Walker-256 Tumour-Induced Cachexia Altered Liver Metabolomic Profile and Function in Weanling and Adult Rats

Abstract

Cancer cachexia occurs in up to 85% of advanced cancer patients, affecting different tissues and organs, mainly the liver, which plays a central role in body metabolism control. However, liver responses to cancer cachexia progression are still poorly understood. Considering the possible different challenges provided by the rodent’s phase of life and the cachexia progression, we evaluated the liver metabolic alterations affected by Walker-256 tumour growth in weanling and young-adult rats. For this, we applied a metabolomics approach associated with protein and gene expression analyses. Higher amino acid levels and impaired glucose metabolism were important features in tumour-bearing animals’ liver tissue. The weanling hosts had more pronounced cachexia, with higher carcass spoliation, liver lipid metabolism and impaired CII and CIV mitochondrial complexes. The liver alterations in young adult tumour-bearing rats were related to energy status and nucleotide metabolites, such as uridine, NAD+, xanthosine, hypoxanthine and inosine. In conclusion, the Walker-256 tumour-induced cachexia impaired liver metabolism, being more severe in the weanling hosts. Further studies are needed to correlate these changes in the preclinical model, which can be correlated to the clinical features of cancer cachexia, allowing for a translational potential involving the liver function and its responses to potential treatments.

L-glutamine supplementation reduced morphological damage in the renal glomerulus of rats with Walker-256 tumor

“…We also observed a decrease in the tumor mass of rats treated with L-glutamine, but this reduction was not significant. In a study with liver cancer, the authors also found no changes in tumor weight 4 ; however, in a previous study conducted by our research group, a significant reduction in tumor mass was observed due to L-glutamine supplementation in the rats with tumor 31 .…”

“…Weight loss is higher in cancer patients, as tumors cause excessive energy consumption and generate energetic inefficiency, being accountable for an increase in the glucose usage, and a depletion in intramuscular and hepatic glycogen 4,31 . The loss of body mass in cachexia is related to reduced muscle and adipose mass due to inadequate neurohormonal anabolic activity and/or excess catabolic activity [5][6][7] .…”

“…Cancer is no longer considered just a mass of cells produced by uncontrolled proliferation, but it is rather a complex tissue composed of multiple distinct cell types that communicate by heterotypic interactions with one another 1 , and it is closely associated to oxidative stress and inflammation 2 . Most patients with cancer develop cachexia 3,4 , a multifactorial metabolic imbalance, influenced by the activation of pro-inflammatory cytokines which lead to weight loss, mainly by reducing muscle mass and adipose tissue [5][6][7] .…”

Recent Advances in Metabolomics and Therapeutics for Cancer Cachexia

“…Miyaguti et al [11] reported higher lipid metabolites and impaired mitochondrial CII and CIV complexes in Walker 256 tumor bearing animals this impairment in liver metabolism was more pronounced in weanling than adult animals.…”