Pancreatic cancer cachexia is a complex, multifactorial syndrome characterised by progressive weight loss, skeletal muscle and fat wasting, and systemic inflammation.

Occurring in over 60% of pancreatic cancer patients, cachexia significantly reduces physical function, impairs treatment tolerance, and shortens overall survival.

Unlike starvation, cachexia cannot be fully reversed by nutritional support alone.

A new review article published in hLife provides a detailed and up-to-date understanding of pancreatic cancer cachexia as a systemic disease that is driven by tumour-host interactions across multiple organs.

Researchers from the Peking Union Medical College Hospital and Harvard T.H. Chan School of Public Health summarise decades of work repositioning cachexia from a localised metabolic disturbance to a cancer-driven, multi-organ pathology.

The review categorises cachexia-inducing factors into inflammatory cytokines (e.g., TNF-α, IL-6), TGF-β superfamily members (e.g., activin A, myostatin, GDF15), catabolic mediators (e.g., proteolysis-inducing factor and lipid mobilising factor), and extracellular vesicles (EVs) released by tumours.

These mediators cause not only muscle atrophy and fat loss, but also appetite suppression, gut dysfunction, neuroendocrine disruption, and cardiac damage.

Pancreatic tumours activate distinct catabolic signalling cascades that disrupt the balance between protein synthesis and degradation in muscle tissue.

In particular, cancer-associated stress leads to the overactivation of the ubiquitin-proteasome pathway (UPP), where key E3 ubiquitin ligases, such as MAFbx (atrogin-1) and MuRF1, are upregulated, resulting in accelerated protein degradation and muscle atrophy.

Simultaneously, adipose tissue loss is primarily attributed to enhanced lipolysis mediated by two key lipases: adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL).

These enzymes break down triglycerides into free fatty acids and glycerol, fuelling the systemic energy demands of the tumour and contributing to whole-body wasting.

The increased activity of these lipases is often potentiated by inflammatory signals and tumour-derived factors, which override the normal anabolic and energy storage functions of adipose tissue.

Notably, the authors highlight emerging evidence showing that organs such as the skeletal muscle, adipose tissue, liver, and brain engage in reciprocal crosstalk with tumours, amplifying metabolic imbalance and organ dysfunction.

These pathophysiological changes are majorly mediated by cachexia-inducing factors delivering molecular signals that exacerbate cachexia through both local and systemic routes.

These findings suggest that cachexia should be addressed as a systemic disease rather than an isolated consequence of cancer.

In addition to providing mechanistic insights, the review discusses existing experimental models, such as genetically engineered mouse models and xenograft models, that enable researchers to dissect the pathophysiology of cachexia.

The authors also describe how promising experimental models, such as organoids and organ chips, can advance the study of this systemic disease.

Proposed therapeutic strategies include blocking key signalling pathways such as IL-6/STAT3, TGF-β/SMAD, and PI3K/Akt/mTOR, neutralisation of cachexia-inducing factors such as GDF15, as well as interfering with the release and uptake of tumour EVs.

Early interventions that target the systemic inflammatory state or alleviate the metabolic dysregulation may significantly improve patient outcomes.

“This review reframes cachexia not as a symptom but as a cancer-initiating, whole-body syndrome,” said Prof. Wenming Wu, corresponding author of the article.

“By identifying the drivers of systemic deterioration, we open the door to more effective diagnostics and interventions.”

The article underscores an urgent need for cross-disciplinary approaches—combining oncology, metabolism, immunology, and neuroscience—to fully understand and combat pancreatic cancer cachexia.

These insights have the potential to transform clinical care and improve the lives of patients with this aggressive disease.

Source: Tsinghua University Press