Posts Tagged ‘cancer’

As many as one in three women treated for breast cancer undergo unnecessary procedures, but a new method for diagnosing it could do a better job distinguishing between benign and aggressive tumors.

Researchers at the University of Michigan are developing a pill that makes tumors light up when exposed to infrared light, and they have demonstrated that the concept works in mice.

Mammography is an imprecise tool. About a third of breast cancer patients treated with surgery or chemotherapy have tumors that are benign or so slow-growing that they would never have become life-threatening, according to a study out of Denmark last year. In other women, dense breast tissue hides the presence of lumps and results in deaths from treatable cancers. All that, and mammograms are notoriously uncomfortable.

“We overspend $4 billion per year on the diagnosis and treatment of cancers that women would never die from,” said Greg Thurber, U-M assistant professor of chemical engineering and biomedical engineering, who led the team. “If we go to molecular imaging, we can see which tumors need to be treated.”

The move could also catch cancers that would have gone undetected. Thurber’s team uses a dye that responds to infrared light to tag a molecule commonly found on tumor cells, in the blood vessels that feed tumors and in inflamed tissue. By providing specific information on the types of molecules on the surface of the tumor cells, physicians can better distinguish a malignant cancer from a benign tumor.

Compared to visible light, infrared light penetrates the body easily—it can get to all depths of the breast without an X-ray’s tiny risk of disrupting DNA and seeding a new tumor. Using a dye delivered orally rather than directly into a vein also improves the safety of screening, as a few patients in 10,000 can have severe reactions to intravenous dyes. These small risks turn out to be significant when tens of millions of women are screened every year in the U.S. alone.

But it’s not easy to design a pill that can carry the dye to the tumor.

“To get a molecule absorbed into the bloodstream, it needs to be small and greasy. But an imaging agent needs to be larger and water-soluble. So you need exact opposite properties,” Thurber said.

Fortunately, they weren’t the only people looking for a molecule that could get from the digestive system to a tumor. The pharmaceutical company Merck was working on a new treatment for cancer and related diseases. They got as far as phase II clinical trials demonstrating its safety, but unfortunately, it wasn’t effective.

“It’s actually based on a failed drug,” Thurber said. “It binds to the target, but it doesn’t do anything, which makes it perfect for imaging.”

The targeting molecule has already been shown to make it through the stomach unscathed, and the liver also gives it a pass, so it can travel through the bloodstream. The team attached a molecule that fluoresces when it is struck with infrared light to this drug. Then, they gave the drug to mice that had breast cancer, and they saw the tumors light up.

The research is described in a study in the journal Molecular Pharmaceutics, titled, “Oral administration and detection of a near-infrared molecular imaging agent in an orthotopic mouse model for breast cancer screening.”

This work was done in collaboration with David Smith, the John G. Wagner Collegiate Professor of Pharmaceutical Sciences at the U-M College of Pharmacy. It was supported by the Foundation for Studying and Combating Cancer and the National Institutes of Health.
Bhatnagar, S., Verma, K. D., Hu, Y., Khera, E., Priluck, A., Smith, D., & Thurber, G. M. (2018). Oral Administration and Detection of a Near-Infrared Molecular Imaging Agent in an Orthotopic Mouse Model for Breast Cancer Screening. Molecular Pharmaceutics. doi:10.1021/acs.molpharmaceut.7b00994

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A small, daily dose of Viagra significantly reduces colorectal cancer risk in an animal model that is genetically predetermined to have the third leading cause of cancer death, scientists report.

Viagra cut in half the formation of polyps, an abnormal and often asymptomatic clump of cells on the lining of the intestines that may become cancer, says Dr. Darren D. Browning, cancer researcher at the Georgia Cancer Center and Department of Biochemistry and Molecular Biology at the Medical College of Georgia at Augusta University.

Next steps should include a clinical trial for the drug in patients considered at high risk of colorectal cancer, such as those with a strong family history, multiple previous polyps and chronic intestinal inflammation like colitis, Browning says.

