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Description
It is well known that physical activity can prevent cancer development, but the molecular mechanisms behind these effects are poorly understood. During exercise, extracellular vesicles (EVs) are released into the circulation and mediate tissue crosstalk with potential effects on tumour cells and the immune tumour microenvironment. The overall aim of CancerBeat is to characterise the molecular cargo of exercise-induced EVs and explore their effects on breast cancer (BC) progression in vitro and in vivo.
We plan to enrol two groups of study subjects – healthy endurance runners and BC patients, who will be randomized into training and standard-of-care groups.The BC training group will undergo aerobic exercise for the whole duration of neoadjuvant chemotherapy. Blood samples will be collected from all participants before and after exercise; in addition, tumour tissue specimens will be collected from BC patients. EVs will be isolated from the blood samples and their cargo will be analysed using RNA sequencing and proteomics, whereas their effects on cancer growth will be analysed using live cell imaging, RNA sequencing and energy metabolism studies.In addition, the effects of exercise-induced EVs on the development of cancer will be studied in murine models of cancer. We believe that the knowledge obtained in this project will lead to the identification of biomarkers that will help to define optimal dose, intensity and type of exercise for the prevention of BC, and open up new avenues for prevention and treatment of cancer.
This project will be implemented in collaboration among Latvian Biomedical Research and Study centre (BMC, Latvia), Oslo University Hospital (OUH, Norway), Latvian Academy of Sport Education (LASE, Latvia), National Cancer Institute (NCI, Lithuania) and National Institute of Chemical Physics and Biophysics (NICPB, Estonia).
Summary of project results
It is well known that physical activity can prevent cancer development, but the molecular mechanisms behind these effects are poorly understood. The main goal of the Baltic Research Programme’s project “Exploring the molecular mechanisms behind the effects of physical exercise on breast cancer prevention” (CancerBeat) was to gain a deeper understanding of the molecular mechanisms behind the beneficial effects of exercise on preventing the progression of breast cancer.
We recruited two groups of study subjects – breast cancer patients, who were randomized into high-intensity interval training (HIIT) and standard-of-care control groups, and healthy endurance runners, who served as a reference. The training group took aerobic exercise sessions for the whole duration of neoadjuvant chemotherapy, while the control group was advised to keep their usual level of physical activity. Pre and post-exercise blood samples were collected from all participants, and tumour tissue specimens were collected from breast cancer patients after surgery. The clinical samples were exploited for various molecular analyses. To gain a deeper understanding of the effects of exercise on tumour microenvironment and metastasis, murine breast cancer models were used.
We found that regular exercise significantly improved response to chemotherapy, helped to maintain a higher quality of life, reduced cancer symptoms and mitigated treatment side effects. RNA sequencing analysis of tumour and normal breast tissues revealed exercise-induced alterations in the tumour-intrinsic gene expression profile and showed that exercise alters the composition of tumour-infiltrating immune cells. We further focused on the role of extracellular vesicles (EVs) in mediating the beneficial effects of exercise. During exercise, EVs are released into the circulation and mediate tissue crosstalk with potential effects on tumour cells and the immune tumour microenvironment. Analysis of exercise-induced EV cargo revealed several miRNAs, mRNAs and proteins that were upregulated during exercise and reflected various physiological processes going on in the body during exercise. However, the effects of exercise-induced EVs on the proliferation, metabolic activity and gene expression profile of BC cells were highly variable among the individuals and cell lines. In mice models of BC, treatment with exercise-induced EVs reduced tumour growth by 19-57% and triggered a proinflammatory antitumor immune response, converting immunologically “cold” to “hot” tumours.
In conclusion, this project demonstrated that HIIT significantly improves response to chemotherapy and quality of life in BC patients thus supporting the incorporation of physical activities in the treatment plans of BC patients and prompting the initiation of a clinical trial investigating the effects of HIIT and/or exercise-induced EVs on the efficacy of immunotherapy.
Results of this project were disseminated via 9 scientific publications (2 published ,6 submitted, 1 in preparation ) and presented at 12 international scientific conferences and served as a basis for 2 EU and 2 national grant applications.
The results of this project provided mechanism-based evidence and consolidated the concept that regular physical exercise should be included as an integral part of supportive care for breast cancer patients undergoing chemotherapy. Communication with healthcare specialists, patient associations and general public was an important part of the project. These activities raised awareness of the beneficial effects of physical activities in cancer patients, helped the patients to get out of their sick mood, and gave motivation to the patients to incorporate regular physical activities into their daily routine.
Indicators achieved in the project: 8 scientific publications have been prepared, 2 joint project applications for further funding were submitted, 19 researchers were supported.
Summary of bilateral results
CancerBeat consortium is composed of multidisciplinary team of experts in oncology, molecular and cellular biology, tumour immunology, bioinformatics, biomarker discovery, sports medicine, exercise physiology, physiotherapy and bioenergetics. Implementation of this project required communication and interaction of the project partners on the daily basis, thus leading to the exchange of knowledge, skills and ideas. For instance, Latvian Academy of Sport Education ( LASE) and Latvian Biomedical Research and Study Centre (BMC) were working together on the collection of clinical samples. National Cancer Institute (NCI), and Oslo University Hospital (OUH) were working together on establishing a mouse model for studying the effects of exercise-induced EVs on tumour progression or prevention. National Institute of Chemical Physics and Biophysics (NICPB) and BMC cooperated on establishing methodology for studying the effects of EVs on energy metabolism in recipient cells. These interactions have led to establishing a strong cooperation among the partners that opens new opportunities for building the next research projects in this area and attracting funding from coming ERA-NET, Horizon Europe and other international and national funding sources.