Cancer Risk Linked to DNA ‘Wormholes’

What You Need to Know: Single-letter genetic variations within parts of the genome once dismissed as ‘junk DNA’ can increase cancer risk through wormhole-like effects on far-off genes. Researchers found that DNA sequences within ‘gene deserts’ — so called because they are completely devoid of genes — can regulate gene activity elsewhere by forming DNA loops across relatively large distances.

The study, led by scientists at The Institute of Cancer Research, London, helps solve a mystery about how genetic variations in parts of the genome that don’t appear to be doing very much can increase cancer risk.

  • Researchers developed a new technique to study the looping interactions and discovered that single-letter DNA variations linked to the development of bowel cancer were found in regions of the genome involved in DNA looping.
  • Their study, published today in Nature Communications, is the first to look comprehensively at these DNA interactions specifically in bowel cancer cells, and has implications for the study of other complex genetic diseases.
  • The researchers developed a technique called Capture Hi-C to investigate long-range physical interactions between stretches of DNA — allowing them to look at how specific areas of chromosomes interact physically in more detail than ever before. Previous techniques used to investigate long-range DNA interactions were not sensitive enough to produce definitive results.

The researchers assessed 14 regions of DNA that contain single-letter variations previously linked to bowel cancer risk. They detected significant long-range interactions for all 14 regions, confirming their role in gene regulation. These interactions are important because they can control how genes behave, and alterations in gene behaviour can lead to cancer — in fact most genetic variations that have been linked to cancer risk are not in genes themselves, but in the areas of the genome that regulate them.

Study leader Professor Richard Houlston, Professor of Molecular and Population Genetics at The Institute of Cancer Research, London, said: “Our new technique shows that genetic variations are able to increase cancer risk through long-range looping interactions with cancer-causing genes elsewhere in the genome. It is sometimes described as analogous to a wormhole, where distortions in space and time could in theory bring together distant parts of the universe. Understanding how long-range genetic regulation works is crucial to understanding how cancer develops — and could be important in finding new ways to treat the disease in the future.”

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said: “A lot of the genetic variants already linked to cancer occur in gene deserts — often very long and quite mysterious DNA sequences that don’t actually contain ‘genes’, but which are involved in causing cancer in ways we do not yet fully understand.

“DNA looping is notoriously difficult to study but this research has taken an important step to understanding what genetic variations in DNA deserts might do to drive the development of bowel cancer.”

I’m Dr. Michael Hunter.


Story Source:

The above story is based on materials provided by Institute of Cancer Research. Note: Materials may be edited for content and length.


Journal Reference:

  1. Roland Jäger, Gabriele Migliorini, Marc Henrion, Radhika Kandaswamy, Helen E. Speedy, Andreas Heindl, Nicola Whiffin, Maria J. Carnicer, Laura Broome, Nicola Dryden, Takashi Nagano, Stefan Schoenfelder, Martin Enge, Yinyin Yuan, Jussi Taipale, Peter Fraser, Olivia Fletcher, Richard S. Houlston. Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci. Nature Communications, 2015; 6: 6178 DOI: 10.1038/ncomms7178

Cite This Page:

Institute of Cancer Research. “Cancer risk linked to DNA ‘wormholes’.” ScienceDaily. ScienceDaily, 19 February 2015. <www.sciencedaily.com/releases/2015/02/150219090349.htm>.

Invadopodia: Have We Found a Key to Stopping Cancer Spread?

What You Need to Know: “Invadopodia” play a key role in the spread of cancer. The study shows that preventing these tentacle-like structures from forming can stop the spread of cancer entirely.

Background: To spread, or “metastasize,” cancer cells must enter the blood stream or lymph system, travel through its channels, and then exit to another area or organ in the body. This final exit is the least understood part of the metastatic process. Previous research has shown cancer cells are capable of producing “invadopodia,” a type of extension that cells use to probe and change their environment. However, their significance in the escape of cancer cells from the bloodstream has been unclear.

