The host response to cancer and cancer-associated cachexia
type: CreativeWork
description: Cachexia, a severe wasting syndrome, affects up to 90% of patients with cancer and causes significant morbidity and mortality worldwide. Patients with cachexia suffer from weight loss, anorexia, sarcopenia, and behavioural changes that eventually lead to death. Given its incidence and prevalence, its negative impact on prognosis and quality of life, and the consequent poor tolerance/response to treatment, cachexia is a major global public health burden. In the first chapter of my thesis, I analyse the usage of ketogenic diets (KD) containing high levels of fats as adjuvant therapies in end-stages of cancer that are associated with cachexia. Metabolism of fats through non-enzymatic lipid peroxidation is a recognized source of highly reactive and mutagenic molecules: lipid peroxidation products (LPPs). The biosynthetic pathway of corticosterone, the main regulator of metabolic stress, and the pathway for detoxification of LPPs require NADPH as cofactor but their biochemical interdependency has not been explored. Using two murine models of cancer-associated cachexia, I demonstrate that KD slows down tumour growth but accelerates onset of cachexia in tumour-bearing mice. Reduced tumour size results from accumulation of LPPs, saturation of the GSH detoxifying pathway and ferroptotic death of cancer cells. Moreover, systemic redox state imbalance in KD-fed tumour-bearing mice causes NADPH depletion and primary hypoadrenalism. Dexamethasone treatment delays the onset of cachexia and extends the survival of tumour-bearing mice fed with KD compared to untreated tumour-bearing mice on either KD or standard feeding by improving metabolic homeostasis and utilization of nutritional substrates. Thus, lack of appropriate corticosterone synthesis during cachexia leads to metabolic maladaptation and an inability to use energy sources in mice fed KD. Dexamethasone administration to KD fed mice improves tissue preservation, energy expenditure and survival while preserving reduced tumo…
abstract: Cachexia, a severe wasting syndrome, affects up to 90% of patients with cancer and causes significant morbidity and mortality worldwide. Patients with cachexia suffer from weight loss, anorexia, sarcopenia, and behavioural changes that eventually lead to death. Given its incidence and prevalence, its negative impact on prognosis and quality of life, and the consequent poor tolerance/response to treatment, cachexia is a major global public health burden. In the first chapter of my thesis, I analyse the usage of ketogenic diets (KD) containing high levels of fats as adjuvant therapies in end-stages of cancer that are associated with cachexia. Metabolism of fats through non-enzymatic lipid peroxidation is a recognized source of highly reactive and mutagenic molecules: lipid peroxidation products (LPPs). The biosynthetic pathway of corticosterone, the main regulator of metabolic stress, and the pathway for detoxification of LPPs require NADPH as cofactor but their biochemical interdependency has not been explored. Using two murine models of cancer-associated cachexia, I demonstrate that KD slows down tumour growth but accelerates onset of cachexia in tumour-bearing mice. Reduced tumour size results from accumulation of LPPs, saturation of the GSH detoxifying pathway and ferroptotic death of cancer cells. Moreover, systemic redox state imbalance in KD-fed tumour-bearing mice causes NADPH depletion and primary hypoadrenalism. Dexamethasone treatment delays the onset of cachexia and extends the survival of tumour-bearing mice fed with KD compared to untreated tumour-bearing mice on either KD or standard feeding by improving metabolic homeostasis and utilization of nutritional substrates. Thus, lack of appropriate corticosterone synthesis during cachexia leads to metabolic maladaptation and an inability to use energy sources in mice fed KD. Dexamethasone administration to KD fed mice improves tissue preservation, energy expenditure and survival while preserving reduced tumo…
author: Ferrer Gonzalez, Miriam
language: eng
keywords: behaviour, cachexia, cancer, host response, IL-6, ketogenic diet, metabolism, neutrophilia, wasting
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2022-08-18
date modified: 2026-07-22T22:24:23Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.95624