Cancer cachexia is a complex and multi-factorial syndrome. As currently available therapeutic options are limited, more in-depth knowledge on cachexia pathophysiology and the underlying molecular mechanisms remains warranted. Studies with animal models provide useful insights but they only mimic the human situation to a certain degree. Furthermore, there is heterogeneity in the design of published animal studies and outcomes. To further address this issue, we performed a comparative study analysing muscle whole genome gene expression of different cachexia studies in mice and human.
We selected data sets from the NCBI Gene Expression Omnibus database containing muscle gene expression data measured by micro-array or RNA-sequencing, at least comprising a cachectic/tumour bearing group (n>3) and a non-cachectic/control group (n>3). This provided 12 datasets; 9 from mouse models and 3 human datasets. All datasets were quality checked, normalised and annotated. Datasets were merged and compared at different levels. General similarity and differences in gene expression were determined using ordered list analysis and principal component analysis (PCA). Moreover, similarities and differences at pathway level were studied by applying gene set enrichment analysis (GSEA) of KEGG pathways.
Animal models displayed similarities to each other and to human datasets at different levels and with different processes. At the gene level, a similarity analysis indicated little similarity between the animal models and the human datasets, while animal models showed high similarity. Only one of the C26 mice models (GSE121972) showed significant similarity to more than one human dataset. Moreover, one human dataset comparing cachectic and non-cachectic cancer patients showed no similarity to any of the other datasets. PCA results indicated that a xenograft model showed most different expression from the other datasets and the Lewis lung carcinoma model to be least different from the human datasets. GSEA results showed four pathways clearly standing out across experiments with downregulation of oxidative phosphorylation and thermogenesis pathway, and upregulation of the proteasome and RNA transport pathway. However, these pathways were not consistently changed in the human datasets.
Our comparative analysis showed that there is currently no basis to define a preferred animal model for human cachexia. More human datasets containing proper controls are needed. Repetition of the current analysis upon publication of additional human datasets is warranted.