Viagra has been used safely for years in a wide range of doses and age groups, from premature infants with pulmonary hypertension to the elderly with erectile dysfunction, he notes.

When placed in the drinking water, Browning’s team found that Viagra reduced polyps in a mouse model with a genetic mutation that occurs in humans, causing them to produce hundreds of polyps starting as teenagers and essentially always resulting in colorectal cancer, says Browning, corresponding author of the study in the journal Cancer Prevention Research.

“Giving a baby dose of Viagra can reduce the amount of tumors in these animals by half,” Browning says.

Viagra is best known for its ability to relax the smooth muscle cells around blood vessels so the vessels can more easily fill with blood, which is how it helps both erectile dysfunction and pulmonary hypertension. But Browning’s lab is showing it also increases levels of the chemical cyclic GMP, which is known to affect the intestinal lining, called the epithelium.

While the details of just how remain unclear, Browning and his team have seen that the results of increased cyclic GMP include suppression of some of the excessive cell proliferation that occurs in the gut and an increase in normal cell differentiation as well as the natural elimination of abnormal cells, through a process called apoptosis.

“When we give Viagra, we shrink the whole proliferating compartment,” says Browning, in an area of our body that directly deals with whatever we put in our mouths and normally experiences high cell turnover “Proliferating cells are more subject to mutations that cause cancer.”

Existing polyps were not affected, more evidence that targeting cyclic GMP signaling appears to be a good prevention strategy in high-risk patients, he says.

Viagra is known to inhibit PDE5, a naturally occurring enzyme in colon cells – and other tissues – that breaks down cyclic GMP so there is more of it available to reduce cell proliferation and improve differentiation into cells like the goblet cells that secret protective mucus.

Guanylyl-cyclase C, or GCC, is the primary source of cyclic GMP in the intestinal lining. Mice like those in his study with the genetic predisposition for polyps, were found to have reduced levels of GCC-activating peptides, which are also commonly lost in human colon cancers.

The mice have mutations in the APC – adenomatous polyposis coli – gene, a known tumor suppressor. Like these mice, people with mutations in the APC gene can develop hundreds of polyps in the colon and rectum and are considered at highest risk for colorectal cancer, says Browning of the inherited disorder called familial adenomatous polyposis. The average age at which individuals develop colon cancer is 39, according to the National Institutes of Health.

The scientists also looked at the prescription drug linaclotide, which is used to treat constipation and irritable bowel syndrome with constipation and, like Viagra, is known to increase cyclic GMP. While linaclotide was also effective at significantly reducing polyp formation, the common side effect of diarrhea at pretty much any dose makes it unlikely that patients would find it tolerable to use long term, even to reduce their cancer risk, Browning says. The low doses of Viagra used by humans and in the lab, on the other hand, have no known side effects, Browning notes.

Browning’s lab published a paper in July in Cancer Prevention Research that showed Viagra cut polyp formation in half in a mouse model of colitis, an inflammation of the colon and risk factor for colorectal cancer. But in this model as well, they found the drug targeted problems from the genetic mutations, although inflammation also was reduced.

He notes that inflammation is the driver in less than 5 percent of colorectal cancers. About 80 percent form spontaneously when cells in this high-cell turnover area divide and develop a mutation that may support uncontrolled proliferation. Mutations occur most often when we consume carcinogens like those found in processed or over-cooked meats.

In one of the first successes of its kind, researchers from Case Western Reserve University School of Medicine and six other institutions have inhibited the spreading of cancer cells from one part of the body to another. In doing so, they relied on a new model of how cancer metastasizes that emphasizes epigenetics, which examines how genes are turned on and off.

In a study published in Nature Medicine, the investigators—including scientists from the National Cancer Institute and Cleveland Clinic—used innovative epigenetic-centered techniques to halt the spread of bone cancer (osteosarcoma) cells to the lungs in mice.