The Study: Scientists injected fluorescent cancer cells into the bloodstream of test models, and then captured the fate of these cells using high-resolution time-lapse imaging. Results confirmed the cancer cells formed invadopodia to reach out of the bloodstream and into the tissue of the surrounding organs — they essentially formed “tentacles” that enabled the tumor cell to enter the organ. However, through genetic modification or drug treatment, the scientists were able to block the factors needed for invadopodia to form. This effectively stopped all attempts for the cancer to spread.

“The spread of cancer works a lot like plane travel,” says lead author Dr. Hon Leong, now a Scientist at Lawson Health Research Institute and Western University. “Just as a person boards an airplane and travels to their destination, tumor cells enter the bloodstream and travel to distant organs like the liver, lungs, or brain. The hard part is getting past border control and airport security, or the vessels, when they arrive. We knew that cancer cells were somehow able to get past these barriers and spread into the organs. Now, for the first time, we know how.”

“Metastasis is the deadliest aspect of cancer, responsible for some 90% of cancer deaths,” says Dr. John Lewis, the Frank and Carla Sojonky Chair in Prostate Cancer Research at the University of Alberta. “These new insights give us both a new approach and a clinical window of opportunity to reduce or block the spread of cancer.”

My Take: The study findings confirm invadopodia play a key role in the spread of cancer. Most importantly, they suggest an important new target for therapy. If a drug can be developed to prevent invadopodia from forming, it could potentially stop the spread of cancer.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad: Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Secondary Reference: University of Alberta Faculty of Medicine & Dentistry. “Preventing cancer from forming ‘tentacles’ stops dangerous spread.” ScienceDaily. ScienceDaily, 29 August 2014. <www.sciencedaily.com/releases/2014/08/140829175428.htm>.

Primary Reference: Hon S. Leong, Amy E. Robertson, Konstantin Stoletov, Sean J. Leith, Curtis A. Chin, Andrew E. Chien, M. Nicole Hague, Amber Ablack, Katia Carmine-Simmen, Victor A. McPherson, Carl O. Postenka, Eva A. Turley, Sara A. Courtneidge, Ann F. Chambers, John D. Lewis. Invadopodia Are Required for Cancer Cell Extravasation and Are a Therapeutic Target for Metastasis. Cell Reports, 2014; DOI: 10.1016/j.celrep.2014.07.050

 

Can We Sort Cancer Cells with Sound Waves?

What You Need to Know: Researchers from MIT, Pennsylvania State University, and Carnegie Mellon University have devised a new way to separate cells by exposing them to sound waves as they flow through a tiny channel. Their device, about the size of a dime, could be used to detect the extremely rare tumor cells that circulate in cancer patients’ blood, helping doctors predict whether a tumor is going to spread. Separating cells with sound offers a gentler alternative to existing cell-sorting technologies, which require tagging the cells with chemicals or exposing them to stronger mechanical forces that may damage them.

“Acoustic pressure is very mild and much smaller in terms of forces and disturbance to the cell. This is a most gentle way to separate cells, and there’s no artificial labeling necessary,” says Ming Dao, a principal research scientist in MIT’s Department of Materials Science and Engineering and one of the senior authors of the paper, which appears this week in the Proceedings of the National Academy of Sciences.’

How They Do It: To sort cells using sound waves, scientists have previously built microfluidic devices with two acoustic transducers, which produce sound waves on either side of a microchannel. When the two waves meet, they combine to form a standing wave (a wave that remains in constant position). This wave produces a pressure node, or line of low pressure, running parallel to the direction of cell flow. Cells that encounter this node are pushed to the side of the channel; the distance of cell movement depends on their size and other properties such as compressibility.

However, these existing devices are inefficient: Because there is only one pressure node, cells can be pushed aside only short distances.
The new device overcomes that obstacle by tilting the sound waves so they run across the microchannel at an angle — meaning that each cell encounters several pressure nodes as it flows through the channel. Each time it encounters a node, the pressure guides the cell a little further off center, making it easier to capture cells of different sizes by the time they reach the end of the channel.

This simple modification dramatically boosts the efficiency of such devices, says Taher Saif, a professor of mechanical science and engineering at the University of Illinois at Urbana-Champaign. “That is just enough to make cells of different sizes and properties separate from each other without causing any damage or harm to them,” says Saif, who was not involved in this work.

