head and neck cancer
Study Reveals How Epstein-Barr Virus May Lead to Cancer
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Chances are good that you’ve had an Epstein-Barr virus (EBV) infection, usually during childhood. More than 90 percent of us have, though we often don’t know it. That’s because most EBV infections are mild or produce no symptoms at all.
But in some people, EBV can lead to other health problems. The virus can cause infectious mononucleosis (“mono”), type 1 diabetes, and other ailments. It also can persist in our bodies for years and cause increased risk later in life for certain cancers, such as lymphoma, leukemia, and head and neck cancer. Now, an NIH-funded team has some of the best evidence yet to explain how this EBV that hangs around may lead to cancer [1].
The paper, published recently in the journal Nature, shows that a key viral protein readily binds to a particular spot on a particular human chromosome. Where the protein accumulates, the chromosome becomes more prone to breaking for reasons that aren’t yet fully known. What the study makes clearer is that the breakage produces latently infected cells that are more likely over time to become cancerous.
This discovery paves the way potentially for ways to screen for and identify those at particular risk for developing EBV-associated cancers. It may also fuel the development of promising new ways to prevent these cancers from arising in the first place.
The work comes from a team led by Don Cleveland and Julia Su Zhou Li, University of California San Diego’s Ludwig Cancer Research, La Jolla, CA. Over the years, it’s been established that EBV, a type of herpes virus, often is detected in certain cancers, particularly in people with a long-term latent infection. What interested the team is a viral protein, called EBNA1, which routinely turns up in those same EBV-related cancers.
The EBNA1 protein is especially interesting because it binds viral DNA in particular spots, which allows the virus to persist and make more copies of itself. This discovery raised the intriguing possibility that the protein may also bind similar sequences in human DNA. While it had been suggested previously that this interaction might play a role in EBV-associated cancers, the details had remained murky—until now.
In the new study, the researchers first made uninfected human cells produce the viral EBNA1 protein. They then peered inside them with a microscope to see where those proteins went. In both healthy and cancerous human cells, they watched as EBNA1 proteins built up at two distinct spots and confirmed that this accumulation was dependent on the protein’s ability to bind DNA.
Next, they mapped where exactly EBNA1 binds to human DNA. Interestingly, it was along a repetitive non-protein-coding stretch of DNA on human chromosome 11. This region includes more than 300 copies of an 18-letter sequence that looks quite similar to the EBNA1-binding sites in its own viral genome.
What’s more, the researchers noticed that the repetitive DNA there takes on a structure that’s known for being unstable. And these so-called fragile sites are inherently prone to breaking.
The team went on to uncover evidence that the buildup of EBNA1 at this already fragile site only makes matters worse. In EBV-infected cells, increasing the amount of EBNA1 protein led to more chromosome 11 breaks. Those breaks showed up within a single day in about 40 percent of cells.
For these cells, those breaks also may be a double whammy. That’s because the breaks are located next to neighboring genes with long recognized roles in regulating cell growth. When altered, these genes can contribute to turning a cell cancerous.
To further nail down the link to cancer, the researchers looked to whole-genome sequencing data for more than 2,400 cancers including 38 tumor types from the international Pan-Cancer Analysis of Whole Genomes consortium [2]. They found that tumors with detectable EBV also had an unusually high number of chromosome 11 abnormalities. In fact, that was true in every single case of head and neck cancer.
The findings suggest that people will vary in their susceptibility to EBNA1-induced DNA breaks along chromosome 11 based on the amount of EBNA1 protein in their latently infected cells. It also will depend on the number of EBV-like DNA repeats present in their DNA.
Given these new findings, it’s worth noting that the presence of EBV and the very same viral protein has been implicated also in the link between EBV and multiple sclerosis (MS) [3]. Together, these recent findings are a reminder of the value in pursuing an EBV vaccine that might thwart this infection and its associated conditions, including certain cancers and MS. And, we’re getting there. In fact, an early-stage clinical trial for an experimental EBV vaccine is now ongoing here at the NIH Clinical Center.
References:
[1] Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats. Li JSZ, Abbasi A, Kim DH, Lippman SM, Alexandrov LB, Cleveland DW. Nature. 2023 Apr 12.
[2] Pan-cancer analysis of whole genomes. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Nature.2020 Feb;578(7793):82-93.
[3] Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Lanz TV, Brewer RC, Steinman L, Robinson WH, et al. Nature. 2022 Mar;603(7900):321-327.