The large majority of deaths associated with osteosarcoma are due to the spreading of the cancer to the lungs, a process known as metastasis. Most human osteosarcoma cases occur in children and young adults between the ages of 10 and 30, with teens the most frequently affected age group. Clinical outcomes for patients with osteosarcoma have not improved for more than 30 years, and there are currently no approved targeted anti-metastatic therapies for the disease in wide clinical use.

“More than 90 percent of all cancer deaths are the result of tumor metastasis, not primary-site tumors,” said the study’s senior author, Peter Scacheri, professor of genetics and genome sciences at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Center. “While many of the genes responsible for metastasis have been identified, the mechanisms that control these genes are not well defined. Our findings demonstrate that altered gene-enhancer activity is fundamental to a cancer cell’s ability to metastasize.”

Gene enhancers are short segments of DNA that, when bound by specialized proteins called transcription factors, function like switches to activate genes. This process is critical for normal development, as when a single fertilized egg develops into the many different cell types that comprise the body.

There are tens of thousands of gene enhancers in each cell, far more than the number of genes; they will be in different “on” and “off” positions in, for example, eye and heart cells (or gradients thereof, like a dimmer switch’s effects on the brightness-level of a light). These distinctive “on and off” profiles lend cells their unique characteristics, even though they all have the same DNA.

But faulty enhancer regulation appears to contribute to tumor-formation and subsequent spreading of cancer cells. In addition, different cancers are distinguishable by different enhancer patterns.

In this new study, the authors show that the on-off switches of cancer cells that have metastasized are in different positions than in the cells of the source tumor.

“Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumors to form in the first place,” said the study’s lead author, James J. Morrow, a medical student in the Medical Scientist Training Program at Case Western Reserve University School of Medicine. “Unfortunately, searching for gene mutations that drive metastasis has not substantially improved outcomes for patients with metastatic disease. Five-year survival rates for cancer patients with regional or localized disease have significantly improved for many types of cancer. But with few exceptions, outcomes for patients with metastatic cancer have remained stagnant.

“It is well established that primary tumor formation is driven by a combination of genetic and epigenetic events,” he continued. “So based on the knowledge that enhancers drive both normal cell development and tumor-formation, we hypothesized that they may play a similar role in the transition of cancer cells from one developmentally distinct tissue to another during metastatic progression.”

Through epigenomic profiling experiments, the Case Western Reserve-led researchers consistently identified certain bunched clusters of enhancers—known as metastatic variant enhancer loci (Met-VELs)—near cancer genes in lung metastases of patients with osteosarcoma, indicating that they were central to the metastatic process. Using experimental mouse models, the researchers then showed that growth of osteosarcoma cells in the lung can be mitigated by using BET inhibitors (anti-cancer drugs currently in clinical trials), which broadly interrupt the function of Met-VELs in driving gene expression.

Second, they demonstrated that the metastatic capacity of osteosarcoma cells can be diminished by blocking expression of individual genes regulated by Met-VELs or the transcription factors driving that regulation. They verified that a particular Met-VEL-linked gene, Tissue Factor (F3), is essential for metastatic colonization. Specifically, interrupting the signaling and pro-coagulant (blood clotting) functions of F3 with antibodies inhibiting these functions was sufficient to prevent metastasis. Additionally, they showed that deleting a single Met-VEL regulating F3 expression via the TALEN gene-editing process achieved a similar effect.

“Our experiments show that removing a single enhancer of the F3 gene in tumor cells virtually eliminates their ability to metastasize in mice,” said Scacheri. “Collectively, our findings establish that enhancer elements endow tumor cells with metastatic capacity and that targeted inhibition of genes associated with enhancer alterations, or deleting altered enhancers themselves is sufficient to block metastatic colonization and proliferation. While our work focused on lung metastasis in osteosarcoma, the findings have implications for other types of metastatic cancer as well.”