My Take: Circulating tumor cells in clinical settings are very rare: A 1-milliliter sample of blood may contain only a few tumor cells. If we can detect these rare circulating tumor cells, we may be able to study their biology and determine whether the patient is at a high risk for the cancer taking hold in organs such as the liver, lungs, bones, or brain. While not ready for clinical use, this method is a move in the direction of better detecting circulating tumor cells in the body. I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad: Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

‘Game Theory’ Model Reveals Vulnerable Moments for Metastatic Cancer Cells

What You Need to Know: Cancer’s no game, but researchers are borrowing ideas from evolutionary game theory to learn how cells cooperate within a tumor to gather energy. Their experiments, they say, could identify the ideal time to disrupt metastatic cancer cell cooperation and make a tumor more vulnerable to anti-cancer drugs.

Game theory is a mathematical study of strategic decision-making, and has been widely used to predict conflict and cooperation between individuals and even nations, but increasingly is applied to forecasting cell-to-cell interactions in biology with an ecological perspective.

Tumors contain a variety of cells shifting between cooperative-like to competitive-like states, said Ardeshir Kianercy, Ph.D., a postdoctoral researcher in Pienta’s lab. “To study tumor cells in isolation is not enough,” he noted. “It makes sense to study their behavior and relationship with other cells and how they co-evolve together.”

In their research, the Johns Hopkins scientists used mathematical and computer tools to set up game parameters based on biological interactions between two types of tumor cells, one oxygen-rich and the other oxygen-poor. Cells within a tumor engage in different types of energy metabolism depending on how close they are to an oxygen-rich blood supply. Tumor cells in oxygen-poor areas use the sugar glucose to produce energy and, as part of the process, release a compound called lactate. Oxygen-rich cells use this lactate in a different type of energy metabolism process and, as a result, release glucose that can be used by oxygen-poor cells to burn for their own energy.

Generally, the process is an efficient partnership that can help a tumor thrive, but the partnership is always changing as the tumor cells mutate. The mutation rate influences the strength of the energy partnerships between the oxygen-rich and oxygen-poor cells and levels of glucose and lactate production and uptake, according to the scientists.

Applying game theory calculations that accounted for the tumor cells’ mutation rates and potential glucose and lactate levels, the scientists found that within certain ranges of mutation rates, “there are critical transitions when a tumor suddenly switches between different types of energy metabolic strategies,” Kianercy said. This switch in the playbook of energy production tactics may happen when tumors progress and spread.

The scientists think tumors might be especially vulnerable within this window of strategy-switching, making it a potentially ideal time for clinicians to disrupt the tumor’s environment and wreck the partnership among its cells.

Some tumor cells, for instance, may provoke the normal cells around them to release lactate for fuel. A therapy that disrupts lactate transport to the tumor cells during a critical transition “could push a tumor to a condition where cells are not cooperating with each other,” Kianercy explained. “And if they become non-cooperative, they are most likely to stay in that state and the tumor may become more vulnerable to anti-cancer therapies.”

Pienta said it isn’t clear yet whether this type of metabolic cooperation occurs in all tumors. But the game theory model used in the study gives scientists a new way to understand how cancers may progress. “We ultimately want to test how we can interrupt this process with therapies for cancer patients,” he said.

I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad: Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: Johns Hopkins Medicine. “‘Game theory’ model reveals vulnerable moments for metastatic cancer cells’ energy production.” ScienceDaily. ScienceDaily, 15 July 2014. <www.sciencedaily.com/releases/2014/07/140715141750.htm>.

 

How Dark Chocolate, Not Milk Chocolate, May Help Blood Flow

 Background: The idea that eating cocoa-rich, dark chocolate may offer greater health benefits than milk chocolate is not new. Cocoa is loaded with compounds called polyphenols that have been shown to help our bodies fend off inflammation and maybe even improve our moods.

New Evidence: And now a small study published in the Journal of the American Heart Association offers evidence of another possible benefit: improving vascular health by increasing blood flow.