Links:
About Epstein-Barr Virus (Centers for Disease Control and Prevention, Atlanta)
Head and Neck Cancer (National Cancer Institute,/NIH)
Multiple Sclerosis (National Institute of Neurological Disorders and Stroke/NIH)
Don W. Cleveland Lab (University of California San Diego, La Jolla, CA)
NIH Support: National Institute of General Medical Sciences; National Institute of Environmental Health Sciences; National Cancer Institute
Seven More Awesome Technologies Made Possible by Your Tax Dollars
Posted on by Dr. Francis Collins
We live in a world energized by technological advances, from that new app on your smartphone to drones and self-driving cars. As you can see from this video, NIH-supported researchers are also major contributors, developing a wide range of amazing biomedical technologies that offer tremendous potential to improve our health.
Produced by the NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB), this video starts by showcasing some cool fluorescent markers that are custom-designed to light up specific cells in the body. This technology is already helping surgeons see and remove tumor cells with greater precision in people with head and neck cancer [1]. Further down the road, it might also be used to light up nerves, which can be very difficult to see—and spare—during operations for cancer and other conditions.
Other great things to come include:
- A wearable tattoo that detects alcohol levels in perspiration and wirelessly transmits the information to a smartphone.
- Flexible coils that produce high quality images during magnetic resonance imaging (MRI) [2-3]. In the future, these individualized, screen-printed coils may improve the comfort and decrease the scan times of people undergoing MRI, especially infants and small children.
- A time-release capsule filled with a star-shaped polymer containing the anti-malarial drug ivermectin. The capsule slowly dissolves in the stomach over two weeks, with the goal of reducing the need for daily doses of ivermectin to prevent malaria infections in at-risk people [4].
- A new radiotracer to detect prostate cancer that has spread to other parts of the body. Early clinical trial results show the radiotracer, made up of carrier molecules bonded tightly to a radioactive atom, appears to be safe and effective [5].
- A new supercooling technique that promises to extend the time that organs donated for transplantation can remain viable outside the body [6-7]. For example, current technology can preserve donated livers outside the body for just 24 hours. In animal studies, this new technique quadruples that storage time to up to four days.
- A wearable skin patch with dissolvable microneedles capable of effectively delivering an influenza vaccine. This painless technology, which has produced promising early results in humans, may offer a simple, affordable alternative to needle-and-syringe immunization [8].
If you like what you see here, be sure to check out this previous NIH video that shows six more awesome biomedical technologies that your tax dollars are helping to create. So, let me extend a big thanks to you from those of us at NIH—and from all Americans who care about the future of their health—for your strong, continued support!
References:
[1] Image-guided surgery in cancer: A strategy to reduce incidence of positive surgical margins. Wiley Interdiscip Rev Syst Biol Med. 2018 Feb 23.
[2] Screen-printed flexible MRI receive coils. Corea JR, Flynn AM, Lechêne B, Scott G, Reed GD, Shin PJ, Lustig M, Arias AC. Nat Commun. 2016 Mar 10;7:10839.
[3] Printed Receive Coils with High Acoustic Transparency for Magnetic Resonance Guided Focused Ultrasound. Corea J, Ye P, Seo D, Butts-Pauly K, Arias AC, Lustig M. Sci Rep. 2018 Feb 21;8(1):3392.
[4] Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals. Bellinger AM, Jafari M1, Grant TM, Zhang S, Slater HC, Wenger EA, Mo S, Lee YL, Mazdiyasni H, Kogan L, Barman R, Cleveland C, Booth L, Bensel T, Minahan D, Hurowitz HM, Tai T, Daily J, Nikolic B, Wood L, Eckhoff PA, Langer R, Traverso G. Sci Transl Med. 2016 Nov 16;8(365):365ra157.
[5] Clinical Translation of a Dual Integrin avb3– and Gastrin-Releasing Peptide Receptor–Targeting PET Radiotracer, 68Ga-BBN-RGD. Zhang J, Niu G, Lang L, Li F, Fan X, Yan X, Yao S, Yan W, Huo L, Chen L, Li Z, Zhu Z, Chen X. J Nucl Med. 2017 Feb;58(2):228-234.
[6] Supercooling enables long-term transplantation survival following 4 days of liver preservation. Berendsen TA, Bruinsma BG, Puts CF, Saeidi N, Usta OB, Uygun BE, Izamis ML, Toner M, Yarmush ML, Uygun K. Nat Med. 2014 Jul;20(7):790-793.