The Case Western Reserve University School of Medicine focus on epigenetics in the new study represents a break with the prevailing model for metastasis, which largely explores mutations in the genes—not if or how certain genes are turned on or off. And the preponderance of current cancer research takes place on the early stages of disease, such as how tumors are formed and on what distinguishes cancer cells from normal cells, and not on metastasis. Additionally, most cancer medications and treatments today were developed to kill primary tumors, not cancer cells that have spread elsewhere.

http://thedaily.case.edu/researchers-inhibit-cancer-metastases-via-novel-steps/

Is your child having a tough time sleeping properly? You may need to keep a check on his/her body mass index (BMI) as a new research suggests that there is a co-relation between the two and can lead to cancer in adulthood.

“Childhood obesity very often leads to adult obesity. This puts them at greater risk of developing obesity-related cancers in adulthood,” said study lead author Bernard Fuemmeler, Professor and Associate Director for Cancer Prevention and Control at the Virginia Commonwealth University.

For the study, researchers enrolled 120 children, with an average age of eight, whose mothers had participated in the Newborn Epigenetic Study both pre-birth and during early childhood.

To track the sleep-wake cycle, the children wore accelerometers continuously for 24 hours a day for a period of at least five days.

They found that shorter sleep duration, measured in hours, was associated with a higher BMI z-score (body mass index adjusted for age and sex).

Each additional hour of sleep was associated with a .13 decrease in BMI z-score and with a 1.29 cm decrease in waist circumference.

More fragmented rest-activity rhythms and increased intradaily variability — a measure of the frequency and extent of transitions between sleep and activity — were also associated with greater waist circumferences.

The study results, to be presented at Obesity and Cancer: Mechanisms Underlying Etiology and Outcomes, indicate that while sleep duration is important, examining markers of sleep quality may also be useful in designing childhood obesity prevention strategies.

“Today, many children are not getting enough sleep. There are a number of distractions, such as screens in the bedroom, that contribute to interrupted, fragmented sleep. This, perpetuated over time, can be a risk factor for obesity,” Fuemmeler said.

“Because of the strong links between obesity and many types of cancer, childhood obesity prevention is cancer prevention.”

Proper sleep in children may prevent cancer later

By DEBORAH NETBURN

Scientists have developed a noninvasive blood test that can detect signs of eight types of cancer long before any symptoms of the disease arise.

The test, which can also help doctors determine where in a person’s body the cancer is located, is called CancerSEEK. Its genesis is described in a paper published Thursday in the journal Science.

The authors said the new work represents the first noninvasive blood test that can screen for a range of cancers all at once: cancer of the ovary, liver, stomach, pancreas, esophagus, colon, lung and breast.

Together, these eight forms of cancer are responsible for more than 60% of cancer deaths in the United States, the authors said.

In addition, five of them — ovarian, liver, stomach, pancreatic and esophageal cancers — currently have no screening tests.

“The goal is to look for as many cancer types as possible in one test, and to identify cancer as early as possible,” said Nickolas Papadopoulos, a professor of oncology and pathology at Johns Hopkins who led the work. “We know from the data that when you find cancer early, it is easier to kill it by surgery or chemotherapy.”

CancerSEEK, which builds on 30 years of research, relies on two signals that a person might be harboring cancer.

First, it looks for 16 telltale genetic mutations in bits of free-floating DNA that have been deposited in the bloodstream by cancerous cells. Because these are present in such trace amounts, they can be very hard to find, Papadopoulos said. For example, one blood sample might have thousands of pieces of DNA that come from normal cells, and just two or five pieces from cancerous cells.

“We are dealing with a needle in a haystack,” he said.

To overcome this challenge, the team relied on recently developed digital technologies that allowed them to efficiently and cost-effectively sequence each individual piece of DNA one by one.

“If you take the hay in the haystack and go through it one by one, eventually you will find the needle,” Papadopoulos said.

In addition, CancerSEEK also screens for eight proteins that are frequently found in higher quantities in the blood samples of people who have cancer.

