Posted on by Dr. Francis Collins
Tumors rely on a variety of tricks to grow, spread, and resist our best attempts to destroy them. Now comes word of yet another of cancer’s surprising stunts: when chemotherapy treatment hits hard, some cancer cells survive by cannibalizing other cancer cells.
Researchers recently caught this ghoulish behavior on video. In what, during this Halloween season, might look a little bit like The Blob, you can see a down-for-the-count breast cancer cell (green), treated earlier with the chemotherapy drug doxorubicin, gobbling up a neighboring cancer cell (red). The surviving cell delivers its meal to internal compartments called lysosomes, which digest it in a last-ditch effort to get some nourishment and keep going despite what should have been a lethal dose of a cancer drug.
Crystal Tonnessen-Murray, a postdoctoral researcher in the lab of James Jackson, Tulane University School of Medicine, New Orleans, captured these dramatic interactions using time-lapse and confocal microscopy. When Tonnessen-Murray saw the action, she almost couldn’t believe her eyes. Tumor cells eating tumor cells wasn’t something that she’d learned about in school.
As the NIH-funded team described in the Journal of Cell Biology, these chemotherapy-treated breast cancer cells were not only cannibalizing their neighbors, they were doing it with remarkable frequency . But why?
A possible explanation is that some cancer cells resist chemotherapy by going dormant and not dividing. The new study suggests that while in this dormant state, cannibalism is one way that tumor cells can keep going.
The study also found that these acts of cancer cell cannibalism depend on genetic programs closely resembling those of immune cells called macrophages. These scavenging cells perform their important protective roles by gobbling up invading bacteria, viruses, and other infectious microbes. Drug-resistant breast cancer cells have apparently co-opted similar programs in response to chemotherapy but, in this case, to eat their own neighbors.
Tonnessen-Murray’s team confirmed that cannibalizing cancer cells have a survival advantage. The findings suggest that treatments designed to block the cells’ cannibalistic tendencies might hold promise as a new way to treat otherwise hard-to-treat cancers. That’s a possibility the researchers are now exploring, although they report that stopping the cells from this dramatic survival act remains difficult.
 Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival. Tonnessen-Murray CA, Frey WD, Rao SG, Shahbandi A, Ungerleider NA, Olayiwola JO, Murray LB, Vinson BT, Chrisey DB, Lord CJ, Jackson JG. J Cell Biol. 2019 Sep 17.
Breast Cancer (National Cancer Institute/NIH)
James Jackson (Tulane University School of Medicine, New Orleans)
NIH Support: National Institute of General Medical Sciences
Posted on by Dr. Francis Collins
Exercise can work wonders for your health, including strengthening muscles and bones, and boosting metabolism, mood, and memory skills. Now comes word that staying active may also help to lower your odds of developing cancer.
After reviewing the scientific evidence, a panel of experts recently concluded that physical activity is associated with reduced risks for seven common types of cancer: colon, breast, kidney, endometrial, bladder, stomach, and esophageal adenocarcinoma. What’s more, the experts found that exercise—both before and after a cancer diagnosis—was linked to improved survival among people with breast, colorectal, or prostate cancers.
About a decade ago, the American College of Sports Medicine (ACSM) convened its first panel of experts to review the evidence on the role of exercise in cancer. At the time, there was limited evidence to suggest a connection between exercise and a reduced risk for breast, colon, and perhaps a few other cancer types. There also were some hints that exercise might help to improve survival among people with a diagnosis of cancer.
Today, the evidence linking exercise and cancer has grown considerably. That’s why the ACSM last year convened a group of 40 experts to perform a comprehensive review of the research literature and summarize the level of the evidence. The team, including Charles Matthews and Frank Perna with the NIH’s National Cancer Institute, reported its findings and associated guidelines and recommendations in three papers just published in Medicine & Science in Sports & Exercise and CA: A Cancer Journal for Clinicians [1,2,3].
Here are some additional highlights from the papers:
There’s moderate evidence to support an association between exercise and reduced risk for some other cancer types, including cancers of the lung and liver.
While the optimal amount of exercise needed to reduce cancer risk is still unclear, being physically active is clearly one of the most important steps in general that people of all ages and abilities can take.
Is sitting the new smoking? Reducing the amount of time spent sitting also may help to lower the risk of some cancers, including endometrial, colon, and lung cancers. However, there’s not enough evidence to draw clear conclusions yet.
Every cancer survivor should, within reason, “avoid inactivity.” There’s plenty of evidence to show that aerobic and resistance exercise training improves many cancer-related health outcomes, reducing anxiety, depression, and fatigue while improving physical functioning and quality of life.
Physical activity before and after a diagnosis of cancer also may help to improve survival in some cancers, with perhaps the greatest benefits coming from exercise during and/or after cancer treatment.
Based on the evidence, the panel recommends that cancer survivors engage in moderate-intensity exercise, including aerobic and resistance training, at least two to three times a week. They should exercise for about 30 minutes per session.
