The selfish tumour : Cachexia-associated changes in skeletal muscle

Summary

Skeletal muscle wasting is a common hallmark of (late stage) cancer, which is also called cancer cachexia. Cancer cachexia is due to the (selfish) tumour present in the body, which activates many processes in multiple organs eventually leading to the loss of muscle mass. When we unravel the mechanisms involved, treatments to prevent or counteract the cancer cachexia can be developed.

In this thesis the impact of vibration training was tested in an animal model of cancer cachexia. Analysis of transcriptome data revealed that vibration training reduced the tumour-related effects in muscle. These effects were associated with an attenuation of the upregulation of the proteasome pathway in the soleus muscle. We also found that the oxidative phosphorylation pathway was among the most abundant downregulated pathways in muscle of the cachectic animals.

Secondly, muscle cells were used to investigate the effects of secreted immune signalling molecules by the tumour cells on muscle development. Global gene expression, measured by RNA sequencing, showed a significant upregulation of immune pathways. Oxidative phosphorylation was again found in the top downregulated pathways.

Next to this, the role of mitochondria in cachexia were studied. Mitochondria are an important part of the (muscle) cells, as they generate most of the energy molecules. Our literature analysis showed that the expression of genes involved in mitochondrial fusion, fission, ATP production and mitochondrial density is decreased, while that of genes involved in reactive oxygen species (ROS) detoxification and mitophagy is increased. When investigating the effects of secreted molecules by the tumour cells on muscle development we found that about 70% of the significant differentially expressed MitoCarta genes were downregulated. In contrast, the whole genome expression consisted mainly of upregulated genes. The in vivo data turned out to have an overlap with the in vitro data, eight MitoCarta genes were found in both the GCM and the in vivo models. These eight MitoCarta genes were also all downregulated in the cachectic animal model. Moreover, vibration training seemed to counteract this downregulation to a small extent. The translatability of these results to in vivo data shows the relevance of these cancer cachexia models.

Lastly, to investigate muscle gene expression in humans, to gain more insight in the underlying processes and to confirm our results on skeletal muscle mitochondrial gene expression, the COMUNEX study was designed. In an update of the COMUNEX study, data of 21 of the 30 primary colon cancer patients undergoing a tumour resection were discussed. Most participants are suffering from sarcopenia. However, a comparison with the, still to be included, control and liver metastatic groups is needed for interpretation of other data regarding muscle wasting, including transcriptomics.

Based on the results of this thesis, one major conclusion is that immune signalling molecules from tumour cells directly impair muscle activity and myogenesis. A second major conclusion is that the secreted immune signalling molecules of cachexia-inducing cancer cell lines have a direct impact on mitochondrial function. Vibration training can influence muscle gene expression, and it modulates the expression of the eight identified MitoCarta cachexia signature genes positively.