By measuring these two signals in tandem, CancerSEEK was able to detect cancer in 70% of blood samples pulled from 1,005 patients who had already been diagnosed with one of eight forms of the disease.

The test appeared to be more effective at finding some types of cancer than others, the authors noted. For example, it was able to spot ovarian cancer 98% of the time, but was successful at detecting breast cancer only 33% of the time.

The authors also report that CancerSEEK was better at detecting later stage cancer compared to cancer in earlier stages. It was able to spot the disease 78% of the time in people who had been diagnosed with stage III cancer, 73% of the time in people with stage II cancer and 43% of the time in people diagnosed with stage I cancer.

“I know a lot of people will say this sensitivity is not good enough, but for the five tumor types that currently have no test, going from zero chances of detection to what we did is a very good beginning,” Papadopoulos said.

It is also worth noting that when the researchers ran the test on 812 healthy control blood samples, they only saw seven false-positive results.

“Very high specificity was essential because false-positive results can subject patients to unnecessary invasive follow-up tests and procedures to confirm the presence of cancer,” said Kenneth Kinzler, a professor of oncology at Johns Hopkins who also worked on the study.

Finally, the researchers used machine learning to determine how different combination of proteins and mutations could provide clues to where in the body the cancer might be. The authors found they could narrow down the location of a tumor to just a few anatomic sites in 83% of patients.

CancerSEEK is not yet available to the public, and it probably won’t be for a year or longer, Papadopoulos said.

“We are still evaluating the test, and it hasn’t been commercialized yet,” he said. “I don’t want to guess when it will be available, but I hope it is soon.”

He said that eventually the test could cost less than $500 to run and could easily be administered by a primary care physician’s office.

In theory, a blood sample would be taken in a doctor’s office, and then sent to a lab that would look for the combination of mutations and proteins that would indicate that a patient has cancer. The data would then go into an algorithm that would determine whether or not the patient had the disease and where it might be.

“The idea is: You give blood, and you get results,” Papadopoulos said.

http://beta.latimes.com/science/sciencenow/la-sci-sn-blood-test-cancer-20180118-story.html

by Laura Elizabeth Lansdowne

Researchers have gained a new understanding of the link between obesity and cancer. In the presence of excess fat, the immune surveillance system fails due to an obesity-fueled lipid accumulation in natural killer (NK) cells, preventing their cellular metabolism and trafficking. The new findings were published in Nature Immunology.1

More than 1.9 billion adults are either overweight or obese and a growing amount of evidence proposes that numerous cancer types (including liver, kidney, endometrial and pancreatic cancers)2 are more common in overweight or obese people. Cancer risk is increased in those with higher body fat, with up to 49% of certain types attributed to obesity.3

Previous findings from the GLOBOCAN project indicate that, in 2012 in the United States, approximately 28,000 new cases of cancer in men and approximately 72,000 in women were associated with being obese or overweight.4

The 2018 study1 investigated the effect of obesity on the cellular metabolism, gene expression, and function of NK cells, and its influence on cancer development.

NK cells are cells of the innate immune system that limit the spread of tumors – numerous in vitro models have shown that tumor cells are recognized as ‘targets’ by NK cells.5 These cells destroy their targets by secreting lytic granules containing perforin and apoptosis-inducing granzymes. NK cells require a greater amount of energy to support their anti-tumor activity, therefore they switch their metabolic activity from oxidative phosphorylation (OXPHOS) to glycolysis to meet the increased demand for ATP.1

The researchers discovered that NK cells in an ‘obese environment’ display increased lipid accumulation which affects their cellular bioenergetics, resulting in ‘metabolic paralysis’. This lipid-induced metabolic paralysis led to loss of anti-tumor activity both in vitro and in vivo models. They were able to mimic obesity through fatty-acid administration and by using PPARα/δ agonists, which inhibited mechanistic target of rapamycin (mTOR)-mediated glycolysis.1

However, the researchers also discovered that it was possible to reverse the metabolic paralysis by either inhibiting PPARα/δ or by blocking lipid transport, suggesting that metabolic reprogramming of NK cells could restore their anti-tumor activity in human obesity.1

Corresponding author of the study, Lydia Lynch commented on the importance of the findings in a recent press release: “Despite increased public awareness, the prevalence of obesity and related diseases continue. Therefore, there is increased urgency to understand the pathways whereby obesity causes cancer and leads to other diseases, and to develop new strategies to prevent their progression.”

