Regular physical activity reduces the risk of cancer occurrence, progression, and recurrence. Epidemiological studies have shown that physical activity and a healthy diet can prevent 40% of all cancers in the US, and regular exercise reduces the risk of developing breast cancer by 30-40%.
The anti-cancer effect of physical exercise can be explained because physical activity causes systemic, tissue, and cellular adaptation, including enhancing antitumor inflammatory, hormonal and immune responses, stimulating DNA repair and miRNA expression, which fight carcinogenesis.
During exercise, skeletal muscles contract and release a wide range of biologically active molecules that directly or indirectly affect the tumor microenvironment and have an antitumor effect. Biologically active molecules include myokines, growth factors, chemokines, exosomes, and skeletal muscle microRNAs.
Myokines
Skeletal muscles secrete various proteins: cytokines, peptides, and growth factors when contracting. All these proteins are called myokines.
Myokines act not only locally in the muscle or neighboring tissues but also affect distant organs, regulating inter-tissue interactions. Thus, muscle contraction affects several diseases associated with chronic inflammation, oxidative stress, and metabolic disorders.
Myokines contribute to cancer prevention, affect the tumor microenvironment, resist tumor progression, and reduce the side effects of chemotherapy. Myokines can be divided into those that directly affect the tumor microenvironment (secreted cysteine-rich protein (SPARC), oncostatin M and irisin) and those that indirectly affect cancer development by enhancing the antitumor immune response (IL-6, IL-7, and IL-15).
Laboratory studies on breast, colon, and prostate cancer cells showed that treating cancer cells with exercised human serum reduced metabolic activity and accelerated cancer cell death. At the same time, serum did not affect the viability of healthy cells.
Myokines Inhibit Cancer Development
SPARC
One of the best-studied myokines is the SPARC protein – osteonectin. SPARC is released from skeletal muscle into the bloodstream after a single exercise session in healthy humans and rodents with colon cancer. SPARC expression is increased with regular physical activity. Regular exercise suppressed colon tumorigenesis in mice, while the antitumor effect of exercise was abolished in mice lacking the SPARC protein. A study in patients with gastrointestinal cancer found that above-average levels of SPARC improved survival.
Oncostatin M (OSM)
The OSM protein inhibits the development of cancer. A single physical activity leads not only to the activation of OSM in skeletal muscles but also to its increased secretion into the bloodstream. Incubation of breast cancer cells with post-exercise human serum containing OSM suppressed the division of cancer cells and stimulated their death. OSM blocking reduced the antitumor effects of the serum. Studies in mice have confirmed that aerobic exercise increases OSM levels, reducing tumor volume.
Decorin
Decorin is also secreted by skeletal muscle after exercise. In response to physical activity, decorin prevents muscle loss by inhibiting another myokine, myostatin, which contributes to muscle wasting and sarcopenia. In addition to resisting muscle wasting, decorin inhibits tumor growth. Decorin reduces the rate of division and the metastatic potential of cancer cells, while decorin increases the expression of genes that suppress tumor formation.
Irisin
Irisin regulates fat metabolism by promoting the switch from white to brown adipose tissue and stimulating glucose uptake by skeletal muscle. Recombinant irisin significantly reduces the ability of breast cancer cells to divide and migrate without affecting the viability of healthy cells. Moreover, even a slight increase in serum irisin levels minimizes the likelihood of developing breast cancer by up to 90%, and higher serum irisin levels protect against spinal metastases in breast cancer.
Interleukin-6 (IL-6)
Depending on the origin and signaling pathways, IL-6 can both suppress cancer development and promote tumor growth. If tumor cells and cancer-associated macrophages, fibroblasts, adipocytes, or mesenchymal stem cells over-secrete IL-6, this creates favorable conditions for tumor development and metastasis. However, if IL-6 is secreted by skeletal muscle cells in response to exercise, it inhibits tumor initiation and growth by increasing the anti-cancer activity of immune cells.
IL-15 and IL-7
IL-15 stimulates the proliferation of immune cells that resist tumor formation. NK cells, T-killers and T-helpers, and CD8 + T-memory cells are among them. A clinical study in patients with metastatic cancer showed that recombinant administration of IL-15 increased NK and gamma delta T cell levels. Moreover, in two patients with melanoma, lung metastases wholly disappeared.
IL-7 plays a crucial role in replenishing the pool of T-lymphocytes. IL-7 maintains the survival and division of young, naive T cells produced in the thymus. In addition, the production of memory T cells and participation in the immune response depends on IL-7.
Myokines and Sarcopenia Associated with Cancer
Sarcopenia is severe muscle atrophy that occurs in various types of cancer, impairs patients’ functionality and quality of life, and can lead to death. Sarcopenia may occur in cancer patients as a side effect of chemotherapy or the tumor secreting proteins that disrupt skeletal muscle homeostasis and inhibit protein synthesis. There is a shift of fast fibers in cancer patients into slow ones. In this context, exercise plays a key role in maintaining skeletal muscle mass through the secretion of various myokines during muscle contraction.
The level of IL-6, which has anti-cancer properties, increases dramatically after exercise in both healthy people and cancer patients. IL-6 is involved in myogenesis, promotes skeletal muscle protein synthesis and hypertrophy, and reduces muscle wasting associated with cancer.
One of the proteins that inhibit muscle growth is myostatin. In animal studies with various malignancies, elevated myostatin levels have been associated with muscle wasting, while pharmacological blockade of myostatin prevented muscle loss and increased survival. Clinical studies in patients with sarcopenic cancer have also shown that administration of anti-myostatin antibodies increases muscle volume and muscle mass without serious side effects. In addition, physical exercise reduces myostatin secretion, thereby resisting muscle atrophy.
These data confirm that exercise in the presence of cancer can prevent or reduce muscle atrophy.
Physical Exercise Regulates miRNA Levels
MicroRNAs are molecules that regulate gene expression.
Recent studies have shown that 45 minutes of aerobic exercise can drastically change the expression of miRNAs involved in cancer development. In particular, aerobic exercise increases the expression of myomiR-206, a molecule that inhibits the proliferation and migration of cancer cells.
In addition, a 5-week interval aerobic exercise program combined with hormonal therapy resulted in the upregulation of miR-206 and let-7 expression and downregulation of miR-21 in breast cancer mice. Both miR-206 and let-7 suppress the tumor, while miR-21, on the contrary, promotes tumor growth and invasion.
Physical activity affects the tumor microenvironment and inhibits the invasion and metastasis of cancer cells. Physical exercise alters miRNA expression and inhibits the development and progression of cancer.
Output
Lack of physical activity is associated with a high incidence of cancer. On the contrary, regular exercise reduces the risk of cancer occurrence and progression. During contraction, skeletal muscles secrete myokines and microRNAs that stimulate the immune response, counteract muscle atrophy, and suppress cancer growth. Regular exercise as an adjunct to mainstream treatment can help patients contain cancer, prevent a recurrence, and mitigate the side effects of cancer treatments.
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Reference
Physical Exercise Restrains Cancer Progression through Muscle-Derived Factors
