Role of Physical Exercise and Metformin in in vitro models of tumor progression control

Epidemiological data show that structured physical exercise can positively impact the risk of developing cancer and decrease the risk of disease recurrence. The main hypothesis on the positive effects of exercise oncology has focused on lowering the basal systemic levels of cancer risk factors with exercise training, but the effects of cancer-preventive components released after an intense session of exercise have recently gained attention. The cellular and molecular mechanisms involved in these beneficial effects of physical exercise are still unknown; among the hypothesized mechanisms, the main proposed is the production of myokines, with probable inhibitory effects in tumor proliferation. In this project,the capacity of exercise- conditioned sera to modulate tumorigenesis of triple-negative breast cancer (TNBC) and prostate cancer cells have been considered, also analyzing the possible molecular mechanisms involved. After the optimization of the experimental conditions for evaluating the anti-cancer potential of exercise bouts in in vitro anchorage-dependent conditions and a three-dimensional anchorage-independent cell growth assay (soft agar), the second part of the thesis focused on the evaluation of systemic responses to structured high-intensity endurance cycling (HIEC) sessions of exercise and to a high-intensity interval training period. The modulation of the proliferative and tumorigenic capacities of TNBC and prostate cancer cells stimulated with the exercise-conditioned human sera were evaluated. Moreover, the possible relations between the in vitro results and the biological responses measured during the exercise were assessed. The present study showed that human sera conditioned by HIEC-sessions impact the proliferative and tumorigenic capacities of TNBC and prostate cancer cells; furthermore, possible relationships between the results obtained in the tumorigenic potential of prostate cancer cells and some exercise parameter predictors have been shown. Finally, given the uncertainty of the molecular mechanisms involved in the physical exercise-induced beneficial effects found in this project, and given that the autophagic process has been hypothesized as one of the mechanisms involved in cancer prevention, the effects of a pharmacological approach in cancer prevention and progression have been assessed. Metformin has been used in evaluating the autophagy- related effects in cancer initiation and progression in non-tumorigenic cells, and in assessing the tumorigenic process induction in autophagy-deficient cells, under H2O2 stress, too. The results showed the crucial role of autophagy as an inducer of massive cell death in pre-neoplastic cells in the presence of tumor promoter phorbol, and in H2O2-stressed cells. Moreover, metformin did not lead to cell death in autophagy-deficient cells and it would suggest that autophagic cell death can be considered as a mechanism involved in eliminating damaged cells and potential tumorigenic cells, inhibiting the cancer initiation process. Starting from the obtained results, a possible synergism between physical exercise and metformin will be considered in future studies, to study its possible role in TNBC and prostate cancer prevention and modulation.