Cancer cachexia: multilevel metabolic dysfunction

Cancer cachexia is a complex metabolic disorder marked by unintentional body weight loss or 'wasting' of body mass, driven by multiple aetiological factors operating at various levels. It is associated with many malignancies and significantly contributes to cancer-related morbidity and mortality. With emerging recognition of cancer as a systemic disease, there is increasing awareness that understanding and treatment of cancer cachexia may represent a crucial cornerstone for improved management of cancer. Here, we describe the metabolic changes contributing to body wasting in cachexia and explain how the entangled action of both tumour-derived and host-amplified processes induces these metabolic changes. We discuss energy homeostasis and possible ways that the presence of a tumour interferes with or hijacks physiological energy conservation pathways. In that context, we highlight the role played by metabolic cross-talk mechanisms in cachexia pathogenesis. Lastly, we elaborate on the challenges and opportunities in the treatment of this devastating paraneoplastic phenomenon that arise from the complex and multifaceted metabolic cross-talk mechanisms and provide a status on current and emerging therapeutic approaches. In this Review, the authors highlight cancer cachexia as a complex and multifactorial disorder, and discuss the underlying host-driven and tumour-driven metabolic changes, therapeutic opportunities and the pertinent challenges in the treatment of cancer cachexia.