References

1. Michelet, X., et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nature Immunology. (2018) https://www.nature.com/articles/s41590-018-0251-7
2. Mason, L. E., The Link Between Cancer and Obesity. Technology Networks. Available at: https://www.technologynetworks.com/cancer-research/articles/the-link-between-cancer-and-obesity-298207. Accessed: November 12, 2018
3. Renehan, A. G., et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. (2008) 371, 569–578
4. Arnold, M., et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. (2015) 16(1): 36–46
5. Vivier, E., et al. Functions of natural killer cells. Nature Immunology. (2008) 9, 503–510

https://www.technologynetworks.com/cancer-research/news/obesity-and-cancer-fat-clogged-immune-cells-fail-to-fight-tumors-311744?utm_campaign=NEWSLETTER_TN_Breaking%20Science%20News&utm_source=hs_email&utm_medium=email&utm_content=68543465&_hsenc=p2ANqtz–8ZbNt7sDLF6bujB3qX9CeJA-hpSQwPHeSLoR5Ju1WYXA6SnOEepdO0o-J7qw_1aGB3nfwldpf30hV3pAvVi7SzJa8fw&_hsmi=68543465

by Sara Ashley O’Brien

When his one-year-old son was diagnosed with a rare form of cancer, Ryan Green turned to videogames. It was in part an escape, but also a way to share the the ups and downs of his family’s experiences.
In January 2016 — two years after four-year-old Joel passed away — ‘That Dragon, Cancer’ was released.

The two-hour game is less choose-your-own adventure and more about immersive experience — putting the player right in the center of the Green family’s battle for Joel’s life. You see the diagnosis, the tears, the desperate prayers — but you also hear Joel’s laughter, lots of it.

Green said that people have embraced it, despite the fact that it’s not the type of game you’d sit down to play over and over again.

“It was incredible, the groundswell of interest,” said Green, onstage at the Wired Business Conference in New York City on Thursday. “We were able to share our story and that gave other people permission to share theirs. That grief process — that’s all I could hope for.”

Green said the game was a team effort. There were four full-time people working on it, and his wife Amy wrote the script.

Green used the metaphor of a boat to describe players’ engagement with the game.

“If you’re in a boat, you’re going where it’s going. You can be freaked out and flail and try to drive it limited way,” he said. “[But] we invite you in as a friend. You go downstream with us. It’s about the discovery of the story … It’s about grace in the midst of having no choice.”

The game, which costs $14.99, was a memorial to Joel — but has also made him live on through the experiences of stranger.

Green said people write him and say, “‘The thing that I loved most was making Joel laugh.’ They wanted to comfort him as if he was present. I hope it adds to their life experience — to have loved Joel.”

But Green doesn’t return to the game himself.

“That work is done,” he said. “It’s been all consuming: losing Joel, grieving Joel — it needs to be done.”

As for what’s next? Green — who has four children — said his next project will be in the virtual reality space, although he won’t disclose details. His studio, Numinous Games, also plans to bring ‘That Dragon, Cancer’ to mobile devices, in order to share Joel’s story with even more people. Right now, it’s just available on Macs and PCs.

“We hope to continue to tell meaningful stories and show people that life is complex,” he said onstage. “It’s not all tears but it’s also laughter.”

http://money.cnn.com/2016/06/16/technology/that-dragon-cancer-ryan-green/index.html