Researchers studied patients with peripheral artery disease, or PAD, which affects about 20 percent of adults older than 70 in the U.S. and other Western countries. People who have PAD can have trouble walking and exercising since blood flow to their limbs becomes impaired. Cramping can be a problem, too.

As part of the study, researchers gave half of the 20 participants 40 grams (about 1.5 ounces) of dark chocolate that had at least 85 percent cocoa. The other half of the group received 40 grams of milk chocolate that had less than 30 percent cocoa. The aim was to test whether the dark chocolate could improve those patients’ ability to walk on their own on a treadmill.

“After eating the dark chocolate, [the participants] walked an average 11 percent farther,” notes study author Lorenzo Loffredo of Sapienza University of Rome.

He and his colleagues observed improved blood flow among the participants who ate the dark chocolate. “Conversely, we did not observe effects on blood flow and on walking autonomy in PAD patients after milk chocolate consumption.”

So what explains the link between dark chocolate and improved walking? The researchers say the polyphenols in dark chocolate can help reduce oxidative stress and help the body form more nitric oxide, a compound that causes blood vessels to dilate.

Interestingly, there’s another kind of intervention that leads to a similar effect: meditation. That’s right, slowing down and centering yourself, or being in the moment, as mindfulness meditation teaches, has been shown to have the same nitric oxide-producing effect in the body. And this may be beneficial for lots of people, not just those with PAD. When blood vessels open up, blood pressure tends to go down.

As hypertension expert Randy Zusman explained it when I reported on the meditation study, you can think of it as a plumbing issue. “You’re pushing the same amount of blood through a bigger pipe,” he said. “That’s what nitric oxide … does in response to relaxation.” And, it seems, dark chocolate helps that process along.

Do the results suggest that chocolate could be used as treatment? Not so fast. As physician Mark Creager of Brigham and Women’s Hospital, who reviewed the study, points out, “The overall effect [of the dark chocolate] was relatively modest.” In an email, he pointed out to us that the 11 percent increase in walking distance doesn’t add up to much — only about 40 extra feet.

“To put this in context,” says Creager, “with other forms of treatment, such as supervised exercise training, maximal walking distance increases by approximately 100 percent.”

Creager says the new study highlights the potential role of antioxidant treatment, but he says follow-up studies, including a larger number of participants, would be needed to see if the findings hold up.

I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad: Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: National Public Radio (USA): http://www.npr.org/blogs/thesalt/2014/07/02/327775106/how-dark-chocolate-not-milk-chocolate-may-help-blood-flow?utm_source=facebook.com&utm_medium=social&utm_campaign=npr&utm_term=nprnews&utm_content=20140702

Does Dietary Fiber Protect Against Asthma?

inhaler asthma breathing

The Western diet probably has more to do with the asthma epidemic than has been assumed so far because developing asthma is related to the amount of fruit and vegetables consumed. Gut bacteria ferment the dietary fibers contained in them and fatty acids enter the blood as a result, influencing the immune response in the lungs. This has been shown by a research project funded by the Swiss National Science Foundation (SNSF).

In the West, an increasing number of people have developed allergic asthma in the past fifty years. But dietary habits have also changed during the same period: fruit and vegetables are playing an ever smaller role in people’s diets. Now new results suggest that these two developments are not merely simultaneous, they are also causally linked. A team of researchers led by Benjamin Marsland from Lausanne University Hospital (CHUV) has shown in experiments with mice that the lack of fermentable fibers in people’s diet paves the way for allergic inflammatory reactions in the lungs.

When the researchers exposed the mice to an extract of house dust mites, the mice with the low-fiber food developed a stronger allergic reaction with much more mucus in the lungs than the mice with the standard diet. Conversely, a comparison between mice on a standard diet and mice who received food enriched with fermentable fibers likewise showed that these dietary fibers have a protective influence.

This protection is the result of a multi-level reaction chain, as Marsland’s team has now shown. First the fibers reach the intestine, where they are fermented by bacteria and transformed into short-chain fatty acids. These acids then enter the bloodstream and influence the development of immune cells in the bone marrow. Attracted by the extract of house dust mites, these immune cells wander into the lungs, where they eventually trigger a weaker allergic response.