The recommendation is based on added confirmation that exercise is generally safe for cancer survivors. The data indicate exercise can lead to improvements in anxiety, depression, fatigue, overall quality of life, and in some cases survival.
The panel also recommends that treatment teams and fitness professionals more systematically incorporate “exercise prescriptions” into cancer care. They should develop the resources to design exercise prescriptions that deliver the right amount of exercise to meet the specific needs, preferences, and abilities of people with cancer.
The ACSM has launched the “Moving Through Cancer” initiative. This initiative will help raise awareness about the importance of exercise during cancer treatment and help support doctors in advising their patients on those benefits.
It’s worth noting that there are still many fascinating questions to explore. While exercise is known to support better health in a variety of ways, correlation is not the same as causation. Questions remain about the underlying mechanisms that may help to explain the observed associations between physical activity, lowered cancer risk, and improved cancer survival.
An intensive NIH research effort, called the Molecular Transducers of Physical Activity Consortium (MoTrPAC), is underway to identify molecular mechanisms that might explain the wide-ranging benefits of physical exercise. It might well shed light on cancer, too.
As that evidence continues to come in, the findings are yet another reminder of the importance of exercise to our health. Everybody—people who are healthy, those with cancer, and cancer survivors alike—should make an extra effort to remain as physically active as our ages, abilities, and current health will allow. If I needed any more motivation to keep up my program of vigorous exercise twice a week, guided by an experienced trainer, here it is!
 Exercise Is Medicine in Oncology: Engaging Clinicians to Help Patients Move Through Cancer. Schmitz KH, Campbell AM, Stuiver MM, Pinto BM, Schwartz AL, Morris GS, Ligibel JA, Cheville A, Galvão, DA, Alfano CM, Patel AV, Hue T, Gerber LH, Sallis R, Gusani NJ, Stout NL, Chan L, Flowers F, Doyle C, Helmrich S, Bain W, Sokolof J, Winters-Stone KM, Campbell KL, Matthews CE. CA Cancer J Clin. 2019 Oct 16 [Epub ahead of publication]
 American College of Sports Medicine Roundtable Report on Physical Activity, Sedentary Behavior, and Cancer Prevention and Control. Patel AV, Friedenreich CM, Moore SC, Hayes SC, Silver JK, Campbell KL, Gerber LH, George SM, Fulton JE, Denlinger C, Morris GS, Hue T, Schmitz KH, Matthews CE. Med Sci Sports Exerc. 2019 Oct 16. [Epub ahead of publication]
 Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable. Campbell KL, Winters-Stone KM, Wiskemann J, May AM, Schwartz AL, Courneya KS, Zucker DS, Matthews CE, Ligibel JA, Gerber LH, Morris GS, Patel AV, Hue TF, Perna FM, Schmitz KH. Med Sci Sports Exerc. 2019 Oct 16. [Epub ahead of publication]
Physical Activity and Cancer (National Cancer Institute/NIH)
Moving Through Cancer (American College of Sports Medicine, Indianapolis, IN)
Charles Matthews (NCI)
Frank Perna (NCI)
NIH Support: National Cancer Institute
Posted on by Dr. Francis Collins
Researchers continue to produce impressive miniature human tissues that resemble the structure of a range of human organs, including the livers, kidneys, hearts, and even the brain. In fact, some researchers are now building on this success to take the next big technological step: placing key components of several miniature organs on a chip at once.
These body-on-a-chip (BOC) devices place each tissue type in its own pea-sized chamber and connect them via fluid-filled microchannels into living, integrated biological systems on a laboratory plate. In the photo above, the BOC chip is filled with green fluid to make it easier to see the various chambers. For example, this easy-to-reconfigure system can make it possible to culture liver cells (chamber 1) along with two cancer cell lines (chambers 3, 5) and cardiac function chips (chambers 2, 4).
Researchers circulate blood-mimicking fluid through the chip, along with chemotherapy drugs. This allows them to test the agents’ potential to fight human cancer cells, while simultaneously gathering evidence for potential adverse effects on tissues placed in the other chambers.
This BOC comes from a team of NIH-supported researchers, including James Hickman and Christopher McAleer, Hesperos Inc., Orlando, FL. The two were challenged by their Swiss colleagues at Roche Pharmaceuticals to create a leukemia-on-a-chip model. The challenge was to see whether it was possible to reproduce on the chip the known effects and toxicities of diclofenac and imatinib in people.
As published in Science Translational Medicine, they more than met the challenge. The researchers showed as expected that imatinib did not harm liver cells . But, when treated with diclofenac, liver cells on the chip were reduced in number by about 30 percent, an observation consistent with the drug’s known liver toxicity profile.
As a second and more challenging test, the researchers reconfigured the BOC by placing a multi-drug resistant vulva cancer cell line in one chamber and, in another, a breast cancer cell line that responded to drug treatment. To explore side effects, the system also incorporated a chamber with human liver cells and two others containing beating human heart cells, along with devices to measure the cells’ electrical and mechanical activity separately.
