Skeletal muscle loss and disease progression in mouse models of metastatic colorectal cancer: Nutritional and exercise intervention strategies

Abstract

During my PhD, we investigated skeletal muscle loss and disease progression in mouse models of metastatic colorectal cancer. As patients with advanced CRC often suffer from cancer cachexia syndrome and experience weight loss, reduced muscle mass, fatigue and loss of appetite as a result of the disease and treatment, there is a clear need for better understanding of which interventions can be beneficial to mitigate cancer cachexia. We investigated the effects of specialized nutrition to support muscle function during chemotherapeutic treatment in preclinical models of cancer cachexia and CRC. We showed that specialized nutrition, containing ω-3 polyunsaturated fatty acid (EPA and DHA), leucine-enriched, high-protein, additional vitamin D, and prebiotic fibers attenuated chemotherapy-associated toxicity in C2C12 differentiated muscle cells while treatment responses of 3D-patient derived organoids were unaffected. Specialized nutrition preserved muscle mass and function without attenuating treatment response in the C26 mouse model. By using patient-derived 3D tumor organoids and microsurgical techniques, we aimed to improve preclinical modeling of advanced metastatic CRC in vivo. These models provided a platform to investigate the effects of exercise on metastasis formation and organotropism, as well as onward metastasis from colorectal liver metastasis. We found that organoid-initiated tumors growing in the liver were significantly more efficient in seeding distant metastases (spreading to distant liver lobes, lung and peritoneum) compared to organoid-initiated tumors of the same origin growing in the caecum (primary tumor site). The enhanced metastatic capacity of the liver tumors was associated with the formation of ‘hotspots’ of vitronectin-positive blood vessels surrounded by macrophages. Lastly, we investigated the effect of voluntary exercise on metastatic organotropism and metastasis of colorectal cancer. Our results suggest that exercise has the potential to influence the patterns and extent of metastasis by the observation of metastatic organotropism shifting from liver to lung. Moreover, our results indicate that the degree and intensity of exercise are likely to be important variables in these changes in disease progression. By answering the question how to tailor multimodal interventions towards individual patients’ needs, we can build towards improved nutritional and exercise intervention strategies for (metastatic) CRC patients. Furthermore, the continuous improvement of preclinical models with high translational potential, such as the application of patient-derived 3D organoids and orthotopic modeling of metastatic disease, will provide a solid platform for identification of factors influencing processes of (onward) metastasis of colorectal cancer.