to any purchasing control, but he suggests that other ways of limiting availability should be tested, rather than targeting the smokers. Collins says "Marketing control is already generally strong in Europe, but plain packaging would constitute a massive step forward. Beyond that (...) there is a need for blue skies thinking".

Second-hand smoking: the invisible killer

But are ideas like the smoker's licence that radical when we consider the health consequences of smoking not only for smokers, but non-smokers as well? Over half a million non-smokers die every year from exposure to second-hand smoke. Smoking bans in public spaces were designed to protect passive smokers but measures like this might not be enough. A survey done in 2006 by the Australian Institute of Health and Welfare revealed that smokers are less likely to agree that second-hand smoking causes health problems, even though it is well-established that second-hand smoking causes heart disease and lung cancer in non-smoking adults, and respiratory diseases in children. This unawareness of the dangers of second-hand smoking puts non-smokers at risk, children in particular.

A study published in the December issue of Pediatrics on 795 smoking parents reports that although most parents restrain from smoking in the house, about 70% smoke in the car, and nearly half of these smoke in the car when their children are present. Research shows that the air quality inside a car when someone is smoking with a window opened is similar to that of a smoky bar. A few countries like Australia, South Africa and Canada have recognised this problem and started implementing laws interdicting smoking in vehicles carrying children specifically to protect children from second-hand smoking, but in most countries this problem seems largely ignored.

The beginning of the end?

Tobacco continues to kill millions around the world but it is not all bad news. Most new cars don't have ashtrays or cigarette lighters, and crystal ashtrays are no longer a traditional item in wedding lists. These are signs that smoking is no longer a glamorous or ordinary affair, and at least in developed countries, these cultural changes are here to stay.

And there is more good news. Recent research shows that the health benefits of quitting smoking are even greater than previously thought. For instance, a new study led by researchers at Oxford University on over 1.2 million women shows that women who stop smoking before middle age can live up to 10 years longer than those who continue smoking. And even those who stop smoking later in their lives have about 50-70% less risk of developing smoking-related diseases and dying prematurely, and these results confirm previous studies performed in men.

The first smoking bans on airplanes 15 years ago caused public uproar. About ten years later, the introduction of smoke-free laws in indoor public spaces also caused intense public debate. Perhaps society is not ready for a smoker's licence yet, but maybe in a decade or two, just as we now deem smoking on airplanes absurd, we will condemn how purchasing and consuming tobacco products was once as easy as breathing air.

Image credits: FreeDigitalPhotos.net

References:

Levy, D., de Almeida, L., & Szklo, A. (2012). The Brazil SimSmoke Policy Simulation Model: The Effect of Strong Tobacco Control Policies on Smoking Prevalence and Smoking-Attributable Deaths in a Middle Income Nation PLoS Medicine, 9 (11) DOI: 10.1371/journal.pmed.1001336 

Chapman S. (2012). The Case for a Smoker's License, PLoS Medicine, 9 (11) e1001342. DOI: 10.1371/journal.pmed.1001342 

Collin J. (2012). The Case against a Smoker's License, PLoS Medicine, 9 (11) e1001343. DOI: 10.1371/journal.pmed.1001343 

Nabi-Burza E., Regan S., Drehmer J., Ossip D., Rigotti N., Hipple B., Dempsey J., Hall N., Friebely J. & Weiley V. & (2012). Parents Smoking in Their Cars With Children Present, PEDIATRICS, 130 (6) e1471-e1478. DOI: 10.1542/peds.2012-0334 

Pirie K et al. (2012) The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. The Lancet. DOI: 10.1016/S0140-6736(08)61345-8

Tobacco in Australia: A comprehensive online resource

http://www.tobaccoinaustralia.org.au/

This article was published in The Munich Eye on 7-12-12. You can read it here.

Cancer stem cell discovery could lead to new therapies

Scientists have discovered that cancers are fueled by small populations of cancer stem cells. These cells are resistant to current therapies and are thought to drive cancer relapse and metastasis, which are the main cause of death in cancer patients. The exciting findings published in August in the journals Nature and Science could lead to revolutionary new strategies for cancer treatment. 



Cancer is the second cause of death in the US and Europe, and despite an increase in cancer survival in some cancers due to prevention and early diagnosis, the survival rate for patients with cancers in advanced stages has not changed significantly in the past decades.

 



After a tumor is removed surgically or by chemo and radiotherapy, it often grows back (relapse) and spreads to other parts of the body (metastasis). Scientists have believed for many years that a small population of cancerous stem cells is resistant to therapy and responsible for tumor growth, including during relapse and metastasis- this is called 'cancer stem cell hypothesis'. 


During the past 15 years, several research groups have described cancer stem cells in many types of cancer, and transplantation experiments, in which cells from biopsies of cancer patients are injected into mice, have shown that such cells could generate new tumors. However, these studies did not provide direct evidence for the existence of cancer stem cells. "This manipulation of tumors could potentially bring pitfalls and stronger evidence from unperturbed tumors were needed," said Gregory Driessens, a molecular biologist from the Université Libre de Bruxelles in Belgium.



Now researchers from three independent groups were able to 'see' cancer stem cells labeled with fluorescent markers promoting tumor growth in the brain, skin and digestive system of mice. "Our finding confirms that cancer stem cells really exist as it was suggested but not formally proven so far by grafting experiments," said Driessens, who led the study that identified cancer stem cells in skin.



Cancer stem cells consist of only about 1-3% of all cells in a tumor. So why is their discovery so important? Cancer stem cells could be the source of the most aggressive cancers with a poor prognostic. "This the first time researchers have traced the cell of origin within different tumors. Because cancers are proving to be so complex, we don't yet know how relevant this research in mice is to humans, but it gives us new insights into how cancers might develop and why they can sometimes grow back after therapy." explains Michaela Frye, a Cancer Research UK scientist based at the University of Cambridge (UK). 



"Anticancer treatments should not only be evaluated on their efficacy on the bulk tumor but also specifically for the effect on cancer stem cells, since these cells could be more resistant to chemo and radiotherapies," adds Driessens. These discoveries therefore open the way for the development of new therapies targeting cancer stem cells, which could revolutionize the treatment of cancer.

This article was published in The Munich Eye on the 14th of September 2012. You can find it here.

Sources:

Driessens, G., Beck, B., Caauwe, A., Simons, B. D. & Blanpain, C. (2012) Nature 

http://dx.doi.org/10.1038/nature11344 

Chen, J. et al. (2012) Nature http://dx.doi.org/10.1038/nature11287 

Schepers, A. G. et al. (2012) Science http://dx.doi.org/10.1126/science.1224676