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Simple Summary: High-impact publications have reported both the beneficial and harmful effects of catecholamines on cancer hallmarks and outcomes—a contradiction that is underappreciated and poorly explained. Here, we aimed to investigate whether differences in adrenergic receptor isoform expression can explain different cancer hallmark responses to catecholamines, since cancer cells can vary greatly in the expressions of nine adrenergic receptors. For this purpose, we cultured two cancer cell lines that systematically differ in their adrenergic receptor expressions: A673 cells, which express α1D-, α2C-, β1-, and β3-adrenergic receptors, and RD sarcoma cells, which barely express any adrenergic receptors. The cells were treated with noradrenaline to elucidate the effects of noradrenaline exposure on cell proliferation, migration, and cAMP signaling. While the A673 cells responded to noradrenaline treatment with decreased cell numbers, cell proliferation and migration, and increased cAMP signaling, the RD cells did not respond to noradrenaline. Therefore, our findings indicate that the adrenergic receptor isoform expressions might indeed explain why cancers can respond differently to increases in catecholamine concentrations due to, e.g., a bout of exercise, psychosocial stress, surgery, or drugs such as β-blockers. Background: Exercise has beneficial effects on cancer and its treatment, but the underlying mechanisms are poorly understood. Some studies have linked the positive impact of exercise to catecholamine signaling. In contrast, cancer stress studies have typically reported that catecholamines worsen cancer hallmarks and outcomes. Here, we aimed to investigate whether adrenergic receptor isoform expression can explain the contradictory effects of catecholamines in cancer. Methods: We cultured two pediatric sarcoma cancer cell lines that either express (A673 cell line) or do not express (RD cell line) adrenergic receptors. The cells were treated with a 5× dilution series of noradrenaline to assess the effects of noradrenaline on cell numbers. After these dose-finding experiments, we treated both cancer cell lines with 60 μM noradrenaline to examine its effect on cell proliferation and migration and cAMP signaling. Results: Treatment with 60 μM noradrenaline significantly decreased the cell numbers by 61.89% ± 10.36 (p ≤ 0.001), decreased cell proliferation by 15.88% ± 6.76 (p ≤ 0.05), decreased cell migration after 24 h (p ≤ 0.001), and increased cAMP concentrations 38-fold (p ≤ 0.001) in the A673 cells, which express adrenergic receptors, but not in the RD cells, which do not express adrenergic receptors. Conclusions: Our results indicate, as a proof of principle, that the effects of catecholamines on cancer progression and metastasis might depend on the expressions of the nine adrenergic receptor isoforms. As cancers express adrenergic and other receptors differentially, this has implications for the response of cancers to exercise, stress, and medication and may help to further personalize cancer treatments. [ABSTRACT FROM AUTHOR]

Exercise is recommended for the healthy population as it increases fitness and prevents diseases. Moreover, exercise is also applied as an adjunct therapy for patients with various chronic diseases including cancer. Childhood cancer is a rare, heterogeneous disease that differs from adult cancer. Improved therapeutic strategies have increased childhood cancer survival rates to above 80% in developed countries. Although this is higher than the average adult cancer survival rate of about 50%, therapy results often in substantial long-term side effects in childhood cancer survivors. Exercise in adult cancer patients has many beneficial effects and may slow down tumor progression and improve survival in some cancer types, suggesting that exercise may influence cancer cell behavior. In contrast to adults, there is not much data on general effects of exercise in children. Whilst it seems possible that exercise might delay cancer progression or improve survival in children as well, there is no reliable data yet to support this hypothesis. Depending on the type of cancer, animal studies of adult cancer types show that the exercise-induced increase of the catecholamines epinephrine and norepinephrine, have suppressive as well as promoting effects on cancer cells. The diverse effects of exercise in adult cancer patients require investigating whether these results can be achieved in children with cancer. [ABSTRACT FROM AUTHOR]

Nearly 100 years ago, Otto Warburg investigated the metabolism of growing tissues and discovered that tumors reprogram their metabolism. It is poorly understood whether and how hypertrophying muscle, another growing tissue, reprograms its metabolism too. Here, we studied pyruvate kinase muscle (PKM), which can be spliced into two isoforms (PKM1, PKM2). This is of interest, because PKM2 redirects glycolytic flux towards biosynthetic pathways, which might contribute to muscle hypertrophy too. We first investigated whether resistance exercise changes PKM isoform expression in growing human skeletal muscle and found that PKM2 abundance increases after six weeks of resistance training, whereas PKM1 decreases. Second, we determined that Pkm2 expression is higher in fast compared to slow fiber types in rat skeletal muscle. Third, by inducing hypertrophy in differentiated C2C12 cells and by selectively silencing Pkm1 and/or Pkm2 with siRNA, we found that PKM2 limits myotube growth. We conclude that PKM2 contributes to hypertrophy in C2C12 myotubes and indicates a changed metabolic environment within hypertrophying human skeletal muscle fibers. PKM2 is preferentially expressed in fast muscle fibers and may partly contribute to the increased potential for hypertrophy in fast fibers. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-6 can prevent or promote cancer development, depending on the context. IL-6 is released from skeletal muscles during exercise. IL-6 is also secreted by leukocytes and stromal cells at sites of inflammation and in the tumour microenvironment. Muscle-derived IL-6 enhances insulin sensitivity in glycogen-storing tissues, stimulates the appearance of anti-inflammatory cytokines in the blood, mobilises cytotoxic immune cells, and reduces DNA damage in cancer cells. These biological effects may help protect against cancer formation and progression. By contrast, sustained IL-6 signalling at sites of inflammation and in the tumour microenvironment promotes chronic low-grade inflammation and activates tumour-promoting signalling pathways. Interleukin (IL)-6 elicits both anticancer and procancer effects depending on the context, which we have termed the 'exercise IL-6 enigma'. IL-6 is released from skeletal muscles during exercise to regulate short-term energy availability. Exercise-induced IL-6 provokes biological effects that may protect against cancer by improving insulin sensitivity, stimulating the production of anti-inflammatory cytokines, mobilising immune cells, and reducing DNA damage in early malignant cells. By contrast, IL-6 continuously produced by leukocytes in inflammatory sites drives tumorigenesis by promoting chronic inflammation and activating tumour-promoting signalling pathways. How can a molecule have such opposing effects on cancer? Here, we review the roles of IL-6 in chronic inflammation, tumorigenesis, and exercise-associated cancer prevention and define the factors that underpin the exercise IL-6 enigma. [ABSTRACT FROM AUTHOR]