Separating anorexia -dependent and -independent effects in cancer cachexia

Abstract Cancer cachexia is characterized by unintentional weight loss and wasting away of fat and muscle tissues. Anorexia, or reduced food intake, is often implicated as a contributor to the negative energy balance in this condition. However, to what extent anorexia alone accounts for body weight loss and wasting of different tissues, and whether anorexia is responsible for other cachectic phenotypes such as physical performance impairment remains insufficiently characterized in preclinical models and patients. In this study, we demonstrate the critical need to address these questions in cancer cachexia research. Using the colon carcinoma 26 (C26) model of cancer cachexia as an example, we systematically determined how much each of the key phenotypes of cancer cachexia is driven by anorexia. Anorexia was the predominant driver for body weight loss, adipose tissue wasting, and muscle wasting, strikingly suggesting the lack of other mechanisms for causing these phenotypes in this model. In contrast, anorexia had no impact on physical performance, pointing to the existence of anorexia-independent mechanisms in causing fatigue. Thus, for a given preclinical model or patient group, anorexia can be the main cause for certain cachectic phenotypes and play no role in causing other cachectic phenotypes. Discriminating between anorexia-mediated and independent effects is essential for guiding research focus and ultimately unraveling the causal pathways of cancer cachexia.