Study of the Role of Exercise and IGF-1 in 3D Cell Culture Models for the Prevention of Cancer Recurrence

Epidemiological studies have shown that increased physical activity and lifestyle modifications are associated with a lower risk of cancer recurrence. This PhD Thesis explored the effects of exercise on prostate cancer (PC) and the effects of exercise and lifestyle interventions on breast cancer (BC) recurrence and progression, using a translational approach based on exercise-conditioned human serum and three-dimensional cell culture models. We first demonstrated that serum obtained from healthy males after 5 km and 10 km running sessions reduced spheroid number and volume in PC cell lines, particularly 3 hours post-exercise. No differences were observed between distances, suggesting that shorter bouts can be as effective as longer ones, with muscle mass and cardiorespiratory fitness enhancing the effect. Secondly, we examined the effects of single bouts of aerobic exercise in BC survivors performed at moderate and vigorous intensity. Serum collected 3 hours post-exercise, especially after the moderate-intensity bout, significantly reduced triple-negative breast cancer (TNBC) spheroid formation, demonstrating that even moderate exercise – more achievable for BC survivors often facing fatigue and treatment-related limitations – can exert meaningful anti-oncogenic effects. Given that cumulative epidemiological evidence shows the importance of lifestyle changes in the prevention of BC risk and recurrence, we also evaluated the effects of a 12-week home-based lifestyle intervention combining exercise and nutritional counselling in BC survivors. Post-intervention serum reduced TNBC spheroid formation, with insulin-like growth factor 1 (IGF-1) identified as the only key predictor of tumour growth. Increased IGF-1 levels are associated with a higher risk of BC and recurrence. Since N-glycosylation plays a crucial role in the secretion of mature IGF-1, we demonstrated that glucose-dependent IGF-1 secretion promotes hormone-responsive BC cell proliferation and spheroid formation via IGF-1R, ERK1/2, and Akt pathways, emphasizing the importance of glycemic control in lifestyle interventions aimed at preventing BC recurrence. Collectively, these results demonstrate that acute exercise, also integrated with nutritional and metabolic management, can effectively modulate tumorigenic processes in PC and BC. Short, moderate-intensity exercise elicits anti-oncogenic effects, and lifestyle interventions further enhance cancer-protective mechanisms. The works included in this Thesis provide translational evidence supporting feasible exercise and lifestyle strategies to reduce cancer recurrence, offering insights to improve practical guidelines for exercise oncology in a tertiary cancer prevention context.