These studies showed that tamoxifen, commonly used to treat breast cancer, indeed killed a significant number of the breast cancer cells on the BOC. But, it only did so after liver cells on the chip processed the tamoxifen to produce its more active metabolite!
Meanwhile, tamoxifen alone didn’t affect the drug-resistant vulva cancer cells on the chip, whether or not liver cells were present. This type of cancer cell has previously been shown to pump the drug out through a specific channel. Studies on the chip showed that this form of drug resistance could be overcome by adding a second drug called verapamil, which blocks the channel.
Both tamoxifen alone and the combination treatment showed some off-target effects on heart cells. While the heart cells survived the treatment, they contracted more slowly and with less force. The encouraging news was that the heart cells bounced back from the tamoxifen-only treatment within three days. But when the drug-drug combination was tested, the cardiac cells did not recover their function during the same time period.
What makes advances like this especially important is that only 1 in 10 drug candidates entering human clinical trials ultimately receives approval from the Food and Drug Administration (FDA) . Often, drug candidates fail because they prove toxic to the human brain, liver, kidneys, or other organs in ways that preclinical studies in animals didn’t predict.
As BOCs are put to work in testing new drug candidates and especially treatment combinations, the hope is that we can do a better job of predicting early on which chemical compounds will prove safe and effective in humans. For those drug candidates that are ultimately doomed, “failing early” is key to reducing drug development costs. By culturing an individual patient’s cells in the chambers, BOCs also may be used to help doctors select the best treatment option for that particular patient. The ultimate goal is to accelerate the translation of basic discoveries into clinical breakthroughs. For more information about tissue chips, take a look at NIH’s Tissue Chip for Drug Screening program.
 Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. McAleer CW, Long CJ, Elbrecht D, Sasserath T, Bridges LR, Rumsey JW, Martin C, Schnepper M, Wang Y, Schuler F, Roth AB, Funk C, Shuler ML, Hickman JJ. Sci Transl Med. 2019 Jun 19;11(497).
 Clinical development success rates for investigational drugs. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Nat Biotechnol. 2014 Jan;32(1):40-51.
Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)
James Hickman (Hesperos, Inc., Orlando, FL)
NIH Support: National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
Tumor cells thrive by exploiting the willingness of normal cells in their neighborhood to act as accomplices. One of their sneakier stunts involves tricking the body into helping them form new blood vessels. This growth-enabling process of sprouting new blood vessels, called tumor angiogenesis, remains a vital area of cancer research and continues to yield important clues into how to beat this deadly disease.
The two-panel image above shows one such promising lead from recent lab studies with endothelial cells, specialized cells that line the inside of all blood vessels. In tumors, endothelial cells are induced to issue non-stop SOS signals that falsely alert the body to dispatch needed materials to rescue these cells. The endothelial cells then use the help to replicate and sprout new blood vessels.
The left panel demonstrates the basics of this growth process under normal conditions. Endothelial cells (red and blue) were cultured under special conditions that help them grow in the lab. When given the right cues, those cells sprout spiky extensions to form new vessels.
But in the right panel, the cells can’t sprout. The reason is because the cells are bathed in a molecule called miR-30c, which isn’t visible in the photo. These specialized microRNA molecules—and humans make a few thousand different versions of them—control protein production by binding to and disabling longer RNA templates, called messenger RNA.
This new anti-angiogenic lead, published in the Journal of Clinical Investigation, comes from a research team led by Andrew Dudley, University of Virginia Medical School, Charlottesville . The team made its discovery while studying a protein called TGF-beta that tumors like to exploit to fuel their growth.
Their studies in mice showed that loss of TGF-beta signals in endothelial cells blocked the growth of new blood vessels and thus tumors. Further study showed that those effects were due in part to elevated levels of miR-30c. The two interact in endothelial cells as part of a previously unrecognized signaling pathway that coordinates the growth of new blood vessels in tumors.
Dudley’s team went on to show that levels of miR-30c vary widely amongst endothelial cells, even when those cells come from the very same tumor. Cells rich in miR-30c struggled to sprout new vessels, while those with less of this microRNA grew new vessels with ease.
Intriguingly, they found that levels of this microRNA also predicted the outcomes for patients with breast cancer. Those whose cancers had high levels of the vessel-stunting miR-30c fared better than those with lower miR-30c levels. While more research is needed, it does offer a potentially promising new lead in the fight against cancer.
 Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1. McCann JV, Xiao L, Kim DJ, Khan OF, Kowalski PS, Anderson DG, Pecot CV, Azam SH, Parker JS, Tsai YS, Wolberg AS, Turner SD, Tatsumi K, Mackman N, Dudley AC. J Clin Invest. 2019 Mar 11;130:1654-1670.
Angiogenesis Inhibitors (National Cancer Institute/NIH)
Dudley Lab (University of Virginia School of Medicine, Charlottesville)
NIH Support: National Cancer Institute; National Heart, Lung, and Blood Institute
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