Metabolic Biomarkers for the Early Detection of Cancer Cachexia.

Thomas M O’Connell,Rafael Barreto,Lilian Golzarri-Arroyo,Marion E Couch,Andrea Bonetto,Stephanie L Dickinson,Fabrizio Pin

doi:10.3389/fcell.2021.720096

Abstract

Background: Cancer cachexia is a severe metabolic disorder characterized by progressive weight loss along with a dramatic loss in skeletal muscle and adipose tissue. Like cancer, cachexia progresses in stages starting with pre-cachexia to cachexia and finally to refractory cachexia. In the refractory stage, patients are no longer responsive to therapy and management of weight loss is no longer possible. It is therefore critical to detect cachexia as early as possible. In this study we applied a metabolomics approach to search for early biomarkers of cachexia.Methods: Multi-platform metabolomics analyses were applied to the murine Colon-26 (C26) model of cachexia. Tumor bearing mice (n = 5) were sacrificed every other day over the 14-day time course and control mice (n = 5) were sacrificed every fourth day starting at day 2. Linear regression modeling of the data yielded metabolic trajectories that were compared with the trajectories of body weight and skeletal muscle loss to look for early biomarkers of cachexia.Results: Weight loss in the tumor-bearing mice became significant at day 9 as did the loss of tibialis muscle. The loss of muscle in the gastrocnemius and quadriceps was significant at day 7. Reductions in amino acids were among the earliest metabolic biomarkers of cachexia. The earliest change was in methionine at day 4. Significant alterations in acylcarnitines and lipoproteins were also detected several days prior to weight loss.Conclusion: The results of this study demonstrate that metabolic alterations appear well in advance of observable weight loss. The earliest and most significant alterations were found in amino acids and lipoproteins. Validation of these results in other models of cachexia and in clinical studies will pave the way for a clinical diagnostic panel for the early detection of cachexia. Such a panel would provide a tremendous advance in cachectic patient management and in the design of clinical trials for new therapeutic interventions.

Highlights

It has been estimated that up to 80% of all patients with advanced cancer will be afflicted with the severe wasting syndrome known as cancer cachexia (Tisdale, 2002; Fearon et al, 2011)
The results of this study demonstrate that metabolic biomarkers of cancer-induced cachexia can be detected several days in advance of the detection of weight loss
This study suggests that some biomarkers of cachexia may be compromised at the later stages due to potentially competing mechanisms associated with the moribund status of the animals in the final days

Summary

Introduction

It has been estimated that up to 80% of all patients with advanced cancer will be afflicted with the severe wasting syndrome known as cancer cachexia (Tisdale, 2002; Fearon et al, 2011). This multifactorial syndrome is characterized by progressive body weight loss accompanied by a pernicious depletion of skeletal muscle mass, with or without the loss of adipose tissue (Evans et al, 2008). Cachexia is often accompanied by anorexia, it is distinct from starvation and cannot be reversed by nutritional interventions (Fearon et al, 2011) This progressively worsening condition leads to functional impairment and a reduced quality of life. In this study we applied a metabolomics approach to search for early biomarkers of cachexia

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