It has been well documented that exercise can have a positive effect on cancer survival, but whether more gentle forms of movement, such as tai chi, can also have a beneficial impact on cancer isn’t known. A team of U.S. scientists has now shown how daily stretching exercises in a mouse model of breast cancer can hold back tumor growth by more than 50%, without any other form of treatment. Their analyses further suggested that stretching may impact on two possibly related mechanisms that are relevant to cancer—immune cell exhaustion and inflammation resolution.
The scientists, headed by Helene Langevin, M.D., and a team at Harvard Medical School and Brigham and Women’s Hospital, and Jean J. Zhao, Ph.D., professor of biological chemistry and molecular pharmacology at Harvard Medical School and Dana Faber Cancer Institute, say it may be feasible that a regimen of gentle stretching could benefit human cancer patients. Writing in their published paper in Scientific Reports, the researchers conclude, “The potential clinical significance of our results lies in the possibility of developing a method of gentle stretching that could be well tolerated and testable in humans for primary or secondary cancer prevention, or in conjunction with cancer treatment.” The paper is entitled “Stretching Reduces Tumor Growth in a Mouse Breast Cancer Model.”
“We know, generally, that physical activity is beneficial in cancer patients but not why that is,” says Dr. Langevin, who is director of the Osher Center for Integrative Medicine and co-corresponding author of the published report. “Gentle stretching is something that many cancer patients not only can do but enjoy doing. We wanted to develop a preclinical model that could help us study the effects of stretching on tumor growth and, if safe and effective, be translated into a regimen for humans.”
There is a growing interest in developing nonpharmacological approaches to boosting the body’s natural defenses against cancer, both to help prevent and potentially treat the disease. Physical activity is known to be of benefit to cancer patients, but animal studies of exercise in cancer models have yielded mixed results. “Some animal models of exercise show benefit, others don't,” Dr. Langevin notes. Preclinical studies have also involved vigorous aerobic exercise, which may not be suitable for cancer patients. “On the other hand, gentle movement-based techniques such as yoga, tai chi, and qi gong are popular and well-tolerated among cancer patients for managing symptoms and improving mobility and well-being,” the scientists suggest.
Their prior research in mice had indicated that gentle daily stretching for 10 minutes can significantly reduce local connective tissue inflammation and fibrosis through mechanical effects that act directly on the stretched tissues. There is also a growing body of research indicating that mechanical factors within the stroma can influence the growth of tumors. “We therefore hypothesized that stretching would reduce the growth of tumors implanted within locally stretched tissues, and tested this hypothesis in a mouse model of breast cancer.”
The researchers adapted a well-established protocol for gentle stretching in mice, which involves lifting the animals gently by the tail, while allowing their front paws to grasp a bar. Mice can quickly become accustomed to holding this position for 10 minutes at a time, without evidence of discomfort.
The team applied this gentle stretching technique to mice for 10 minutes every day, over four weeks. Prior to starting their stretching regimen, the animals received injections of primary breast cancer cells into mammary fat pads that are surrounded by subcutaneous and deeper tissues that are pulled as a result of the stretching motion. Tumor growth in the stretched animals was then compared with that in control animals that didn’t undergo daily stretching exercises.
The results showed that tumor growth from weeks 2 to 4 was significantly slower in the stretch group mice, and final tumor volume was also 52% smaller in the stretch group, compared with the no-stretch animals. Further analyses showed that stretch-group animals demonstrated upregulated overall levels of inflammatory mediators. The stretch-group animals also exhibited immune response-related gene signatures. Stretching was in addition more specifically found to increase the number of INF-γ+ CD4+ T cells within the inflammatory lesion, within just days.
The authors point out that diminished cytotoxic immunity is a mechanism that underpins the state of T-cell exhaustion in cancer, and is linked with lower levels of effector cytokines and the presence of inhibitor receptors on T cells, which permits tolerance to the cancer cells. “Because INF-γ is one of the key effector cytokines in cytotoxic immune responses, these results support a role for stretching in promoting TH-1 cytotoxic immunity,” they note.
Given the increased levels of INF-γ in the stretch-group animals, the researchers reasoned that this physical act of stretch restores cytotoxic immunity. When they next looked at T-lymphocyte populations, they found that mice in the stretch group exhibited lower levels of programmed death receptor-1 (PD-1) checkpoint-bearing CD8+ T cells, one of the major markers of T-cell exhaustion, suggesting that stretching may in addition counteract CD8+ T-cell impairment and “allow adaptive cytotoxic immune responses against the tumor to take place.”
While inflammatory responses can help to fight the tumor, inflammation can also be detrimental and promote tumor growth. “Inflammation is a double-edge sword in cancer,” Dr. Langevin states. “Although it is an essential component of all immune responses, it needs to be limited both in location and duration.” Wtih this in mind, the researchers next looked at the effects of stretching on tumor levels of the lipid-derived specialized pro-resolution mediators (SPMs) RvD1 and RvD2, which promote the natural resolution of inflammation and have been shown to inhibit tumor growth in mouse models. Their measurements showed that levels of RvD1 and RvD2 were significantly higher in the stretch group.
“Together, our results suggest that pro-resolution mechanisms may act in concert with increased cytotoxic immunity to reduce the growth of tumors in response to stretching,” the team concludes. They highlight the “interesting possibility” that stretching could effectively keep inflammation under control, without suppressing the natural cytotoxic immune response against the cancer cells, and then rescuing the cytotoxic function of exhausted T cells. “To our knowledge there has been no previous research linking inflammation resolution to T-cell recovery from immune exhaustion,” they state. “Finding changes in both markers of the immune system ramping up its attack on cancer cells as well as markers of inflammation resolution suggests a potentially important link between these two areas of inquiry,” Dr. Langevin adds.
The authors do acknowledge that the active stretching model in mice is complex, and factors such as mild stress may also be relevant. Although the animals were not suspended, they were restrained by the tail, which may cause a low level of stress. Some muscle activity is also needed to maintain the stretched position. “We therefore cannot rule out that mild stress may have contribute[d] to the beneficial effect of stretching in the cancer model, similar to the beneficial effect of acute stress during exercise, perhaps in conjunction with tissue stretching,” they write. Nevertheless, the researchers point out, whether stress is involved or not, the possibility that the act of stretching has a mechanically driven effect on the local tumor stroma and immune environment is of particular interest, especially given increasing amounts of research in the field of cancer mechanobiology.
The mouse model of stretching, in which both the hind limbs and forelimbs are simultaneously extended, is also a core component of yoga poses that are commonly used with cancer patients, the team states. “These yoga poses therefore could be a good starting point for developing a stretching protocol to be tested in humans, once preclinical dosing and safety studies have been completed….Although the mechanisms underlying the beneficial effects of stretching in our mouse breast cancer model remain to be elucidated, our results point to a possible link between inflammation resolution and immune exhaustion mechanisms that could be important in basic cancer biology.”