Abstract
ABSTRACT
Background
Cancer cachexia is a multifactorial syndrome characterized by substantial metabolic disturbances including systemic inflammation, and muscle atrophy, which may affect the regulation of iron metabolism in patients. This study aimed to characterize this regulation in two murine models of colorectal and pancreatic cancer, both associated with a high prevalence of cachexia.
Methods
Histological, biochemical and molecular analyses were performed in serum, skeletal muscle, liver, spleen and tumor from UN-KC-6141 pancreatic tumor bearing mice and from
Apc
Min/+
mice (colorectal cancer model), both models exhibiting variable cachexia severity.
Results
Both models induce cachexia, but diverge markedly in their regulation of iron metabolism. UNKC mice display reduced plasma iron availability (-9.6% transferrin saturation, pApc
Min/+
mice exhibit anemia together with hepatic and splenic iron depletion (-48.4%, pApc
Min/+
mice, iron deficiency is associated with decreased FPN and ferritin (-87.9%, p
Conclusion
These findings reveal cancer type-specific signatures of iron regulation in cachexia, which appear to be more driven by cancer type specific features than by cachexia severity itself, with skeletal muscle iron metabolism impaired mainly when cachexia is associated with anemia. This suggests that the clinical management of iron metabolism in cachectic patients should be guided by the underlying cancer type.
Abstract figure legend
Cancer cachexia is associated with iron redistribution, diverging between UN-KC-6141 pancreatic cancer model and the
Apc
Min/+
colorectal cancer model. In pancreatic cancer, hepatic hepcidin is upregulated, likely in response to inflammation, and induces splenic iron sequestration, resulting in decreased plasma iron availability. In colorectal cancer, cachexia is associated with anemia together with splenic and hepatic iron depletion, whose signals probably drive hepcidin downregulation despite inflammation. Whatever the model, skeletal muscle appears to engage cellular adaptive regulatory mechanisms to preserve itself from the systemic iron dysregulation induced by cancer cachexia and its associated features.