[7] The promise of organ and tissue preservation to transform medicine. Giwa S, Lewis JK, Alvarez L, Langer R, Roth AE, et a. Nat Biotechnol. 2017 Jun 7;35(6):530-542.
[8] The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial. Rouphael NG, Paine M, Mosley R, Henry S, McAllister DV, Kalluri H, Pewin W, Frew PM, Yu T, Thornburg NJ, Kabbani S, Lai L, Vassilieva EV, Skountzou I, Compans RW, Mulligan MJ, Prausnitz MR; TIV-MNP 2015 Study Group.
Links:
National Institute of Biomedical Imaging and Bioengineering (NIH)
Center for Wearable Sensors (University of California, San Diego)
Hyperpolarized MRI Technology Resource Center (University of California, San Francisco)
Center for Engineering in Medicine (Massachusetts General Hospital, Boston)
Center for Drug Design, Development and Delivery (Georgia Tech University, Atlanta)
NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases
The Science of Saliva
Posted on by Dr. Francis Collins
Credit: Swati Pradhan-Bhatt, Christiana Care Health System, Newark, DE
Whether it’s salmon sizzling on the grill or pizza fresh from the oven, you probably have a favorite food that makes your mouth water. But what if your mouth couldn’t water—couldn’t make enough saliva? When salivary glands stop working and the mouth becomes dry, either from disease or as a side effect of medical treatment, the once-routine act of eating can become a major challenge.
To help such people, researchers are now trying to engineer replacement salivary glands. While the research is still in the early stages, this image captures a crucial first step in the process: generating 3D structures of saliva-secreting cells (yellow). When grown on a scaffold of biocompatible polymers infused with factors to encourage development, these cells cluster into spherical structures similar to those seen in salivary glands. And they don’t just look like salivary cells, they act like them, producing the distinctive enzyme in saliva, alpha amylase (blue).
Optimizing Radio-Immunotherapy for Cancer
Posted on by Dr. Francis Collins
Zachary Morris
Credit: Alan Leon
Zachary Morris has certainly done some memorable things. As a Rhodes Scholar, he once attended an evening reception at Buckingham Palace, played a game of pick-up football with former President Bill Clinton, and traveled to South Africa to take a Robben Island Prison tour, led by the late Nelson Mandela. But something the young radiation oncologist did during his medical residency could prove even more momentous. He received a special opportunity from the American Board of Radiology to join others in studying how to pair radiation therapy with the emerging cancer treatment strategy of immunotherapy.
Morris’s studies in animals showed that the two treatments have a unique synergy, generating a sustained tumor-specific immune response that’s more potent than either therapy alone. But getting this combination therapy just right to optimize its cancer-fighting abilities remains complicated. Morris, now a researcher and clinician at the University of Wisconsin School of Medicine and Public Health, Madison, has received a 2017 NIH Director’s Early Independence Award to look deeper into this promising approach. He and his collaborators will use what they learn to better inform their future early stage clinical trials of radio-immunotherapy starting with melanoma, head and neck cancers, and neuroblastoma.
Head and Neck Cancer: Building the Evidence Base for Precision Oncology
Posted on by Dr. Francis Collins
Caption: Triple immunohistochemical stained oral squamous cell carcinoma: nuclei in brown, cytoplasm in red, and cytoplasmic membranes in blue green.
Credit: Alfredo A. Molinolo, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH
An exciting new era in cancer research is emerging, called precision oncology. It builds on decades of research establishing that cancers start with glitches in the genome, the cell’s instruction book. Researchers have now identified numerous ways that mutations in susceptible genes can drive the cancer process. Knowing where and how to look for them brings greater precision to diagnosing cancers and gives doctors key clues about which treatments might work and which ones won’t.
To build a firmer evidence base for precision oncology, more and more cancer genomes, from many different body sites, must be analyzed for clues about the drivers of the malignant process. That’s why it’s always exciting to see a new genomic analysis that adds substantially to our understanding of a common tumor. The latest to appear, published online at the journal Nature, comes from an NIH-supported study on the most common type of head and neck cancer, called squamous cell carcinoma. The technologically advanced analysis confirms that many previously suspected genes do indeed play a role in head and neck cancer. But that’s not all. The new data also identify several previously unknown subtypes of this cancer. The first descriptions of the abnormal molecular wiring in these subtypes are outlined, suggesting possible strategies to neutralize or destroy the cancer cells. That’s potentially good news to help guide and inform the treatment of the estimated 55,000 Americans who are diagnosed with a head and neck cancer each year.
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