What moves wasting muscle? : Cancer cachexia; treatment, targets and translation

Cachexia is a common, serious and yet often under-recognised complication of cancer. Most obvious clinical manifestations of cachexia are loss of muscle mass, sometimes also including loss of fat mass and hence weight loss. This is driven by metabolic changes with or without a reduction in food intake, including elevated energy expenditure, excess catabolism and inflammation. Cachexia affects most patients with advanced stage cancer, with in some cancers more than 60% of all patients showing weight loss. Patients suffering from cachexia often also experience fatigue, muscle weakness and reduced response to cancer treatment. Conventional nutritional support is generally ineffective, the more so as anorexia often also develops in these patients. Together, these factors not only contribute to a reduced quality of life in these patients but are also assumed to be directly responsible for 20% of all cancer deaths. Thereby, aim of the current thesis was to get more insight into the processes driving this complex cachexia syndrome. Moreover, possible treatment targets and modalities were tested. In view of the variation in degree and clinical manifestations of cancer cachexia, variations in body composition and relative amounts of lean or fat mass are commonly occurring. To investigate possible consequences for the pharmacokinetics of cancer medication, associations between body composition and side-effects of chemotherapeutic treatment were studied in chapter 2. This was performed in a cohort of colon cancer patients receiving a treatment regimen consisting of capacetabine and oxaliplatin. Most patients [90%] experienced some side-effect during their treatment. Reductions in the dose of oxaliplatin were most common, while capecitabine treatment was usually not reduced. In contradiction to literature, we found that the amount of muscle mass, both absolute and relative to fat mass, was not associated with side-effects. However, we did find that the amount of fat infiltration in muscle tissue was associated with having more side-effects of the chemotherapy. Fat infiltration in muscle is a marker of poor muscle health. Therefore, our findings suggest that in our study population, not muscle quantity, but muscle functional quality is associated with side-effects of chemotherapy treatment. The complexity of the cachexia syndrome has thus far severely hampered the development of effective treatment regimens. General consensus exists that treatment should consist of a multi-modal program including nutrition, exercise and drugs. However, research on different treatment options in patients is difficult because of their situation and vulnerability. Therefore, animal studies are commonly used. In chapter 3 and 4, we studied effects of two treatment modalities for cachexia: nutrition (chapter 3) and training (chapter 4). To this end, we used the cancer cachexia model where C26 tumour cells are injected in the flank of a mouse to induce tumour development. In chapter 3, we studied the effects of a specific nutritional combination, high in protein, leucine and fish-oil, on circulating calcium levels in the C26 model. We found that the tumour increased calcium levels in the blood plasma. Moreover, plasma hypercalcemia was correlated with carcass mass and multiple organ masses. The specific nutritional combination was able to reduce the hypercalcemia. Subsequently, potential mechanisms underlying this effect were studied. Here, we focussed on the production of parathyroid hormone related protein (PTHrP) by the tumour cells that were used for the induction of cancer in the animals. PTHrP is a molecule well-known for its capacity of inducing hypercalcemia. We found that exposing the cells to the fish-oil component docosahexaenoic-acid (DHA) reduced their PTHrP production. Moreover, we also found that this was independent of cyclooxygenase-type 2 (COX-2), an enzyme involved in both DHA and PTHrP regulation. These results indicate that fish-oil, and specifically DHA, could be an important treatment component for reducing tumour-induced hypercalcemia. In chapter 4, we investigated the possible effects of an easily accessible exercise treatment modality; whole body vibration training for a period of 19 days, C26 mice daily underwent 15 minutes of whole body vibration training. Our main finding was that in the tumour bearing group, training shifted the muscle transcriptome, measured using a micro array, towards a pattern comparable to that obtained in control mice. On in-vivo cachexia outcomes, we found that the vibration training was not able to reduce body weight loss or muscle loss. Moreover, minimal effects were found on muscle function of the m. soleus. Despite that no major visible effects on body composition were found, the shift in muscle transcriptome seems promising and more studies into whole body vibration training as treatment component for cachexia seem warranted. In chapter 5, we studied to what extent the animal model that we used in chapter 3 and 4 mimics human cancer cachexia. This is important to assess the translatability of results from animal models to human patients. To do so, we compared publically available gene expression data, measured by micro-array or RNA-sequencing, in muscle tissue from different animal models with three human datasets. We found that there is no animal model outperforming other models in terms of similarity to the human datasets. Both on gene level and on pathway level, animal models not only displayed marked mutual and inter-study differences, but were also found to differ from human cachexia patients. Moreover, we found that on pathway level, different processes play different roles in different models. Unfortunately, due to the low number of human datasets, we were not able to draw firm conclusions based on this comparison. Therefore, upon appearance of additional well-described datasets, repetition of this comparison seems useful. Within the field of cancer cachexia research, large amounts of data are increasingly being generated. Potential for future research is to focus more on sharing and integrating data. By doing so, more thorough insight can be gained in the complex mechanisms driving cachexia allowing the design of more specific and personalized treatment strategies.