Another reason why fruit and vegetables are good for you Marsland thinks that the results obtained by his group are clinically relevant not only because the share of plant fibers in Western diets is comparable to the low-fiber food of the mice, but also because the examined aspects of the immune system are virtually indistinguishable in mice and humans. Many questions still remain unanswered.

My Take:  I would like to see the study replicated in humans. Still, just one more reason to eat those fruits and vegetables. I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: Aurélien Trompette, Eva S Gollwitzer, Koshika Yadava, Anke K Sichelstiel, Norbert Sprenger, Catherine Ngom-Bru, Carine Blanchard, Tobias Junt, Laurent P Nicod, Nicola L Harris, Benjamin J Marsland. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesisNature Medicine, 2014; DOI:10.1038/nm.3444

Fiber and Colon Health

colon cancer barium enema abdomen X-ray bowels

Scientists have more reasons for you to eat fiber and not abuse antibiotics. They’ve shown that a receptor doctors already activate with mega-doses of niacin to protect patients’ cardiovascular systems also plays a key role in preventing colon inflammation and cancer, according to a study featured on the cover of the journal Immunity.

Why This Is Important: The finding helps explain why a high-fiber diet reduces the risk of colon problems and indicates that when fiber is lacking, niacin, or vitamin B3, just may help keep the colon healthy as well, said Dr. Vadivel Ganapathy, Chairman of the Department of Biochemistry and Molecular Biology at the Medical College of Georgia at Georgia Regents University and a corresponding study author.

Details, details: Mice lacking the receptor, Gpr109a, were prone to inflammation and cancer of the colon, And, when they gave niacin to mice whose healthy colonic bacteria had been wiped out by antibiotics – a frequent occurrence in chronic antibiotic use – it helped steer immune cells in the colon into a safe, anti-inflammatory mode.

Good bacteria in the colon thrive on fiber and its digestion produces butyrate, a short-chain fatty acid, which the researchers discovered years before naturally activates Gpr109a. However this relationship appears limited to the colon, where butyrate levels can soar in the face of a high-fiber diet. GlaxoSmithKline and the University of Heidelberg, Germany showed in 2003 that Gpr109a receptors on the surface of fat cells mediate the protective cardiovascular effect of niacin, including increasing good cholesterol, or HDL, while decreasing levels of disease-producing LDL. Their search for other activators identified butyrate, which led the current study’s authors to find that not only is the Gpr109a receptor expressed on the surface of colon cells, but that with sufficient fiber intake, butyrate levels in the colon can activate it.

This study shows that activation of Gpr109a in the colon by butyrate prompts immune cells, which are in ample supply in that region, to suppress rather than promote inflammation, a factor in a number of painful conditions such as ulcerative colitis, Crohn’s disease, and colorectal cancer.

Once butyrate activates the Gpr109a receptor on dendritic cells and macrophages in the colon, these immune cells start producing anti-inflammatory molecules and sending messages to the T cells, key orchestrators of immunity, to do the same. Butyrate also prompts epithelial cells that line the colon to produce cytokines, which aid wound-healing, a critical step for resolving the intestinal inflammation that occurs in ulcerative colitis and Crohn’s.

“To protect your colon, you need this receptor, as well as the fiber and butyrate which activate it,” Ganapathy said. For people who won’t or can’t eat high-fiber diets, mega-doses of niacin, may help protect the colon, the way it’s already protecting hearts, the scientists suggest.

I’m Dr. Michael Hunter. Don’t forget that dietary fiber!

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: Nagendra Singh, Ashish Gurav, Sathish Sivaprakasam, Evan Brady, Ravi Padia, Huidong Shi, Muthusamy Thangaraju, Puttur D. Prasad, Santhakumar Manicassamy, David H. Munn, Jeffrey R. Lee, Stefan Offermanns, Vadivel Ganapathy.Activation of Gpr109a, Receptor for Niacin and the Commensal Metabolite Butyrate, Suppresses Colonic Inflammation and CarcinogenesisImmunity, 2014; DOI:10.1016/j.immuni.2013.12.007